Virology Archives • Microbe Online

Antiviral drugs are any agents useful to treat viral infections. Viruses are the leading cause of diseases and deaths in humans, animals, and plants. In humans, viral infections vary from self-resolving to acute, fatal diseases. Viruses are obligate intracellular parasites. They lack enzymes for replication and for making structural components. They use host machinery to perform such activities. In other words, viruses literally 'hijack' the infected cell, taking over its machinery. Therefore, it is much more difficult for drugs to combat viral diseases effectively. Any drug which kills a virus may also destroy cells. So, the drugs targeted against viruses must be selectively toxic to inhibit the viral particles without adversely affecting the host cell. Advances in understanding the molecular biology of virus replication cycles and detailed three-dimensional structures of viral molecules have made it possible to create particular and effective antiviral drugs. Virus: Structure and Replication A virus mainly consists of a genome (nucleic acid) surrounded by a protein coat called a capsid. Nucleic acid is either DNA or RNA (never both). In addition, most animal viruses have a lipid envelope with protein spike receptors for the attachment to the host cell surface. The virus replication cycle or life cycle starts with the attachment of the virus to the host cell with the help of protein in the virus and host cell receptors. Then fusion of viral particles with the host cell membrane is followed by virus entry inside the host cell. Uncoating then occurs to release viral nucleic acid in the cell. Afterward, replication and protein synthesis occur. Now different parts of the virus assemble to make a complete virion particle. Finally, several virion particles (viruses) release from the host cell. The virus's nucleic acid instructs the host cell to produce viral components, which leads to an infectious virus. Mechanisms of Action of Antiviral Drugs Rather than killing or inactivating viruses, antiviral drugs focus on inhibiting viral replication by interfering with specific stages of the viral life cycle. Antiviral drugs use two approaches: targeting the viruses themselves or the host cell factors. Direct virus targets include: The inhibitors of virus attachment/entry Uncoating inhibitors Inhibition of viral replication Inhibition of viral protein synthesis Inhibition of viral assembly Inhibition of release Figure: Antiviral drugs block various stages of viral replication. Source: https://basicmedicalkey.com/antiviral-agents-3/ Inhibitors of virus attachment and entry inhibitors Drugs of this category target host receptors, co-receptors, or viral spike proteins. Drugs that inhibit attachment and virus entry prevent all subsequent steps of the viral replication cycle and virus infection. It permits the clearing of virion by the host immune system at the beginning. Example; a drug maraviroc binds CCR5 of a host cell receptor and blocks the viral attachment. Drugs like enfuvirtide bind gp41 of the viral envelope and inhibit viral fusion with the host cell membrane. Membrane fusion inhibitor drugs target mainly the enveloped viruses. Inhibition of viral uncoating in the host cell Some antiviral drugs, like amantadine, prevent uncoating and the release of the viral genome in the cell. Amantadine is a narrow spectrum drug that works against only Influenza A. Amantadine blocks M2 ion channel function and thereby prevents acidification, dissociation, and uncoating, which prevents the release of nucleic acid from the endosome to the host cell cytosol. Inhibition of viral replication Drugs inhibiting replication of viral nucleic acid target various sites: Polymerase and Reverse Transcriptase Inhibitors Some antiviral drugs target DNA or RNA polymerase to inhibit DNA/RNA replication, e.g., viral DNA polymerase inhibitors, like acyclovir and tenofovir. On the other hand, some drugs target the reverse transcriptase (RT) enzyme inhibiting the synthesis of DNA from RNA. Drugs targeting the RT enzyme are efficient and safe, as RT is present only in viruses, not humans. The drugs that inhibit replication is nucleotide/nucleoside analogs and non-nucleotide/nucleoside analogs. Nucleotide or nucleoside analogs compete with regular nucleotide/ nucleoside and insert themselves into a growing nucleic acid chain. It stops the process prematurely. Nucleoside analogs, like, acyclovir and AZT, lack a 3'OH. Thus, if they get incorporated into a growing nucleic acid strand, all nucleic acid synthesis requires a 3'OH site for adding the next nucleotide. Nonnucleoside inhibitors bind non-competitively to the polymerase or reverse transcriptase, impairing its function, e.g., nevirapine. Nucleoside RT inhibitors (NRTI) and nonnucleoside RT inhibitors (NNRTI) combine to treat HIV with maximum effect. Integrase Inhibitors Integrase inhibitors, like raltegravir, are frequently used. Such drugs prevent the binding of the viral genome to the host genome, which is essential for some viruses. Interferons Interferons are low molecular weight proteins produced by virus-infected cells. Interferon induces protein formation inhibiting transcription of viral mRNA. Artificial interferons are used as antiviral drugs. The mechanism of action of interferon is its transformation to triphosphate following the viral DNA synthesis inhibition. It can increase the cell's resistance to a virus or suppress the viral adsorption in the cell or its diffusion into the cell and its deproteinization process along with antimetabolites that cause the inhibition of nucleic acids synthesis. Viral protein synthesis inhibitors Some drugs inhibit protein synthesis by an antisense mechanism. Antisense antiviral drug is a short synthetic nucleic acid strand that complements the specific part of mRNA, which binds to mRNA and prevents the protein from being translated. An example of such a drug is formivirsen. Inhibitors of viral assembly Protease inhibitor drugs fall under a drug inhibiting viral assembly category. The protease cleaves precursor viral protein into a functional component for viral assembly. Protease