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10.10: Antiviral Agents - Biology

10.10: Antiviral Agents - Biology


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Learning Objectives

  1. State why antibiotics are of no use against viruses and what we must rely on to control viruses.
  2. State the viruses the following antiviral agents are used against:
    1. amantadine, rimantidine, zanamivar, and oseltamivir
    2. acyclovir, famciclovir, penciclovir, and valacyclovir
    3. foscarnet, gancyclovir, cidofovir, valganciclovir, and fomivirsen
    4. AZT (ZDV), didanosine, zalcitabine, stavudine, lamivudine, emtricitabine, tenofovir, and abacavir
    5. nevirapine, delavirdine, and efavirenz
    6. saquinavir, ritonavir, idinavir, nelfinavir, amprenavir, atazanavir, fosamprenavir, ritonavir
    7. telaprevir, boceprevir, simeprevir, sofosbuvir
  3. Compare how the following drugs exhibit their antiviral action against HIV.
    1. nucleoside reverse transcriptase inhibitors
    2. protease inhibitors
    3. entry inhibitors

Since viruses lack the structures and metabolic processes that are altered by common antibiotics, antibiotics are virtually useless in treating viral infections. To date, relatively few antiviral chemotherapeutic agents are available and used to treat just a few limited viruses.

Most of the antiviral agents work by inhibiting viral DNA synthesis. These drugs chemically resemble normal DNA nucleosides, molecules containing deoxyribose and either adenine, guanine, cytosine, or thymine. Viral enzymes then add phosphate groups to these nucleoside analogs to form DNA nucleotide analogs. The DNA nucleotide analogs are then inserted into the growing viral DNA strand in place of a normal nucleotide. Once inserted, however, new nucleotides can't attach and DNA synthesis is stopped. They are selectively toxic because viral polymerases are more prone to incorporate nucleotide analogs into their nucleic acid than are host cell polymerases.

Table (PageIndex{1}): Antivirals used for viruses other than HIV
Antiviral Brand NameUse
amantadineSymmetrelused prophylactically against influenza A ) in high-risk individuals. It prevents influenza A viruses from the uncoating step necessary for viral replication.
rimantidineFlumadineused for treatment and prophylaxis of influenza A. It prevents influenza A viruses from the uncoating step necessary for viral replication.
zanamivir:Relenzaused to limit the duration of influenza A and B infections. It is an inhibitor of the influenza virus surface enzyme called neuraminidase that is needed for release of newly formed influenza viruses from the infected cell.
oseltamivirTamifluused limit the duration of influenza infections. It is an inhibitor of the influenza virus surface enzyme called neuraminidase that is needed for release of newly formed influenza viruses from the infected cell.
acyclovirZoviraxused against herpes simplex viruses (HSV) to treat genital herpes, mucocutaneous herpes in the immunosuppressed, HSV encephalitis, neonatal herpes, and to reduce the rate of recurrences of genital herpes. It is also used against varicella zoster viruses (VZV) ) to treat shingles. It chemically resembles a normal DNA nucleoside. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
trifluridineViropticused to treat eye infection (keratitis and conjunctivitis) caused by HSV. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
famciclovirFamvirused to treat HSV and VZV infections. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
valacyclovir
Valtrexused to treat HSV and VZV infections. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
penciclovirDenavirused in treating HSV infections. Once inserted into the growing DNA chain it inhibits further viral DNA replication.

gancyclovir

Cytovene; Vitrasertused in treating severe cytomegalovirus (CMV) infections such as retinitis. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
valganciclovirValcyteused in treating severe CMV infections such as retinitis). Once inserted into the growing DNA chain it inhibits further viral DNA replication.
foscarnetFoscavirused in treating severe CMV infections such as retinitis. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
cidofovirVistideused in treating CMV retinitis. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
fomivirsenVitraveneused in treating CMV retinitis. Fomivirsen inhibits cytomegalovirus (CMV) replication through an antisense RNA (microRNA or miRNA mechanism. The nucleotide sequence of fomivirsen is complementary to a sequence in mRNA transcripts (Figure (PageIndex{1})) that encodes several proteins responsible for regulation of viral gene expression that are essential for production of infectious CMV. Binding of fomivirsen to the target mRNA results in inhibition of protein synthesis, subsequently inhibiting virus replication.
ribavirinCopegus; Rebetol; Virazoleused in treating severe acute respiratory syndrome (SARS). In combination with other drugs it is used to treat hepatitis C virus (HCV). It chemically resembles a normal RNA nucleoside. Once inserted into the growing RNA chain it inhibits further viral RNA replication.
telaprevirIncivekfor the treatment of chronic hepatitis C (hepatitis C virus or HCV genotype 1). It is a protease inhibitor that binds to the active site of an HCV-encoded protease and prevent it from cleaving the long polyprotein from polycistronic HCV genes into proteins essential to the structure and function of HCV.

boceprevir
Victrelisfor the treatment of chronic hepatitis C (hepatitis C virus or HCV genotype 1) infection. It is used in combination with peginterferon alfa and ribavirin. Boceprevir is a protease inhibitor that binds to the active site of an HCV-encoded protease and prevent it from cleaving the long polyprotein from polycistronic HCV genes into proteins essential to the structure and function of HCV.
simeprevirOlysiouse for the treatment of chronic hepatitis C (hepatitis C virus or HCV genotype 1) infection. Used in combination with peginterferon alfa and ribavirin. Simeprevir is a protease inhibitor that binds to the active site of an HCV-encoded protease and prevent it from cleaving the long polyprotein from polycistronic HCV genes into proteins essential to the structure and function of HCV.
sofosbuvirSovaldiUse for the treatment of chronic hepatitis C infection. Used in combination with ribavirin for hepatitis C virus or HCV genotypes 2 and 4; used in combination with peginterferon alfa and ribavirin for HCV genotypes 1 and 4. The second indication is the first approval of an interferon-free regimen for the treatment of chronic HCV infection. Sofosbuvir is a nucleotide polymerase inhibitor that binds to the active site of an HCV-encoded RNA polymerase preventing the synthesis of the viral RNA genome.
lamivudineEpivir-HBVused in treating chronic hepatitis B. Once inserted into the growing DNA chain it inhibits further viral DNA replication.
adefovir dipivoxilHepseraused in treating hepatitis B.

