Lecture 20: Antivirals I

Question 1

What are some viruses sounded by?

Which are enveloped and non-enveloped

Answer 1

• LIPIDS
• Enveloped: HIV, Flu, Herps, SARS-CoV-2, Filo
• Non-Enveloped: Picorn, Adeno

Question 2

What is the generic virus life cycle?

Answer 2

• Viral attectment and entry –> Uncoating –> Synthesis –> transcription –> Assembly –> Release

Each step is blocked by different drug cless

Question 3

What are the two important parts of a HIV structure?

Answer 3

• gp120: Docking
• gp41

Question 4

What are some of the drug class for the Antivirals?

Answer 4

• Entry & Fusion Inhibitors
• Nucleoside Reverse Transcriptase Inhibitors
• Non-nucleoside Reverse transcriptase Inhibitors
• Integrase Inhibitors
• Protease Inhibitors

Question 5

What is the Mechanism of action for the HIV entry fusion inhibitors?

Maraviroc? Enfuvirtide?

Answer 5

• Maraviroc: Binds to HUMAN CCR5 and blocks gp120 binding
• Enfuvirtide: Binds to HIV gp41 and block gp41 changes

Question 6

What is the HIV Entry Inhibitor?>

Answer 6

• Maraviroc: Will bind to CCR5 preventing gp120 binding [ONLY used in patients with CCR5]

Question 7

What are some of the potential problems with using Maraviroc?

Answer 7

• Mutants that bind to CXCR4
• HIV binds to CCR5

Question 8

What is the HIV Fusion Inhibitor?

Answer 8

• Enfuvirtide [NO FUSION!]
• ONLY active against HIV-1
• Blocks the conformation changes = prevntion into the cell

Question 9

What is some of the resistance toward Enfuviritide?

Answer 9

• Mutantion within the gp41

Question 10

What are the 3 activities for reverse Transcriptase Inhibitors?

Answer 10

• RNA dependent DNA polymerase [makes DNA from RNA]
• Ribonyclease H [Chops up RNA]
• DNA-dependent DNA polymerase [Copies DNA from template]

NRTIs will block the 1st and 3rd one

Question 11

What is the Mechanism of Action for the Nucleoside RT Inhibitors [NRTIs]?

Answer 11

• Lack 3’ OH = inhibitor of reverse transcriptase & DNA chain terminator [inhibits elongation]

Active toward HIV-1 & -2

Question 12

What are the NRTIs that are used?

Answer 12

• Zidovudine [T]
• Stavudine [T]
• Abacavir [G]
• Didanosine [A]
• Tenofovir [A]
• Zalcitabine [C]
• Lamivudine [C]
• Emtricitabine [C]

Question 13

What are some of the important stuctural things to note about the NRTIs?

Answer 13

• Azidothymidine: N=N=N; stops synthesis
• Stavudine: = ; stops synthesis
• Tenofovir: - ; binds enzyme & stops synthesis

Question 14

What is the one things that must happen to the NRTIs?

Answer 14

• MUST be phosphorlyated
• Thymidine Kinase = 1 P
• Thymidylate Kinase = 2 P
• NDP Kinase = 3 P

Question 15

What is important to know about Tenofovir?

Answer 15

• Tenofovir Disoproxilfumarate = Prodrug
• Only needs 2 phos; wierd carboxyl group protects it

The phos CANNOT be cleaved by cellular esterases

Question 16

What are some of the advantages of Tenofivr?

Answer 16

• LONG half life [slows down any mutations that occurs]\
• Highly selective for HIV RT over human & mito

Question 17

What are some of the problems for Tenofovir disoproxilfumarate [TDF]?

Answer 17

• Plamasa Esterases: TDF –> TFV
• TFV is eliminated in the Kidney

Question 18

What is Tenofovir Alafenamide [TAF]?

Answer 18

• Alternative Tenofovir Prodrug; activated differently
• Lower conc., less side effects,. higher lipid levels
• Maybe better targeting [better in lymph & higher intra conc]

Question 19

What are some of the things that TAF might be better at then TDF?

Answer 19

• Targeting HIV; better accumlation in lymph & higher intracellular conc

Question 20

What is the way that TAF is converted into TFV?

Answer 20

• TAF contains Phenol and alaine isopropyl ester to masks the chrage on the phosphonates
• Increase delivery and decrease toxicitiy

Question 21

What are some of the important things to note with summarizing NRTI Activation?

Answer 21

• MUST be activited to their triphos form by cellular Kinases
• Different kinases add the 2 & 3 phos
• Different nucleodies require different kinases
• NRTIs compete with dATP, dCTP, dGTP, and dTTP
• Some are inhibited by DNA Po;ymerase
• Tenofovir requires 2 phos steps

Question 22

What are some of the ways that their is resistance to anti-HIV drugs?

Answer 22

• HIV polymerase is error prone
• RT Inhibitors unable to suppress by >90%
• Large amounts of virus
• decreased drug lebel = increased resistance

Question 24

What are the two specific ways that there is resistance towards NRTIs?

Answer 24

• Discriminartory Mutations: selectively impair the ability of reverse transcriptase into DNA
• Excision Mutation: ATP removal of analogue; selected by AZT & d4T

Question 25

When talking about the resistance to NRTIs, what are some of the main Key Points?

Answer 25

- Mutations are near the active site - Helps distingusih between normal dNTPs or NTRIs & Promote Removal of NRTIs

Question 26

What are some of the adverse effects of the NRTIs?

