Antiviral Drugs Mechanisms of Action, Animation

(USMLE topics) Viral life cycle and antiviral drug targets. Attachment and entry inhibitors, uncoating inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, DNA polymerase inhibitors, protease inhibitors, neuraminidase inhibitors and antisense therapy.
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Antiviral drugs are medications used to treat viral infections. Because viruses replicate entirely inside host cells using the host’s machinery, it is difficult to develop drugs that affect viruses without also harming the host. Antiviral drugs do not inactivate or kill viruses, they merely inhibit viral reproduction by interfering with a certain stage of the virus life cycle.
A virus is composed of a genome, DNA or RNA, wrapped inside a protective protein coat, called a capsid. Most animal viruses also have an additional lipid membrane, called an envelope, with protein spikes that serve to attach to host cells.
A viral life cycle typically consists of the following steps:
- attachment to host cell receptor, followed by viral entry: via endocytosis, membrane fusion, or both.
- release of viral genome, also known as uncoating,
- replication of viral genome,
- synthesis and processing of viral proteins, assembly of viral components into new viruses,
- and release of new viruses from host cell.
Antiviral strategies aim to block viral reproduction at any of these stages.
To prevent viral attachment, a drug can either bind to host cell receptor/coreceptor, or to the viral spike protein. Examples are HIV drugs - CCR5-antagonists. They bind to CCR5 coreceptor, masking its binding site for HIV.
For enveloped viruses, one strategy is to prevent fusion of viral and host cell membrane. An agent can bind directly to the viral protein that is responsible for fusion, or disrupt the condition that is required for fusion.
Several drugs have been developed to inhibit the uncoating of influenza A virus - they impair the function of the protein responsible for viral genome release from endosomes.
Viruses that use reverse transcriptase for replication are usually targeted for this enzyme. Because the process of reverse transcription, converting RNA to DNA, occurs only in these viruses and not human cells, drugs targeting reverse transcriptase are generally safe for humans. Most of these agents are nucleoside or nucleotide analogs. They compete with regular nucleotides, insert themselves into the growing chain of DNA, and stop the process prematurely. There are also non-nucleoside reverse transcriptase inhibitors, which bind non-competitively to the reverse transcriptase, impairing its function. The 2 classes of inhibitors are usually combined for maximum effects.
Retroviruses, such as HIV, use viral enzyme integrase to insert their genome into host cell DNA, a critical step for viral reproduction. Drugs that inhibit integrase have been developed to treat HIV and other retroviruses.
Viruses with large DNA genomes usually encode their own DNA polymerase for DNA replication. Viral DNA polymerases are the target of many currently available antiviral drugs. Most of these drugs are nucleoside analogs, they incorporate into the growing DNA and cause premature termination of viral DNA synthesis.
Another approach is to inhibit viral protein synthesis by antisense mechanism. Antisense antiviral drugs are short synthetic nucleic acid strands that are complementary to part of an essential viral mRNA. They bind specifically to the viral mRNA, effectively preventing it from being translated into protein.
Some viruses require activity of a specific protease to cleave precursor viral proteins into functional components for viral assembly. Several drugs have been developed to target this protease in HIV.
Influenza virus requires action of viral enzyme neuraminidase to release new viruses from host cell. Blocking neuraminidase is an effective way to treat influenza.