Current anti-HIV drugs include the following (classified by their action):

HIV nucleoside-analog reverse transcriptase inhibitors

To replicate, HIV uses the enzyme reverse transcriptase to make a DNA copy of its RNA genome. A complementary copy of this DNA is then made to produce a double-stranded DNA intermediate which is able to insert into host cell chromosomes to form a provirus. Most reverse transcriptase inhibitors are nucleoside analogs. A nucleoside is part of the building block of DNA, consisting of a nitrogenous base bound to the sugar deoxyribose but no phosphate group. A nucleoside analog chemically resembles a normal nucleoside (Figure (PageIndex{2})).

Once phosphate groups are added by either viral or host cell enzymes, the drugs now chemically resemble normal DNA nucleotides, the building block molecules for DNA synthesis. The nucleotide analog binds to the active site of the reverse transcriptase which, in turn, inserts it into the growing DNA strand in place of a normal nucleotide. Once inserted, however, new DNA nucleotides are unable to attach to the drug and DNA synthesis is stopped. This results in an incomplete provirus. For example, zidovudine (AZT, ZDV, Retrovir), as shown in Figure (PageIndex{1}), resembles the deoxyribonucleotide containing the base thymine. Once zidovudine is inserted into the growing DNA strand being transcribed from the viral RNA by reverse transcriptase, no further nucleotides can be attached (Figure (PageIndex{3})).

Examples of nucleoside reverse transcriptase inhibitors include:

  1. zidovudine (AZT; ZDV; Retrovir)
  2. didanosine (ddI; dideoxyinosine; Videx)
  3. stavudine (d4T; Zerit)
  4. lamivudine (3TC; Epivir)
  5. abacavir (ABC; Ziagen)
  6. emtricitabine (FTC; Emtriva, Coviracil)

Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

A NtRTI inhibitor is a a nucleotide analog. A nucleotide is the building block of DNA, consisting of a nitrogenous base bound to the sugar deoxyribose, and a phosphate group. A nucleotide analog chemically resembles a normal nucleotide. An example of nucleoside reverse transcriptase inhibitor is tenofovir (TDF;Viread).

3. HIV Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

These drugs do not resemble regular DNA building blocks. They bind to an allosteric site that regulates reverse transcriptase activity rather than to the enzyme's active site itself as do the above nucleoside analogues (see Figure (PageIndex{4})). This also prevents HIV provirus formation.

  1. nevirapine (NVP; Viramune)
  2. delavirdine (DLV;Rescriptor)
  3. efavirenz (EFV; Sustiva)
  4. rilpivirine (Edurant)
  5. etravirine (ETR, TMC125; Intelence)

Figure (PageIndex{4}): Noncompetitive Inhibition with Allosteric Enzymes. When the end product (inhibitor) of a pathway combines with the allosteric site of the enzyme, this alters the active site of the enzyme so it can no longer bind to the starting substrate of the pathway. This blocks production of the end product.

HIV Protease Inhibitors (PIs)

In order for maturation of HIV to occur, a HIV enzyme termed a protease has to cleave a long HIV-encoded gag-pol polyprotein to produce reverse transcriptase and integrase (coded by the HIV pol gene) and gag polyprotein (coded by the HIV gag gene). The HIV protease then cleaves the gag polyprotein into capsid protein p17, matrix protein p24, and nucleocapsid protein p7, as well as proteins p6, p2, and p1 whose functions are not yet fully understood (see Figs. 4A, 4B, and 4C). Proteases also cleave the env-polyprotein (coded by the HIV env gene) into the envelope glycoproteins gp120 and gp41 (see Figure (PageIndex{5})). Protease inhibitors are drugs that bind to the active site of this HIV-encoded protease and prevent it from cleaving the long gag-pol polyprotein and the gag polyprotein into essential proteins essential to the structure of HIV and to RNA packaging within its nucleocapsid (see 4C). As a result, viral maturation does not occur and noninfectious viral particles are produced.

Protease inhibitors include:

  1. saquinavir (SQV; Inverase)
  2. ritonavir (RTV; Norvir)
  3. idinavir (IDV; Crixivan)
  4. nelfinavir (NFV; Viracept)
  5. amprenavir (APV; Agenerase)
  6. atazanavir (ATV; Reyataz)
  7. fosamprenavir (FPV; Lexiva)
  8. ritonavir (RTV; Norvir)
  9. darunavir (DRV; TMC114; Prezista)
  10. tipranavir (TPV; Aptivus)

Entry Inhibitors (EIs)

EIs are agents interfering with the entry of HIV-1 into cells. During the adsorption and penetration stages of the life cycle of HIV, a portion or domain of the HIV surface glycoprotein gp120 binds to a CD4 molecule on the host cell. This induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor. This brings about another conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 that enables the viral envelope to fuse with the host cell membrane. EIs interfere with various stages of this process.

a. Agents that block the binding of gp120 to host chemokine receptor 5 (CCR5).