inhibitors, like ritonavir, atazanavir, and darunavir, are designed to block the active site of a specific protease. Variation led to ritonavir, indinavir. Due to the action of drugs, polyproteins will not get proteolytically cut into their final proteins. Protease inhibitors against HIV are saquinavir, ritonavir, indinavir, and nelfinavir. Inhibitors of viral release Although, on completion of virus replication and assembly, some drugs inhibit the last step, i.e., viral release from the host cell. Anti- Influenza or anti-COVID-19 drugs like oseltamivir block neuraminidase which is required to release a new virus. Besides the drugs that target viruses, some drugs have been developed that act as immunomodulators. For example, nitazoxanide interferes with host-regulated pathways of virus replication, amplification of type I interferon pathways, and cytoplasmic RNA sensing. Similarly, another drug, ivermectin, inhibits the nuclear import of host and viral proteins. Targets of antiviral DrugsDrugsMechanisms of action of antibioticsInhibitors of viral Attachment/ EntryHydroxychloroquine Chloroquine (COVID-19), Enfuvirtide (HIV) Maraviroc (HIV) Increase in endosomal pH needed for the virus/cell fusion. Interfere with cellular receptor glycosylation of SARS CoV. Block the fusion of virus in the host cell membrane by directly binding to gp41. Binds CCR5 of host receptor blocks fusion and entry of the virus.Uncoating inhibitors prevent the release of the genomeAmantadine and Rimantadine (Influenza)Inhibit M2 ion channel preventing pH-dependent dissociation of viral proteins, which contain the release of nucleic acid to host cell.Inhibition in viral replicationRemdesivir (COVID-19) Favipiravir (COVID-19), Foscarnet (HSV) Acyclovir & Ganciclovir (Herpes)Ribavirin (RSV) Dolutegravir, Elvitegravir and Raltegravur (HIV) Zidovudine(HIV) and Lamivudine (HIV &HBV)Nevirapine & Efavirenz (HIV)RNA dependent RNA polymerase inhibitor, an analog of adenosine nucleotide RNA dependent RNA polymerase inhibitor, an analog of guanosine nucleotide DNA polymerase inhibitor DNA polymerase and Reverse Transcriptase inhibitors (nucleoside analogs) Inhibitor of integrase NRTI (nucleotide analog) NNRTIViral protein synthesis inhibitorsFomivirsen(CMV) Interferon alfa (HBV, HCV)Antisense therapy for termination. Translation inhibitors prevent viral protein synthesis, which promotes the breakdown of viral components.Inhibitors of Viral AssemblyRitonavir/ Lopinavir (COVID-19)Boceprevir (HCV)Atazanavir (HIV)Inhibit proteaseInhibitors of viral releaseOseltamivir (Influenza, COVID-19) and Zanamivir (Influenza)Block neuraminidase which is required for the release of a new virus. Development of Antiviral Drugs and its Challenges Public health measures and vaccinations are an effective way to control viruses to a great extent. However, preventive measures are not always succeeded for numerous viral diseases. Antiviral drugs are necessary if the viral infection is life-threatening or causes serious illness. The first highly successful antiviral drug was acyclovir, developed during the 1970s, which was against HSV-1 and two and VZV. After that, antiviral drug discovery expanded markedly with HIV-AIDS epidemics. Meanwhile, different drugs were developed against the opportunists like HIV and CMV. With time, knowledge about viral genetics, molecular biology, enzymology, and protein structure led to the development modern and more effective approaches against viruses. Now, antiviral drugs are successful in saving lives and relieving suffering. One of the greatest achievements is that HIV is manageable for a lifetime as long as antiretroviral therapy is maintained in infected patients. In addition, an effective host response is required to recover any viral diseases. Antiviral drugs effectively improve public health, and some emerge as life savers. Still, some problems arise while developing antiviral drugs. Most antiviral drugs are prodrugs that require phosphorylation before their work. Some challenges of antiviral drugs include: Selective Toxicity Several compounds inhibit mammalian viruses in tissue culture, but only a few can be used in treating human viral infection; the problem is the lack of selective toxicity. Since viruses are inside the host cell, drugs that affect viruses also affect the host cell. Recovery of a healthy cell after infection is difficult in such infections. In comparison with antibacterial agents, very few are safe antiviral drugs. However, the situation is improving with more new approaches to antiviral therapy. Latency In some cases, the viral nucleic acid does not cause any replication or damage to the host and remains integrated into the host nucleus (latent virus). While in other cases, the production of the virus by the host cell causes cell death. Problems arise in treatment when latent viruses become activated. Current antiviral drugs inhibit only active replication, which resumes following the removal. Such drugs do not recognize and eliminate non-replicating or latent viruses. Variation in species Different viruses, especially respiratory viruses, have similar symptoms, making diagnosis difficult. Antiviral Drug Resistance Antiviral drug resistance is the leading cause to make drug inefficient, and this tendency is increasing with time. The main reason behind the drug resistance is mutant virus strains. Single nucleotide changes are often sufficient for the development of antiviral drug resistance. Nucleotide change leads to critical amino acid substitutes in the target protein, which alters the structure and mechanism of the virus. Viruses have a short generation time (high number of replication cycles), which is one of the reasons for developing the resistant gene. The higher the replication magnitude, the higher the chances of mutation rate, and the more rapidly resistance can develop. A large virus population and drug-resistant mutants will be present among the array of genetic variants. References Kausar, S., Said Khan, F., Ishaq Mujeeb Ur Rehman, M., Akram, M., Riaz, M., Rasool, G., Hamid Khan, A., Saleem, I., Shamim, S., & Malik, A. (2021). 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