Answer 26

- **Mitochondrial Toxicitiy**: anemia, granulocytopeniam myopathy, lactic acidosis - Abacavir Hypersenstivity Reations: **BLACK BOX** --> Malaise, Dizziness, Headache, GI ## Footnote Abacavir associated with HLA-B*5701

Question 27

What are some of the recommended combination fo NRTIs?

Answer 27

- Tenofovir & Emtracitabine [or lamivudine]: QD, less mutation - Abacavir & lamivudiae [or emtracitabine]: If HLA-B*5701

Question 28

When should Antiretoviral medications NOT be offered> ## Footnote **NOT RECOMMENDED**

Answer 28

- Monoterapy - Dual NRTIs Therapy - 3-NRTIs Regimen [maybe abacavir/lamivudine/zidovudine & lamivudine/zidovudine + tenofobir]

Question 29

How do the Nonnucleoside RT inhibitors [NNRTIs] act?

Answer 29

- They Bind to Hydrophobic Pocket, near but distinct from NRTIs - NNRTIs do **NOT** compete wiht nucleotides [noncompetitive] - Block RNA- and DNA-dependent DNA polymerase

Question 30

What is the Mechanism of Action for the NNRTIs?

Answer 30

- Will bind NEAR the active site of RT; blocking polymerization - Single mutation in binding can promote resistance

Question 31

What are the first generation NNRTIs?

Answer 31

- Nevirapine & **Efavirenz** - Half-life = 40-55h; CNS side effecst, Teratogenic

Question 32

What are the second generation NNRTIs?

Answer 32

- Etravirine & Rilpivirine - Diaryl-pyrimidine based; binds in multiple orientations [helps against resistance]

Question 33

What are some of the adverse effects of NNRTIs?

Answer 33

- Rash, Drug Interations - Nevirapine: Hepatotoxicity, SJS - Efavirenz: Neuropsychiatric, Teratogenic [Preg D]

Question 34

What is the way that the NNRTIs are metabolized?

Answer 34

- **ALL by CYP3A** - Interactions with Rifampin [inducer] = reduced levels & inhibitors = increased levels ## Footnote Efavirenz, Nevirapine, Etravirine = Inducers Efavirenz, Delavirdine = Inhibitors 3A4 Etravirine = Inhibitors 2C9 & 2C19

Question 35

What are some of the important things to note about the NNRTIs/

Answer 35

- **DO NOT** require activiation, compete with dNTP or go into DNA - single mutation = **resistance** - **NO** cross-resistance with NRTIs

Question 36

What are some of the important things to know about the Integrase Inhibitors [INI]? ## Footnote MOA? AE? Dosage Form? Interaction?

Answer 36

- **Inhibits insertion of HIV DNA into the human genome** - Most commonly causes: Diarrhea, nausea, fatigue, headache, itching - Orally Active - DOES NOT interact with CYP450

Question 37

What is the main function of Integrase?

Answer 37

- Will inhibit the strand transfer step; stopping HIV from going into cellular DNA

Question 38

What are the Integrase Inhibitors that are used?

Answer 38

- Reltegravir, Elvitegravir, Dolutegravir

Question 39

What are some of the causes for resistance within the Integrase Inhibitores?

Answer 39

- Reduce INI susceptibility - Low Genetic Barriers [Dolutegravir higher] - Cross Resistance [Dolutegravir less affected]

Question 40

What are some of the important things to note about Elvitegravir?

Answer 40

- Metabolised by **3A4** - Given with Cobicistat [cobi NOT active against HIV & boosts elvitegravir]

Question 41

What are some of the important things to note about Dolutegravir?

Answer 41

- Long Plasma Half Life = 14h [QD] - NO boosting - NO 3A4 interations - HIGH barrier for resistance

Question 42

What is the mechanism of action for the HIV Protease?

Answer 42

- Peptides bond cleavage is a **hydroysis** reaction - Makes carboxyic acid and amine

Question 43

What is the Mechanism of action for the HIV Protease Inhibitors?

Answer 43

- Amide Bond is replaced by non-cleavable linkage - Inhibitor will cause conformaiton change [**CLOSED**]

Question 44

What is the Metabolism of the Protease Inhibitors?

Answer 44

- **ALL** are substarates and some are Inhibitors of 3A4 - Drug interactions; increase levels of other 3A4's

Question 45

What is important to know about Saquanivir?

Answer 45

- FIRST protease inhibitor - **Hydroxyethylamine** keeps it trapped - LOW bioavailabilty

Question 46

What is important to know abuot Ritonavir?

Answer 46

- HIGHER bioavailability - **MOST POTENT PI inhibitor of 3A4** - Currently initial treatment

Question 47

What is important to know about Atazanavir?

Answer 47

- QD - MOST POTENT protease prior to darunavir - Efavirenz & tenofovir reduce ATV conc.

Question 48

What is important to know about Darunavir?

Answer 48

- Preferred PI for Initial antiretroviral combo - **Extensive Hydrogen bonds** - **Inhibits HIV protease dimerization** ## Footnote BLOCK activity in multiple spots

Question 49

What are some of the initial treatment [preferred regimens] for HAART ## Footnote INSTI Based

Answer 49

- DTG + ABC/3TC [ONLY if HLA-B 5701 is neg] - DTG [QD] + Tenofovir/FTC - EVG/COBI + Tenofovir/FTC - RAL + Tenofovir/FTC

Question 50

What are some of the initial treatment [Alternative] for HAART? ## Footnote NNRTI

Answer 50

- Boosted DRV or ATV _ TDF/FTC or ABC/3TC [if HLA-B 5701 is neg] - EFV + Tenofovir/FTC - RPV + Tenofovir/FTC