After the gp120 on the envelope of HIV binds to a CD4 molecule on the host cell, it must then also bind to a co-receptor - a chemokine receptor. CCR5-tropic strains of HIV bind to the chemokine receptor CCR5 (see Figure (PageIndex{6})). (An estimated 50%-60% of people having previously received HIV medication have circulating CCR5-tropic HIV.)

maraviroc (MVC; Selzentry; Celsentri) is a chemokine receptor binding blocker that binds to CCR5 and blocks gp120 from binding to the co-receptor thus blocking adsorption of HIV to the host cell.

b. Agents that block the fusion of the viral envelope with the cytoplasmic membrane of the host cell.

enfuvirtide (ENF; T-20; Fuzeon) binds a gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of the viral envelope with the cellular cytoplasmic membrane.

5. Integrase Inhibitors

Integrase inhibitors disable HIV integrase, the enzyme that inserts the HIV double-stranded DNA intermediate into host cell DNA. It prevents production of a provirus.

raltegravir (Isentress)

6. Fixed-dose combinations

Tablets containing two or more anti-HIV medications:

  1. abacivir + lamivudine (Epzicom)
  2. abacivir + lamivudine + zidovudine (Trizivir)
  3. efavirenz + emtricitabine + tenofovir DF (Atripla)
  4. emtricitabine + tenofovir DF (Truvada)
  5. lamivudine + zidovudine (Combivir)

Certain antiviral cytokines called type-1 interferons have been produced by recombinant DNA technology and several are used to treat certain severe viral infections. These include:

  1. recombinant interferon alfa-2a (Roferon-A): a cytokine used to treat Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia.
  2. peginterferon alfa-2a (Pegasys) : used to treat hepatitis C (HCV).
  3. recombinant interferon-alpha 2b (Intron A): a cytokine produced by recombinant DNA technology and used to treat Hepatitis B; malignant melanoma, Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, warts, and Hepatitis C.
  4. peginterferon alfa-2b (PEG-Intron; PEG-Intron Redipen): used to treat hepatitis C (HCV).
  5. recombinant Interferon alfa-2b plus the antiviral drug ribavirin (Rebetron): used to treat hepatitis C (HCV).
  6. recombinant interferon-alpha n3 (Alferon N): used to treat warts.
  7. recombinant iInterferon alfacon-1 (Infergen) : used to treat hepatitis C (HCV).

Most of the current antiviral agents don't kill and eliminate the viruses, but rather inhibit their replication and decrease the severity of the disease. As with other microbes, resistant virus strains can emerge with treatment.

Since there are no antiviral drugs for the vast majority of viral infections and most drugs that are available are only partially effective against limited types of viruses, to control viruses, we must rely on the body's immune responses. As will be seen in detail in Units 5 and 6, the immune responses include innate immunity as well as adaptive immunity (antibody production and cell-mediated immunity). Adaptive immunity can be either naturally acquired or, in some cases, artificially acquired.

For a more detailed description of any specific antimicrobial agent, see the website of RxList - The Internet Drug Index.

Summary

  1. Relatively few antiviral chemotherapeutic agents are currently available and they are only somewhat effective against just a few limited viruses.
  2. Many antiviral agents resemble normal DNA nucleosides molecules and work by inhibiting viral DNA synthesis.
  3. Some antiviral agents are protease inhibitors that bind to a viral protease and prevent it from cleaving the long polyprotein from polycistronic genes into proteins essential to viral structure and function.
  4. Some antiviral agents are entry inhibitors that prevent the virus from either binding to or entering the host cell.
  5. Antiviral agents are available for only a few viruses, including certain influenza viruses, herpes viruses, cytomegaloviruses, hepatitis C viruses, and HIV.
  6. Certain interferon cytokines have been produced by recombinant DNA technology and several are used for certain severe viral infections.

10.10: Antiviral Agents - Biology

COLUMBUS , Ohio Researchers at Ohio State will spend the next two years testing their theories about just how an AIDS-like virus in cats is able to resist the powerful medicines that are thrown against it.

It's one of the latest efforts at understanding one of the leading problem areas in medicine today -- antimicrobial drug resistance. When bacteria or viruses become resistant to drugs, they become more difficult, or even impossible, to treat.

The project, funded by the National Institute on Drug Abuse, could reveal how some viral infections become able to withstand antiviral medications and even thrive in the presence of some drugs.

If successful, the research might pave the way to smarter, more effective treatments for a host of pathogens that have learned to resist most therapeutic efforts.

The project grew from important discoveries made five years ago as part of a controversial research program investigating the impact of methamphetamine on feline immunodeficiency virus (FIV) one of only three animal viruses that can be used to mimick HIV (human immunodeficiency virus) infections in humans.

Surprisingly, that project showed that the virus was able reproduce itself 15 times faster when methamphetamine was present.

The work also showed that FIV mutated rapidly to adapt to grow in astrocytes, the dominant cell type within the brain, and that this phenomenon was accelerated by exposure to methamphetamine.

That observation led to an epiphany of sorts, explained Lawrence Mathes, professor of veterinary biosciences and associate dean for research and graduate studies in the College of Veterinary Medicine and principal investigator on the project.

If the virus becomes drug-resistant as it routinely mutates into this new form, would that drug resistance occur earlier if methamphetamine were present" he asked.

After an initial phase five years ago that used cats as the animal model for the study, research shifted to more refined work with cell cultures of astrocytes grown in the laboratory, focusing on the changes taking place in individual cells. Mathes reasoned that the same mutated form of FIV would probably be present in the brains of infected cats.

He and his colleagues turned to tissue stored from another decade-old unrelated project that looked at how the virus suppressed the animals' immune systems.

We went back to those tissues and, in fact, found that the same virus mutations we saw in the cultured cell experiments were present in that brain tissue but only after long-term infection, he said.

