Antiviral Drugs Flashcards
Describe the 8 steps of HIV retrovirus replication.
- Virus attachment: dependent on binding interactions between viral gp41 and gp120 proteins and host cell CD4 and certain chemokine receptors
- Fusion: of viral membrane (envelope) w/host cell PM allows HIV genome complexed with virion proteins to enter cell
- Uncoating: permits ssRNA HIV genome to be copied by reverse transcriptase into dsDNA
- HIV DNA is integrated into host genome via HIV-encoded integrase
- Gene transcription and post-transcriptional processing by host cell enzymes produce genomic HIV RNA and viral mRNA
- Viral mRNA is translated into proteins on host cell ribosomes
- Proteins assemble into immature virions that bud from host cell membrane
- Virions undergo proteolytic cleavage, maturing into fully infective virions
Name two ways to slow the development of drug resistance.
- Use combinations of drugs that target a single stage (e.g., two or more inhibitors of reverse transcriptase)
- ”” that target more than one stage in HIV life cycle (e.g., reverse transcriptase inhibitors and protease inhibitors)
Describe the 6 stages of influenza virus replication.
- Virus protein hemagglutinin binds to sialylated glycoprotein receptors on host cell surface
- Virus enters cell via receptor-mediated endocytosis
- Uncoating: internalization and acidification permit fusion of host and viral membrane by altering conformation of hemagglutinin (M2 ion channel protein for proton influx)
- Viral ribonucleoproteins (RNPs) released into cytoplasm
- In cell nucleus, viral RNAs are transcribed into mRNAs and replicated via viral RNA-dependent RNA polymerase complex
- Newly synthesized viral RNPs are exported into cytoplasm and, after assembly, mature virions bud from cell surface
Why is the viral incubation period a hindrance in the effectiveness of antiviral drugs?
Many cycles of viral replication occur during the incubation period when the patient is well (no symptoms to prompt treatment). By the time the patient has a recognizable systemic viral disease, the virus has spread throughout the body and it is too late to interdict it
Describe the MOA of Enfuvirtide (T-20).
Synthetic peptide drug that mimics HR2, binds to HR1, and prevents the HR2-HR1 interaction. This traps the virus-host cell interaction at the attachment stage, preventing membrane fusion and viral entry.
Describe the 5 steps of HIV infection of the host cell.
- HIV glycoproteins exist in trimeric form in the viral membrane (envelope). Each gp120 molecule is a ball noncovalently attached to gp41.
- Binding of gp120 to CD4 and certain chemokine receptors in host cell PM causes conformational change in gp41 that exposes the fusion peptide, heptad-repeat region 1 (HR1) and HR2 -> this peptide inserts into host cell PM.
- gp41 undergoes more conformational changes, mainly unfolding and refolding of HR2 repeats
- Completed refolding of HR region creates hemifusion stalk in which outer leaflets of viral and host membranes are fused
- Formation of complete fusion pore allows viral entry into host cell
Describe the MOA of Maraviroc.
Small-molecule antagonist of CCR5 chemokine receptor - blocks cellular infection of HIV strains that use CCR5 for attachment and entry.
NOTE: some HIV strains use different chemokine receptors, making Maraviroc ineffective against these infections.
Describe the influenza virus uncoating process.
- Early endosome contains H+-ATPase that acidifies endosome by pumping protons from cytosol into endosome
- Low-pH dependent conformational change in viral envelope hemagglutinin protein triggers fusion of viral membrane and endosomal membrane
- Fusion NOT sufficient for viral uncoating. Protons from low pH endosome must enter virus through M2, a pH-gated proton channel in the viral envelope that opens in response to acidification
- Entry of protons through the viral envelope causes dissociation of matrix protein from influenza virus RNP, releasing RNP and viral genetic material into host cell cytosol
What is the MOA of Amantadine and Rimantadine?
Block M2 ion channel function and inhibit acidification of interior of virion, dissociation of matrix protein, and uncoating. There is evidence of the drugs both “plugging” the channels, and binding to the outside of the channel.
Describe the MOA of Acyclovir, Ganciclovir, Valacyclovir, and Valganciclovir. What is unique about Valacyclovir and Valganciclovir?
The activated triphosphate form:
- Acts as a competitive inhibitor of dGTP (pppdG) binding
- Becomes incorporated into the growing DNA chain, causing chain termination
- Traps the polymerase on the ACV-terminated DNA chain when the next deoxyribonucleoside triphosphate binds
Vala and Valgan are orally absorbed prodrugs that rapidly liberate the respective active agent (Acyclovir and Ganciclovir) upon entry into the circulation, avoiding the poor oral bioavailability of the parental agents
Describe the MOA of the NRTIs. List their names.
Drugs used to treat HIV (some also for EBV), and target nucleoside reverse transcriptase. Converted to triphosphate nucleotides (tenofovir a monophosphate) by host cell kinases -> competitive inhibition of viral reverse transcriptase by competing with endogenous nucleosides for incorporation into viral DNA. Cause termination of the DNA chain, and inhibition of viral replication.
NOTE: indirectly inhibit the polymerase, and do NOT have the specificity of effect against HIV provided by NNRTIs.
Abacavir, Lamivudine (3-TC), Tenofovir Disoproxil, Zidovudine (AZT), Emtricitabine, Didanosine (ddl), Stavudine
Describe what it means that NRTIs are non-specific.
NRTIs also inhibit host cell mitochondrial DNA polymerase, leading to depletion of mito DNA, RNA, and peptides involved in oxidative phosphorylation. This leads to mito dysfunction, and is believed to be the cause of several of the important toxicities associated with drugs of this class.
Describe cross-resistance to NRTIs.
Associated with mutations at a number of reverse transcriptase codons. Referred to as thymidine analog mutations (TAMs) because of their ability to confer cross-resistance to thymidine analogs.
What is the MOA of NNRTIs? List their names.
Bind to a hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase far from the active site where the NRTIs interact (non-competitive inhibitors). They alter the 3D structure of the enzyme and significantly impede its activity. Unlike NRTIs, these compounds do NOT require IC phosphorylation. Because the binding site is virus-strain-specific, these drugs are active against HIV-1, but not 2 or other retroviruses.
Efavirenz, nevirapine
What is the MOA of Adefovir?
- Converted by cellular enzymes to diphosphate form
- Competitive inhibitor of viral DNA polymerases and reverse transcriptases -> deoxyadenosine triphosphate
- Chain terminator of viral DNA synthesis
- Higher affinity for HBV DNA polymerase vs. cellular polymerases