Antiviral Drugs Flashcards Preview

Block 2 Pharmacology > Antiviral Drugs > Flashcards

Flashcards in Antiviral Drugs Deck (35):

Describe the 8 steps of HIV retrovirus replication.

1. Virus attachment: dependent on binding interactions between viral gp41 and gp120 proteins and host cell CD4 and certain chemokine receptors
2. Fusion: of viral membrane (envelope) w/host cell PM allows HIV genome complexed with virion proteins to enter cell
3. Uncoating: permits ssRNA HIV genome to be copied by reverse transcriptase into dsDNA
4. HIV DNA is integrated into host genome via HIV-encoded integrase
5. Gene transcription and post-transcriptional processing by host cell enzymes produce genomic HIV RNA and viral mRNA
6. Viral mRNA is translated into proteins on host cell ribosomes
7. Proteins assemble into immature virions that bud from host cell membrane
8. Virions undergo proteolytic cleavage, maturing into fully infective virions


Name two ways to slow the development of drug resistance.

1. Use combinations of drugs that target a single stage (e.g., two or more inhibitors of reverse transcriptase)
2. "" 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.

1. Virus protein hemagglutinin binds to sialylated glycoprotein receptors on host cell surface
2. Virus enters cell via receptor-mediated endocytosis
3. Uncoating: internalization and acidification permit fusion of host and viral membrane by altering conformation of hemagglutinin (M2 ion channel protein for proton influx)
4. Viral ribonucleoproteins (RNPs) released into cytoplasm
5. In cell nucleus, viral RNAs are transcribed into mRNAs and replicated via viral RNA-dependent RNA polymerase complex
6. 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.

1. HIV glycoproteins exist in trimeric form in the viral membrane (envelope). Each gp120 molecule is a ball noncovalently attached to gp41.
2. 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.
3. gp41 undergoes more conformational changes, mainly unfolding and refolding of HR2 repeats
4. Completed refolding of HR region creates hemifusion stalk in which outer leaflets of viral and host membranes are fused
5. 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.

1. Early endosome contains H+-ATPase that acidifies endosome by pumping protons from cytosol into endosome
2. Low-pH dependent conformational change in viral envelope hemagglutinin protein triggers fusion of viral membrane and endosomal membrane
3. 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
4. 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:
1. Acts as a competitive inhibitor of dGTP (pppdG) binding
2. Becomes incorporated into the growing DNA chain, causing chain termination
3. 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


What is the MOA of Entecavir?

- Converted by cellular enzymes to triphosphate form
- Competitive inhibitor of HBV DNA polymerase -> deoxyguanosine triphosphate
- Weak inhibitor of cellular DNA and mitochondrial polymerases


What is the MOA of Lamivudine?

- Converted by cellular enzymes to triphosphate form
- Competitively inhibits HBV DNA polymerase, causing chain termination.


What is the MOA of Telbivudine?

- Converted by cellular enzymes to triphosphate form.
- Competitive inhibitor of HBV DNA polymerase (thymidine 5”- triphosphate)
- Little toxicity towards human cellular DNA polymerases


What is the MOA of Ribavirin?

- Incompletely understood mechanism
- Converted by cellular enzymes to the triphosphate form
- Competitively inhibits GTP-dependent 5′ capping of viral messenger RNA, and specifically influenza virus transcriptase activity
- Multiple sites of interacting action on GTP-dependent enzymatic processes
- Some of these (e.g., inhibition of GTP synthesis) may potentiate others
- May enhance viral (lethal) mutagenesis.


What is the MOA of Trifluridine?

- A fluorinated pyrimidine nucleoside that irreversibly inhibits thymidylate synthase and specific DNA polymerases, thus inhibiting DNA synthesis
- To a lesser extent, trifluridine is also incorporated into cellular DNA and is capable of decreasing DNA synthesis in both infected and uninfected cells
- Viral resistance to trifluridine is rare
- Used to treat HSV-induced keratitis and keratoconjunctivitis


What is the MOA of Raltegravir?

Blocks the catalytic activity of the HIV-1 and 2-encoded integrase, preventing integration of viral DNA into the host chromosome. Retains activity against viruses resistant to other antiretroviral classes because of its unique MOA, but viruses can become resistant to this agent through primary mutations in the integrase gene.


Describe the MOA of the protease inhibitors. List their names.

Specific inhibitors of the virus aspartyl protease enzyme responsible for proteolytic cleavage of HIV gag and pol precursor polypeptides including structural and enzymatic (reverse transcriptase, protease, integrase) components of the virus. Prevents the metamorphosis of HIV virus particles into their mature infectious form.

Atazanavir, Ritonavir, Amprenavir, Indinavir, Lopinavir, Nelfinavir, and Saquinavir


Where does resistance to protease inhibitors occur?

Initially, in the active site of the enzyme, with secondary mutations sometimes arising at distant sites on the enzyme.


Describe TWO of the caveats of protease inhibitors.

1. Some of these agents (most notably, Ritonavir) inhibit CYP3A4 metabolic capacity while others (e.g., Atazanavir) do NOT. Can make this effect advantageous by combining a low dose of Ritonavir with other agents to prolong their persistence in plasma.
2. All protease inhibitors are substrates for P-gp, an energy-dependent efflux pump in the GI wall, liver, and the capillary epithelial cells of the BBB- limits their access in these places.