The new research grant will use tissue culture methods to look specifically at how the presence of methamphetamine may increase the virus' ability to resist anitiviral drugs, in this case, a powerful AIDS drug called azidothymidine, or AZT.

We know a lot about AZT, how it works and what mutations it causes in the virus, he said. The researchers will treat FIV-infected cell cultures with low concentrations of AZT, forcing it to develop a resistance to the drug, repeating the procedure in the presence of methamphetamine.

We know how long it normally takes the mutation to appear in the virus. We predict that it will appear earlier in cells exposed to both AZT and methamphetamine, he said.

Mathes said that the first year of the project is focused on continued in vitro studies using both FIV and cat cell lines as well as parallel experiments with HIV in human cell lines.

If the results are promising, the researchers will test the drugs' interactions with the virus in a small study using two dozen cats in the second year.


Contents

Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, SARS-CoV-2, the hepatitis B and C viruses, and influenza A and B viruses. [ citation needed ] Researchers are working to extend the range of antivirals to other families of pathogens.

Designing safe and effective antiviral drugs is difficult because viruses use the host's cells to replicate. This makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and anti-viral drugs is due to viral variation.

The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).

The first experimental antivirals were developed in the 1960s, mostly to deal with herpes viruses, and were found using traditional trial-and-error drug discovery methods. Researchers grew cultures of cells and infected them with the target virus. They then introduced into the cultures chemicals which they thought might inhibit viral activity and observed whether the level of virus in the cultures rose or fell. Chemicals that seemed to have an effect were selected for closer study.

This was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked, it was not efficient in discovering effective antivirals which had few side effects. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle.

Anti-viral targeting Edit

The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled. These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects. The targets should also be common across many strains of a virus, or even among different species of virus in the same family, so a single drug will have broad effectiveness. For example, a researcher might target a critical enzyme synthesized by the virus, but not by the patient, that is common across strains, and see what can be done to interfere with its operation.

Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects or by actually designing the candidate at the molecular level with a computer-aided design program.

The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells. The cells are then cultured for mass production of the protein, which can then be exposed to various treatment candidates and evaluated with "rapid screening" technologies.

Approaches by virus life cycle stage Edit

Viruses consist of a genome and sometimes a few enzymes stored in a capsule made of protein (called a capsid), and sometimes covered with a lipid layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation.

Researchers working on such "rational drug design" strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects. [6] Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral is a long way away. [7] Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:

  1. Attachment to a host cell.
  2. Release of viral genes and possibly enzymes into the host cell.
  3. Replication of viral components using host-cell machinery.
  4. Assembly of viral components into complete viral particles.
  5. Release of viral particles to infect new host cells.

Before cell entry Edit

One anti-viral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific "receptor" molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat.

This stage of viral replication can be inhibited in two ways:

  1. Using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors. This may include VAP anti-idiotypicantibodies, natural ligands of the receptor and anti-receptor antibodies. [clarification needed]
  2. Using agents which mimic the cellular receptor and bind to the VAP. This includes anti-VAP antibodies, receptor anti-idiotypic antibodies, extraneous receptor and synthetic receptor mimics.

This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is partly trial and error, it can be a relatively slow process until an adequate molecule is produced.

Entry inhibitor Edit

A very early stage of viral infection is viral entry, when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets the immune system's white blood cells known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "CD4" and "CCR5". Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.

HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on the cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide, or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.

One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.

Uncoating inhibitor Edit

Inhibitors of uncoating have also been investigated. [8] [9]

Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating. [10]

Pleconaril works against rhinoviruses, which cause the common cold, by blocking a pocket on the surface of the virus that controls the uncoating process. This pocket is similar in most strains of rhinoviruses and enteroviruses, which can cause diarrhea, meningitis, conjunctivitis, and encephalitis.

Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable. Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers have reported in Nature Communications in 2016.

Rhinoviruses are the most common cause of the common cold other viruses such as respiratory syncytial virus, parainfluenza virus and adenoviruses can cause them too. Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree.

During viral synthesis Edit

A second approach is to target the processes that synthesize virus components after a virus invades a cell.

Reverse transcription Edit

One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase (RNA to DNA) than with "normal" transcriptase (DNA to RNA).

The first successful antiviral, aciclovir, is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue.

An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections. One of these drugs, lamivudine, has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.

Another target being considered for HIV antivirals include RNase H—which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA.

Integrase Edit

Another target is integrase, which integrate the synthesized DNA into the host cell genome.

Transcription Edit

Once a virus genome becomes operational in a host cell, it then generates messenger RNA (mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factors. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.

Translation/antisense Edit

Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules. These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named fomivirsen has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus, and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is morpholino antisense.

Morpholino oligos have been used to experimentally suppress many viral types:

Translation/ribozymes Edit

Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes, which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them.

A ribozyme antiviral to deal with hepatitis C has been suggested, [16] and ribozyme antivirals are being developed to deal with HIV. [17] An interesting variation of this idea is the use of genetically modified cells that can produce custom-tailored ribozymes. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle.

Protein processing and targeting Edit

Interference with post translational modifications or with targeting of viral proteins in the cell is also possible. [18]

Protease inhibitors Edit

Some viruses include an enzyme known as a protease that cuts viral protein chains apart so they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to find "protease inhibitors" to attack HIV at that phase of its life cycle. [19] Protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places. [20] Improved protease inhibitors are now in development.

Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the Shiitake mushroom (Lentinus edodes). [21] The presence of this may explain the Shiitake mushroom's noted antiviral activity in vitro. [22]

Long dsRNA helix targeting Edit

Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. DRACO (double-stranded RNA activated caspase oligomerizer) is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. [23] DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.

Assembly Edit

Rifampicin acts at the assembly phase. [24]

Release phase Edit

The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir (Relenza) and oseltamivir (Tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.

