Anti-Virals Flashcards
This anti-viral is an inhibitor of viral fusion that binds N-terminal of gp41 inner glycoprotein. What is it?
Emfuvirtide - 2 injections daily, not used anymore
This anti-viral is an inhibitor of viral fusion that binds the human CCR5 coreceptor to mask human cells from CCR5-tropic HIV virions. What is it?
Maraviroc - never used alone, resistance to CXCR4 mutant strains
This anti-viral is an inhibitor of viral fusion that is a monoclonal antibody which blocks the CD4 receptor. What is it?
Ibalizumab - works for both CCR5 and CXCR4 tropic HIV’s; used as a reserve treatment for those with MDR HIV.
What is the function of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?
These are derivates of nucleosides that LACK 3’ hydroxyl groups thus terminating DNA elongation. They function as suicide substrates and are often delivered as a prodrug (lack phosphates), with a few exceptions.
This drug has a sulfur group that replaces 3’ OH and is administered as a prodrug to prevent chain elongation. What is this NRTI?
Lamivudine
Briefly describe the functions of the 2 drugs that make up the combo-pill Truvada.
- Emtricitabine - fluorinated version of Lamivudien with increased half-life and no P450 interactions.
- Tenofovir disoproxil - nucleoTIDE RTI with little p450 interaction and slow resistance
How do protecting groups increase the efficacy of certain drugs (i.e. NRTIs)?
PGs are stripped off only when inside their target cells (i.e. CD4+ T-cells) instead of at the liver. This allows the same efficacy at lower levels with fewer side effects.
How do NNRTIs differ from NRTIs?
Non-nucleoside reverse transcriptase inhibitors are allosteric inhibitors that bind a pocket on reverse transcriptase to affect the conformational changes.
This antiviral employs “strategic flexibility” to inhibit Reverse transcriptase.
Doravirine = latest NNRTI, lower resistance, higher affinity binding with minimal contacts, once daily pill
List at least 3 limitations to Doravirine (HIV NNRTI).
- Easily metabolized/ eliminated by the liver
- Diarrhea, nausea, headache side effects
- Interact with other drugs that are metabolized by P450s.
Define the function of Integrase Inhibitors
Bind the integrase/ viral DNA complex by displacing the 3’ OH out of the active site. It does this by binding Mg2+ to displace the terminal nucleotide.
What drug is used to boost the half-life of Elvitegravir (an integrase inhibitor)?
Cobicistat = targets P450 metabolism to increase the half life
What 2 integrase inhibitors do not require boosting by Cobicistat?
- Dolutegravir - 1st line anti-HIV that’s more tolerant to HIV mutations than other drugs;
- Bictegravir - a CYP3A4 (P450) substrate
Define the function of Protease inhibitors.
Binds the active site of HIV protease REVERSIBLY with many contacts; reduced ease of acquiring resistance. They mimic the transition state.
How does our protease differ from that of HIV protease? Why are these still toxic?
HIV protease is a dimer (while human protease is a monomer). This makes it a great drug target. These drugs can bind to P450 enzymes resulting in similar toxicities.
List at least 3 adverse effects to early protease inhibitors.
- Changes in body fat distribution
- Hyperlipidemia from disrupted lipid metabolism
- Bad glycemic control for patients with diabetes
What is the reason for multi-drug anti-HIV therapy? What are the limitations?
- HIV can mutate frequently without treatment;
2. Lower adherence to multiple drugs or injectibles
List the 3 parameters that pharma companies use when formulating combo-pills.
Acquire drugs with…
- Few overlapping toxicities
- No overlapping of resistance profiles
- Similar pharmacokinetics (i.e. half-life)
What do the best ways to treat HIV patients have in common?
Involve the use of an integrase inhibitor + 2 NRTI’s. Treat them IMMEDIATELY (not until CD4+ counts <200).
Define the Post-exposure prophylaxis protocol for anyone recently infected with HIV.
Take 3 anti-HIV drugs (Raltegravir + emtricitabine/tenofovir) within 72 hours of exposure for 28 days.
This antiviral drug(s) competes with dGTP to bind viral DNA polymerase as a treatment for HSV infection. What is it?
Acyclovir
Valacyclovir, Famcyclovir too
This antiviral drug inhibits CMV viral UL97 kinase and is taken orally as a protected prodrug or as IV in the other form. What is it?
Valganciclovir / Ganciclovir
What antiviral drug inhibits CMV’s DNAP Polymerase complex from cleaving concatamers into monomers?
Letermovir
What is Oseltamivir (Tamiflu) used to treat? How does it work?
Neuramidase inhibitor that treats Influenza; inhibits the cleavage of sialic residues to prevent viral escape.
What is Rimantadine (Flumadine) used to treat? How does it work?
Adamantanes that treat Influenza; binds M2 protein to block viral acidification/ unsheathing within the endosome.
Describe the cap-snatching reaction that occurs in Influenza infections.
Viral RNA Polymerase doesn’t put a cap on viral mRNA, so the virus STEALS caps from human cell RNAs via cap-dependent endonuclease.
Describe the function of Baloxavir- marboxil.
This is a cap-dependent endonuclease inhibitor that prevents viral RNA’s from stealing human cell RNA-caps.
Define the Sustained Virologic Response for therapy.
SVR is a benchmark for therapy. Relapse with HCV is low (1%)
What are the 2 pan-genomic anti-viral drugs for Hepatitis C infections.
- Glecaprevir = PAN-GENOMIC drug (affects all 6 HCV genotypes)
- Grazoprevir = maintains activity against variants that are resistant to other NS3/4A
What drugs inhibit the viral replication and packaging of HCV?
NS5A Inhibitors (Ledipasvir, Elbasvir, Pibrentasvir)
What is unique about Mavyret?
1st-line drug against treatment-naive HCV patients made of glecaprevir (NS3/4A) + Pibrentasvir (NS5A drug); PAN-GENOMIC and ONLY 8 week duration (compared to other 12 weeks)
What NS5A Inhibitor is effective against genotypes 1 and 4 for HCV?
Elbasvir
What are the 4 sites of interferon viral inhibition for treating HBV?
- Transcription
- Translation
- Protein Processing
- Viral Maturation
Define the function of Entacavir as an HBV antiviral.
Guanosine nucleoside analog that is a chain terminator by DNA distortion (not by lack of 3’ OH).
What 3 drugs can be used when HBV builds up resistance to Entacavir?
- Adefovir (Hepsera)
- Lamivudine (cytosine derivative, chain terminator)
- Telbivudine (synthetic thymidine analog)
Define the “rebounding” phenomenon for HBV infection.
Non-adherence to an anti-viral (i.e. Entecavir) results in a viral load that bounces back immediately.
Define the function of Interferons as HBV drugs.
Activate JAK-STAT signaling to create gene products for anti-viral defense. This increases the lytic effects of CTL’s, but has many toxic side effects (kidney, liver toxicities + auto-immunity).