What is the MOA of Boceprevir and Telaprevir? What are the implications for resistance?

Recently approved for tx of HCV. Following infection, single stranded HCV RNA translated into single polyprotein that is subsequently cleaved into 10 proteins by the enzymes signal peptidase, NS2/3 protease, and NS3/4A serine protease - Boceprevir and Telaprevir are small molecule inhibitors that prevent formation of several of the critical nonstructural proteins.

HCV is rapidly proliferating, meaning mutations in viral genome expand rapidly -> drug resistance occurs quickly. A # of mutations in serine protease confer resistance to both of these drugs.


What is the MOA of Peginterferon?

Long-lasting formulation of interferon conjugated with polyethylene glycol, increasing its durability in circulation. Binding of IFN to specific cell surface receptor molecules signals cell to produce antiviral proteins -> most of these act to inhibit translation of viral proteins, but other steps in viral replication affected (transcription, post-translational processing, and virus maturation and release).


Describe the MOA of Zanamivir and Oseltamivir (and resistance to them).

Potent and selective sialic acid analogue inhibitors that produce conformational changes in active site of Influenza A and B neuraminidases. These enzymes are essential for destruction of terminal sialic acid residues, destroying the receptors recognized by viral hemagglutinin present on cell surface in progeny virions and respiratory secretions (permitting release of the virus from infected cells). These drugs lead to viral aggregation at cell surface and reduced viral spread in respiratory tract.

Resistance: hemagglutinin and/or neuraminidase mutations.


What are the five principles of HIV chemotherapy?

1. All aspects of the disease derived from viral effects on CD4+ T-lymphocytes
2. Long-term suppression of HIV (undetectable plasma HIV RNA levels) and replenishment of CD4+ cells is clinically beneficial
3. Current HIV drugs require actively replicating virus to be effective, and it is unlikely drug treatment will eradicate all HIV-infected cells, esp. if genetic material harbored in long-lived quiescent T-cells
4. Estimates are that some of the T-cells will likely survive for decades, even for the life of the patient
5. Drug therapy does NOT cause the mutations, but provides selective pressure to promote growth of the naturally occurring mutant viruses


What are the four principles of combination therapy?

1. Use at least 3 drugs simultaneously -> initial tx will reduce plasma HIV RNA 4 drugs can be used in pretreated patients harboring drug-resistant virus, but # of agents is limited by toxicity and inconvenience. Even for heavily tx-experienced pts, 3-drug regimen containing at least 2 potent active agents is often as effective as regimens containing additional active agents.
3. Increases in viral RNA levels despite continued adherence to drug regimen is indicative of resistance -> a) regimen must be changed (selection of new agents based on pt. hx and viral resistance testing), b) tx failure usually necessitates changing all drugs, c) resistant strains remain in T-lymphocytes indefinitely
4. Tx failure usually the result of non-adherence; relative "forgiving" nature of regimen toward missed drug doses is based on duration of drug persistence in blood (i.e., longer half-lives better)


What are the principles of HBV chemotherapy?

- Tenofovir disoproxil fumarate & Entecavir are the preferred agents for HBV polymerase
- Other orally active agents include: Telbivudine, Adefovir dipivoxil, Lamivudine, & Emtricitabine


What are the principles of HCV chemotherapy?

- Tx for HCV defined by genotype of infective virus
- Genotype 1 treated with Peginterferon-alfa + Ribavirin + Telaprevir or Boceprevir HCV NS3/4A protease inhibitors
- For genotypes 2 & 3, only Peginterferon-alfa + Ribavirin are used


What are the implications of influenza resistance to antivirals?

- 2008-09 influenza season, virtually all strains of influenza A H1N1 were resistant to neuraminidase inhibitor, OSELTAMIVIR due to overuse of these drugs, incl. in veterinary applications
- Majority of 2009 H1N1 "swine" viruses susceptible to oseltamivir; however, sporadic cases of oseltamivir resistance have been detected even with this strain. All such viruses tested to date were resistant to the adamantine antivirals, amantadine and rimantadine.
- Devo of resistance to these drugs, and spread of resistant viruses, a major challenge in chemotherapy and chemoprophylaxis of influenza and likely to drive future recommendations for use of these drugs in global populations


What is the defining differences between antibacterial and antiviral drug devo? How do we overcome this obstacle?

Viruses replicate by co-opting host cell metabolic machinery, so fewer differenced b/t viruses and human hosts to exploit. More difficult to devo agents active against broad spectrum of viruses that it is against bacteria because viruses heterogeneous, whereas bacteria share common cell wall structure and transcriptional/translational machinery -> most antivirals are active against only a few viruses, whereas most antibacterials target multiple bacterial species

All viruses encode proteins that are substantially different from their human counterparts. And, certain host proteins are more important for viral replication than human health. More viral proteins have been exploited for antiviral therapy than bacterial proteins exploited for antibacterial therapy.


How does the frequency of viral mutations vary?

- Some are much more common than others
- There are often multiple potential mutations in drug target


Are antivirals virostatic or virucidal?

- All antivirals are virustatic, a fundamental difference between these agents and the others we've discussed so far (i.e., ABs and anti-fungals)
- Viruses canNOT replicate by themselves, but rather need a host cell -> potential issue for drug toxicity b/c targeting activities in the host cell