Immune system stimulation Edit

Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system to attack a range of pathogens.

One of the best-known of this class of drugs are interferons, which inhibit viral synthesis in infected cells. [25] One form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis B and C, [26] and other interferons are also being investigated as treatments for various diseases.

A more specific approach is to synthesize antibodies, protein molecules that can bind to a pathogen and mark it for attack by other elements of the immune system. Once researchers identify a particular target on the pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now being sold to help fight respiratory syncytial virus in babies, [27] and antibodies purified from infected individuals are also used as a treatment for hepatitis B. [28]

Antiviral resistance can be defined by a decreased susceptibility to a drug caused by changes in viral genotypes. In cases of antiviral resistance, drugs have either diminished or no effectiveness against their target virus. [29] The issue inevitably remains a major obstacle to antiviral therapy as it has developed to almost all specific and effective antimicrobials, including antiviral agents. [30]

The Centers for Disease Control and Prevention (CDC) inclusively recommends anyone six months and older to get a yearly vaccination to protect them from influenza A viruses (H1N1) and (H3N2) and up to two influenza B viruses (depending on the vaccination). [29] Comprehensive protection starts by ensuring vaccinations are current and complete. However, vaccines are preventative and are not generally used once a patient has been infected with a virus. Additionally, the availability of these vaccines can be limited based on financial or locational reasons which can prevent the effectiveness of herd immunity, making effective antivirals a necessity. [29]

The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab). [29] Influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. Currently, neuraminidase inhibitors (NAIs) are the most frequently prescribed antivirals because they are effective against both influenza A and B. However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding. [31] This was seen in the H257Y mutation, which was responsible for oseltamivir resistance to H1N1 strains in 2009. [29] The inability of NA inhibitors to bind to the virus allowed this strain of virus with the resistance mutation to spread due to natural selection. Furthermore, a study published in 2009 in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza). This finding was based on a performance evaluation of these drugs supposing the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains. [32]

Origin of antiviral resistance Edit

The genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments. [33] Viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment. [29] Immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at the highest risk of developing oseltamivir resistance during treatment. [29] Subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance. [34]

The mechanisms for antiviral resistance development depend on the type of virus in question. RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because RNA polymerases lack proofreading activity. [35] RNA viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain a high frequency of mutations. [36] DNA viruses, such as HPV and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. DNA viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than RNA viruses. [35] In both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. Billions of viruses are produced every day during the course of an infection, with each replication giving another chance for mutations that encode for resistance to occur. [37]

Multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance. [30] This effect, called the quasispecies model, results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with the highest fitness every time the virus is spread to a new host. [38] Also, recombination, the joining of two different viral variants, and reassortment, the swapping of viral gene segments among viruses in the same cell, play a role in resistance, especially in influenza. [36]

Antiviral resistance has been reported in antivirals for herpes, HIV, hepatitis B and C, and influenza, but antiviral resistance is a possibility for all viruses. [30] Mechanisms of antiviral resistance vary between virus types.

Detection of antiviral resistance Edit

National and international surveillance is performed by the CDC to determine effectiveness of the current FDA-approved antiviral flu drugs. [29] Public health officials use this information to make current recommendations about the use of flu antiviral medications. WHO further recommends in-depth epidemiological investigations to control potential transmission of the resistant virus and prevent future progression. [39] As novel treatments and detection techniques to antiviral resistance are enhanced so can the establishment of strategies to combat the inevitable emergence of antiviral resistance. [40]

Treatment options for antiviral resistant pathogens Edit

If a virus is not fully wiped out during a regimen of antivirals, treatment creates a bottleneck in the viral population that selects for resistance, and there is a chance that a resistant strain may repopulate the host. [41] Viral treatment mechanisms must therefore account for the selection of resistant viruses.

The most commonly used method for treating resistant viruses is combination therapy, which uses multiple antivirals in one treatment regimen. This is thought to decrease the likelihood that one mutation could cause antiviral resistance, as the antivirals in the cocktail target different stages of the viral life cycle. [42] This is frequently used in retroviruses like HIV, but a number of studies have demonstrated its effectiveness against influenza A, as well. [43] Viruses can also be screened for resistance to drugs before treatment is started. This minimizes exposure to unnecessary antivirals and ensures that an effective medication is being used. This may improve patient outcomes and could help detect new resistance mutations during routine scanning for known mutants. [41] However, this has not been consistently implemented in treatment facilities at this time.

While most antivirals treat viral infection, vaccines are a preemptive first line of defense against pathogens. Vaccination involves the introduction (i.e. via injection) of a small amount of typically inactivated or attenuated antigenic material to stimulate an individual's immune system. The immune system responds by developing white blood cells to specifically combat the introduced pathogen, resulting in adaptive immunity. [44] Vaccination in a population results in herd immunity and greatly improved population health, with significant reductions in viral infection and disease. [45]

Vaccination policy Edit

Vaccination policy in the United States consists of public and private vaccination requirements. For instance, public schools require students to receive vaccinations (termed "vaccination schedule") for viruses and bacteria such as diphtheria, pertussis, and tetanus (DTaP), measles, mumps, rubella (MMR), varicella (chickenpox), hepatitis B, rotavirus, polio, and more. Private institutions might require annual influenza vaccination. The Center for Disease Control and Prevention has estimated that routine immunization of newborns prevents about 42,000 deaths and 20 million cases of disease each year, saving about $13.6 billion. [46]

Vaccination controversy Edit

Despite their successes, in the United States there exists plenty of stigma surrounding vaccines that cause people to be incompletely vaccinated. These "gaps" in vaccination result in unnecessary infection, death, and costs. [47] There are two major reasons for incomplete vaccination:

