Anti-Virals

Question 1

This anti-viral is an inhibitor of viral fusion that binds N-terminal of gp41 inner glycoprotein. What is it?

Answer 1

Emfuvirtide - 2 injections daily, not used anymore

Question 2

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?

Answer 2

Maraviroc - never used alone, resistance to CXCR4 mutant strains

Question 3

This anti-viral is an inhibitor of viral fusion that is a monoclonal antibody which blocks the CD4 receptor. What is it?

Answer 3

Ibalizumab - works for both CCR5 and CXCR4 tropic HIV’s; used as a reserve treatment for those with MDR HIV.

Question 4

What is the function of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?

Answer 4

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.

Question 5

This drug has a sulfur group that replaces 3’ OH and is administered as a prodrug to prevent chain elongation. What is this NRTI?

Answer 5

Lamivudine

Question 6

Briefly describe the functions of the 2 drugs that make up the combo-pill Truvada.

Answer 6

1. Emtricitabine - fluorinated version of Lamivudien with increased half-life and no P450 interactions.
2. Tenofovir disoproxil - nucleoTIDE RTI with little p450 interaction and slow resistance

Question 7

How do protecting groups increase the efficacy of certain drugs (i.e. NRTIs)?

Answer 7

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.

Question 8

How do NNRTIs differ from NRTIs?

Answer 8

Non-nucleoside reverse transcriptase inhibitors are allosteric inhibitors that bind a pocket on reverse transcriptase to affect the conformational changes.

Question 9

This antiviral employs “strategic flexibility” to inhibit Reverse transcriptase.

Answer 9

Doravirine = latest NNRTI, lower resistance, higher affinity binding with minimal contacts, once daily pill

Question 10

List at least 3 limitations to Doravirine (HIV NNRTI).

Answer 10

1. Easily metabolized/ eliminated by the liver
2. Diarrhea, nausea, headache side effects
3. Interact with other drugs that are metabolized by P450s.

Question 11

Define the function of Integrase Inhibitors

Answer 11

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.

Question 12

What drug is used to boost the half-life of Elvitegravir (an integrase inhibitor)?

Answer 12

Cobicistat = targets P450 metabolism to increase the half life

Question 13

What 2 integrase inhibitors do not require boosting by Cobicistat?

Answer 13

1. Dolutegravir - 1st line anti-HIV that’s more tolerant to HIV mutations than other drugs;
2. Bictegravir - a CYP3A4 (P450) substrate

Question 14

Define the function of Protease inhibitors.

Answer 14

Binds the active site of HIV protease REVERSIBLY with many contacts; reduced ease of acquiring resistance. They mimic the transition state.

Question 15

How does our protease differ from that of HIV protease? Why are these still toxic?

Answer 15

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.

Question 16

List at least 3 adverse effects to early protease inhibitors.

Answer 16

1. Changes in body fat distribution
2. Hyperlipidemia from disrupted lipid metabolism
3. Bad glycemic control for patients with diabetes

Question 17

What is the reason for multi-drug anti-HIV therapy? What are the limitations?

Answer 17

1. HIV can mutate frequently without treatment;

2. Lower adherence to multiple drugs or injectibles

Question 18

List the 3 parameters that pharma companies use when formulating combo-pills.

Answer 18

Acquire drugs with…

1. Few overlapping toxicities
2. No overlapping of resistance profiles
3. Similar pharmacokinetics (i.e. half-life)

Question 19

What do the best ways to treat HIV patients have in common?

Answer 19

Involve the use of an integrase inhibitor + 2 NRTI’s. Treat them IMMEDIATELY (not until CD4+ counts <200).

Question 20

Define the Post-exposure prophylaxis protocol for anyone recently infected with HIV.

Answer 20

Take 3 anti-HIV drugs (Raltegravir + emtricitabine/tenofovir) within 72 hours of exposure for 28 days.

Question 21

This antiviral drug(s) competes with dGTP to bind viral DNA polymerase as a treatment for HSV infection. What is it?

Answer 21

Acyclovir

Valacyclovir, Famcyclovir too

Question 22

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?

Answer 22

Valganciclovir / Ganciclovir

Question 23

What antiviral drug inhibits CMV’s DNAP Polymerase complex from cleaving concatamers into monomers?

Answer 23

Letermovir

Question 24

What is Oseltamivir (Tamiflu) used to treat? How does it work?

Answer 24

Neuramidase inhibitor that treats Influenza; inhibits the cleavage of sialic residues to prevent viral escape.

Question 25

What is Rimantadine (Flumadine) used to treat? How does it work?

Answer 25

Adamantanes that treat Influenza; binds M2 protein to block viral acidification/ unsheathing within the endosome.

Question 26

Describe the cap-snatching reaction that occurs in Influenza infections.

Answer 26

Viral RNA Polymerase doesn’t put a cap on viral mRNA, so the virus STEALS caps from human cell RNAs via cap-dependent endonuclease.

Question 27

Describe the function of Baloxavir- marboxil.

Answer 27

This is a cap-dependent endonuclease inhibitor that prevents viral RNA’s from stealing human cell RNA-caps.

Question 28

Define the Sustained Virologic Response for therapy.

Answer 28

SVR is a benchmark for therapy. Relapse with HCV is low (1%)

Question 29

What are the 2 pan-genomic anti-viral drugs for Hepatitis C infections.

Answer 29

1. Glecaprevir = PAN-GENOMIC drug (affects all 6 HCV genotypes)
2. Grazoprevir = maintains activity against variants that are resistant to other NS3/4A

Question 30

What drugs inhibit the viral replication and packaging of HCV?

Answer 30

NS5A Inhibitors (Ledipasvir, Elbasvir, Pibrentasvir)

Question 31

What is unique about Mavyret?

Answer 31

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)

Question 32

What NS5A Inhibitor is effective against genotypes 1 and 4 for HCV?

Answer 32

Elbasvir

Question 33

What are the 4 sites of interferon viral inhibition for treating HBV?

Answer 33

1. Transcription
2. Translation
3. Protein Processing
4. Viral Maturation

Question 34

Define the function of Entacavir as an HBV antiviral.

Answer 34

Guanosine nucleoside analog that is a chain terminator by DNA distortion (not by lack of 3’ OH).

Question 35

What 3 drugs can be used when HBV builds up resistance to Entacavir?

Answer 35

1. Adefovir (Hepsera)
2. Lamivudine (cytosine derivative, chain terminator)
3. Telbivudine (synthetic thymidine analog)

Question 36

Define the “rebounding” phenomenon for HBV infection.

Answer 36

Non-adherence to an anti-viral (i.e. Entecavir) results in a viral load that bounces back immediately.

Question 37

Define the function of Interferons as HBV drugs.

Answer 37

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).