  1. Vaccines, like other medical treatments, have a risk of causing complications in some individuals (allergic reactions). Vaccines do not cause autism, as stated by national health agencies, such as the US Centers for Disease Control and Prevention, [48] the US Institute of Medicine, [49] and the UK National Health Service[50]
  2. Low rates of vaccine-preventable disease, as a result of herd immunity, also make vaccines seem unnecessary and leave many unvaccinated. [51][52]

Although the American Academy of Pediatrics endorses universal immunization, [53] they note that physicians should respect parents' refusal to vaccinate their children after sufficient advising and provided the child does not face a significant risk of infection. Parents can also cite religious reasons to avoid public school vaccination mandates, but this reduces herd immunity and increases risk of viral infection. [45]

Limitations of vaccines Edit

Vaccines boosts the body's immune system to better attack viruses in the "complete particle" stage, outside of the organism's cells. They traditionally consist of an attenuated (a live weakened) or inactivated (killed) version of the virus. These vaccines can, in very rare cases, harm the host by inadvertently infecting the host with a full-blown viral occupancy [ citation needed ] . Recently "subunit" vaccines have been devised that consist strictly of protein targets from the pathogen. They stimulate the immune system without doing serious harm to the host [ citation needed ] . In either case, when the real pathogen attacks the subject, the immune system responds to it quickly and blocks it.

Vaccines are very effective on stable viruses but are of limited use in treating a patient who has already been infected. They are also difficult to successfully deploy against rapidly mutating viruses, such as influenza (the vaccine for which is updated every year) and HIV. Antiviral drugs are particularly useful in these cases.

Antiretroviral therapy as HIV prevention Edit

Following the HPTN 052 study and PARTNER study, there is significant evidence to demonstrate that antiretroviral drugs inhibit transmission when the HIV virus in the person living with HIV has been undetectable for 6 months or longer. [54] [55]

Use and distribution Edit

Guidelines regarding viral diagnoses and treatments change frequently and limit quality care. [56] Even when physicians diagnose older patients with influenza, use of antiviral treatment can be low. [57] Provider knowledge of antiviral therapies can improve patient care, especially in geriatric medicine. Furthermore, in local health departments (LHDs) with access to antivirals, guidelines may be unclear, causing delays in treatment. [58] With time-sensitive therapies, delays could lead to lack of treatment. Overall, national guidelines, regarding infection control and management, standardize care and improve healthcare worker and patient safety. Guidelines, such as those provided by the Centers for Disease Control and Prevention (CDC) during the 2009 flu pandemic caused by the H1N1 virus, recommend, among other things, antiviral treatment regimens, clinical assessment algorithms for coordination of care, and antiviral chemoprophylaxis guidelines for exposed persons. [59] Roles of pharmacists and pharmacies have also expanded to meet the needs of public during public health emergencies. [60]

Stockpiling Edit

Public Health Emergency Preparedness initiatives are managed by the CDC via the Office of Public Health Preparedness and Response. [61] Funds aim to support communities in preparing for public health emergencies, including pandemic influenza. Also managed by the CDC, the Strategic National Stockpile (SNS) consists of bulk quantities of medicines and supplies for use during such emergencies. [62] Antiviral stockpiles prepare for shortages of antiviral medications in cases of public health emergencies. During the H1N1 pandemic in 2009–2010, guidelines for SNS use by local health departments was unclear, revealing gaps in antiviral planning. [58] For example, local health departments that received antivirals from the SNS did not have transparent guidance on the use of the treatments. The gap made it difficult to create plans and policies for their use and future availabilities, causing delays in treatment.


10.10: Antiviral Agents - Biology

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Novel antiviral strategy for treatment of COVID-19

Proposed structure of Bi-bound zinc-bindnig domain of SARS-CoV-2 helicase. Through kicking out the crucial zinc(II) ions in the zinc-binding domain of SARS-CoV-2 helicase, RBC demonstrated its ability to potently suppress the replication of SARS-CoV-2. Credit: The University of Hong Kong

A research team led by Professor Hongzhe SUN, Norman & Cecilia Yip Professor in Bioinorganic Chemistry, Department of Chemistry, Faculty of Science, and Professor Kwok Yung YUEN, Henry Fok Professor in Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine of the University of Hong Kong (HKU), has discovered a novel antiviral strategy for treatment of COVID-19.

They discovered that a class of metallodrugs currently used in the treatment of other infectious diseases is showing efficacy to potently suppress SARS-CoV-2 replication and relieve viral-associated symptoms in an animal model.

The findings provide a new and readily available therapeutic option with high clinical potential for infection with SARS-CoV-2. This ground-breaking work has been published online in a top-class scientific journal Nature Microbiology. A related patent has been filed in the US.

SARS-CoV-2 is an emerging coronavirus that has caused over 30 million laboratory-confirmed cases and more than 1 million deaths globally of COVID-19 since December 2019. As the process of developing an effective vaccine is still ongoing, another approach for prevention and treatment of the disease is to identify anti-COVID-19 agents from existing virus-specific antiviral drugs to repurpose their uses to target the new virus. Remdesivir, a broad-spectrum antiviral drug, has been reported to show efficacy towards SARS-CoV-2. However, global shortage of the drug, its relatively high price and lack of significant clinical benefits in severe cases, are factors that have limited its wider applications. Clinical trials on a series of antiviral agents are still ongoing which have yet to demonstrate therapeutic efficacies. Therefore, greater efforts are needed to extend the evaluation to cover a wider spectrum of clinically approved drugs, which hopefully could open the way to alternative treatment strategies against the disease through some readily available channels.

Generally, metal compounds are used as anti-microbial agents their antiviral activities have rarely been explored. After screening a series of metallodrugs and related compounds, the research team identified ranitidine bismuth citrate (RBC), a commonly used anti-ulcer drug which contains the metal Bismuth for treatment of Helicobacter pylori-associated infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo.

RBC targets the vital non-structural protein 13 (Nsp13), a viral helicase essential for SARS-CoV-2 to replicate, by displacing the crucial zinc(II) ions in the zinc-binding with Bismuth-ions, to potently suppress the activity of the helicase.

RBC has been demonstrated to greatly reduce viral loads by over 1,000-folds in SARS-CoV-2-infected cells. In particular, in a golden Syrian hamster model, RBC suppresses SARS-CoV-2 replications to reduce viral loads by

100 folds in both the upper and lower respiratory tracts, and mitigates virus-associated pneumonia. RBC remarkably diminishes the level of prognostic markers and other major pro-inflammatory cytokines and chemokines in severe COVID-19 cases of infected hamsters, compared to the Remdesivir-treated group and control group.

RBC exhibits a low cytotoxicity with a high selectivity index at 975 (the larger the number the safer the drug), as compared to Remdesivir which has a low selectivity index at 129. The finding indicates a wide window between the drug's cytotoxicity and antiviral activity, which allows a great flexibility in adjusting its dosages for treatment.

The team investigated the mechanisms of RBC on SARS-CoV-2 and revealed for the first time the vital Nsp13 helicase as a druggable target by RBC. It irreversibly kicks out the crucial zinc(II) ions in the zinc-binding domain to change it to bismuth-bound via a distinct metal displacement route. RBC and its Bi(III) compounds dysfuntionalised the Nsp13 helicase and potently inhibited both the ATPase (IC50=0.69 μM) and DNA-unwinding (IC50=0.70 μM) activities of this enzyme.

The research findings highlight viral helicases as a druggable target, and the high clinical potential of bismuth(III) drugs and other metallodrugs for treatment of SARS-CoV-2 infections. Hopefully, following this important breakthrough, more antiviral agents from readily available clinically approved drugs could be identified for potential treatment of COVID-19 infections. They can be in the form of combination regimens (cocktails) with drugs that exhibit anti-SARS-CoV-2 activities including RBC, dexamethasone and interferon-β1b.


Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 2019 (COVID-19). No treatment is available. Micro-RNAs (miRNAs) in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are potential novel therapeutic agents because of their ability to regulate gene expression by inhibiting mRNA. Thus, they may degrade the RNA genome of SARS-CoV-2. EVs can transfer miRNAs to recipient cells and regulate conditions within them. MSC-EVs harbor major therapeutic miRNAs that play important roles in the biological functions of virus-infected host cells. Here, we examined their potential impact on viral and immune responses. MSC-EVs contained 18 miRNAs predicted to interact directly with the 3’ UTR of SARS-CoV-2. These EVs suppressed SARS-CoV-2 replication in Vero E6 cells. In addition, five major miRNAs suppressed virus activity in a luciferase reporter assay by binding the 3’ UTR. MSC-EVs showed strong regenerative effects and potent anti-inflammatory activity which may prevent lethal cytokine storms. We confirmed that EVs regulated inflammatory responses by several cell types, including human brain cells that express the viral receptor ACE2, suggesting that the brain may be targeted by SARS-CoV-2. miRNAs in MSC-EVs have several advantages as therapeutic agents against SARS-CoV-2: 1) they bind specifically to the viral 3’ UTR, and are thus unlikely to have side effects 2) because the 3’ UTR is highly conserved and rarely mutates, MSC-EV miRNAs could be used against novel variants arising during viral replication and 3) unique cargoes carried by MSC-EVs can have diverse effects, such as regenerating damaged tissue and regulating immunity.


Introduction

The horrific pandemic outbreak of COVID-19 (coronavirus disease 2019) around the world caught the health care systems in every country by storm, most if not all were caught off guard without proper defense mechanisms to cope with and to control such a pandemic. COVID-19, caused by a new and novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), has recently been identified and characterized [1••]. Coronaviruses are named for their crown-like spikes on their surface and there are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta [1, 2]. SARS-CoV-2 belongs to the beta sub-grouping, and is one of the seventh coronavirus to date infecting humans [1••]. Some coronaviruses such as 229E alpha coronavirus [3], OC43 beta coronavirus [4], NL63 alpha coronavirus [5], and HKU1 beta coronavirus [6] were associated with mild clinical symptoms, whereas SARS-CoV beta coronavirus [7], Middle East respiratory syndrome coronavirus (MERS-CoV) beta coronavirus [8], and SARS-CoV-2 caused severe diseases [2].

SARS-CoV-2 is a positive-sense single-stranded RNA virus with 29,891 bases, 96% identical at the whole-genome level to a bat coronavirus, and shares 79.6% sequence identity to SARS-CoV [1••]. SARS-CoV-2 encodes spike S protein containing receptor binding domain (RBD) that binds to the human angiotensin-converting enzyme 2 (ACE2), and promotes membrane fusion and uptakes of the virus into human cells such as the lung by endocytosis [1, 9,10,11]. Upon entering the human cells, SARS-CoV-2, like other coronaviruses, will takeover or hijack the human cells’ protein synthesis machinery to synthesize the viral proteins and assemble the proteins and subsequent viral replication [12•].

Once inside the human body, viruses in general will trigger a series of good versus bad host responses including autophagy, apoptosis, stress response, and innate immunity [13]. Fortunately, majority (more than 80%) of SARS-CoV-2-infected individuals are asymptomatic or have mild symptoms, most likely due to the activation of the good response. These good responders would likely activate the body’s innate immune system by activating the body’s antiviral defense mechanisms including natural killer cells and antiviral T cells, and induction of interferon (IFN) [13,14,15,16]. Unfortunately, in about 20% of SARS-CoV-2-infected individuals including the immune compromised, elderly, patients with underlying health conditions such as cardiovascular and pulmonary problems, diabetics, hypertension, obesity, chronic obstructive pulmonary disease (or COPD, such as emphysema), pulmonary fibrosis, asthma, and interstitial lung disease [17, 18] would encounter more severe disease characterized by significant respiratory symptoms leading to acute respiratory distress syndrome (ARDS) and even death. An important consideration to note is that ARDS occurs later in disease progression and is preceded by acute lung injury (ALI) [19]. This distinction may inform treatment strategy in terms of drugs directed towards cytokine storm and thrombosis which is described in this manuscript. A study on SARS-CoV and MERS-CoV has found that these two coronaviruses appear to have evolved mechanisms to attenuate or delay IFN production, resulting in enhanced inflammatory host responses and severe lung injury [12, 13, 20,21,22]. This aberrant host immune response with the production of powerful inflammatory cytokines, known as “cytokine storm” found in SARS-CoV- and MERS-CoV-infected patients, would correlate with disease severity and poor prognosis [13, 16, 20,21,22,23]. Severe COVID-19 patients exhibit profound inflammatory response [24, 25]. Transcriptomic RNA-seq analysis of COVID-19 patients has revealed that several immune pathways and pro-inflammatory cytokines CXCL, CCL2, CXCL2, CCL8, IL33, and CCL3L1 in bronchoalveolar lavage fluid (BALF) and TNFSF10, CXCL10, IL10, TIMP1, C5, IL18, AREG, and NRG1 in peripheral blood mononuclear cells (PBMC) were induced by SARS-CoV-2 infection, suggesting a sustained inflammation and cytokine storm [26]. Importantly, SARS-CoV-2 infection–induced excessive cytokine release correlates with lung tissue injury and COVID-19 pathogenesis [26]. This estimated 20% of patients developing more severe disease with SARS-CoV-2 infection are most likely due to genetics, epigenetics, and or other factors, with dampened innate immune response to fight the virus coupled with enhanced viral load leading to cytokine storm, severe inflammatory/oxidative stress response, and severe lung injury secondary to ARDS. While there is clear understanding that the respiratory system is dramatically impacted in COVID-19 patients, evidence suggests that other organ systems are also affected. Emerging data show that SARS-CoV-2 may lead to damage to other organs including the heart and brain. Nearly 20% of hospitalized patients with COVID-19 have indication of cardiac damage [17]. Furthermore, neurologic symptoms have been reported in patients and infection of SARS-CoV-2 has been found in the brainstem of both humans and experimental animals [18, 19].

Currently, there is no vaccine and/or specific therapeutic drugs targeting the SARS-CoV-2. Hence, it remains a major challenge to decide what potential therapeutic regimens to prevent and treat the severely sick COVID-19 patients. Effective vaccines are essential to combat against the extremely contagious SARS-CoV-2. At present, a lot of research efforts have been invested to develop vaccines around the world. Until we have specific vaccines or therapeutic drugs targeting SARS-CoV-2, “repurposed” drugs that have been approved by the FDA in the USA for other indications have been used to treat COVID-19 patients. This review will summarize the most current pharmacotherapeutics prescribed in the treatment of severe cases of COVID-19 patients. These include antiviral therapy, antibiotics, systemic corticosteroids and anti-inflammatory drugs (including anti-arthritis drugs), neuraminidase inhibitors, RNA synthesis inhibitors, convalescent plasma, and traditional herbal medicines.


Synthesis and biological activity of certain nucleoside and nucleotide derivatives of pyrazofurin

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Introduction

Emerging viruses and associated diseases, as well as nosocomial viral infections, have become a real issue in medical fields, along with the potential environmental resistance of viral particles and the possibility of their transfer between contaminated hosts, mainly from the hands to environmental surfaces, and the converse. Antiviral antisepsis and disinfection are crucial for preventing the environmental spread of viral infections. Indeed, very few efficient and specific treatments are available to fight most of these infections.

Proper evaluation of the efficacy of antiseptics-disinfectants (ATS-D) on viruses is very important. Essentially, ATS-D antiviral activity is evaluated by combining viruses and the product to be tested for an appropriately defined and precise contact time, neutralizing product activity, and estimating the loss of viral infectivity due to the product activity. Neutralization of the ATS-D plays a key role in the test procedure it ensures a precise contact time, the elimination of the residual activity and cytotoxicity of the tested product, and the successful recovery of viruses not killed by the product. These tests require appropriate controls, especially to check the absence of interference due to the test itself on viral infectivity, efficiency of neutralization, removal of cytotoxicity, and reproducible and well defined test conditions (e.g., contact time and environmental temperature). A germicide can be considered to have an efficient ATS-D antiviral activity if it induces a log10 reduction in viral titers, in a defined contact time, higher than 3 or 4 log10, depending on American and European regulatory agencies, respectively (ASTM, 2004 AFNOR, 2007 ).

This unit describes a global methodology for evaluating ATS-D activity of chemicals on viruses. The viral model used to validate this method is the human coronavirus, strain 229E (HCoV 229E), grown on L-132 cells. Cultivation parameters for the cells and the viruses are described in Support Protocols 1 and 2, respectively. In the assay procedure described in the

1). It is also necessary to ensure the efficiency of the neutralization step. To verify that the tested germicide is retained by the column and thus neutralized, two approaches have been taken, a biological approach checking the absence of cytotoxicity of the filtrates (see

3) and a physicochemical approach, determining the retention rate of the germicide using UV-visible spectrophotometry (see

4). Supported by these preliminary results, the ATS-D virucidal assay can be performed as described in the


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