Antivirals

Question 1

HIV entry inhibitors: example and mechanism

Answer 1

Maraviroc

Binds CCR5 on cell, so HIV virus cannot enter cell

Question 2

HIV fusion inhibitor: example and mechanism

Answer 2

Efuviritide binds viral gp41 (viral surface protein that normally facilitates viral fusion to host cell)

Question 3

HIV Fusion inhibitor mechanism of resistance

Answer 3

Env encodes structural genes; mutations in env –> resistance

Question 4

HIV integrase inhibitors: example and mechanism

Answer 4

“-tegravir” (raltegravir, dolutegravir, elvitegravir)

Blocks viral integrase, which normally allows viral DNA (post reverse transcription) to integrate with host DNA

Question 5

HIV Integrase inhibitors mechanism of resistance

Answer 5

Integrase encoded by pol; mutation here–>resistance

Question 6

Mechanism of HIV infection–>release

Answer 6

1. Attachment (viral gp120 to cell CXCR4 or CCR5)
2. Fusion (via viral gp41)
3. Uncoating
4. Reverse transcription
5. Integration into host DNA via integrase
6. Transcription, translation
7. Protease (bc HIV proteins translated as long polyproteins that need to be cleaved by proteases from immature precursors–>mature virion

Question 7

NRTIs: what are they?

Answer 7

Nucleoside reverse transcription inhibitors
Indirectly inhibit reverse transcription
Nucleotides or nucleosides with absent hydroxyl @ 3’ end–>DNA elongation terminated because can’t make 3’-5’ phosphodiester bond

Question 8

NRTIs: how do they get activated in cells?

Answer 8

Nucleosides need to be phosphorylated by cell enzymes to be activated
Nucleotides (ie tenofovir) do not (“naht for tenofovir”)

Question 9

NRTIs: important SEs overall

Answer 9

Mitochondrial toxicity, lactic acidosis

Question 10

Lamivudine, stavudine, didanosine SE

Answer 10

peripheral neuropathy

Question 11

NNRTIs: what are they and how do they work?

Answer 11

Non-nucleoside reverse transcriptase inhibitors
Directly inhibit reverse transcriptase by direct binding–>allosteric inhibition
Doesn’t need intracell phosphor

Question 12

NNRTIs mechanism of resistance

Answer 12

Mutation in viral pol gene

Question 13

NNRTIs important side effects

Answer 13

Liver failure
Stevens Johnson Syndrome
Teratogenic (elfavirenz and dilavirdine)

Question 14

Protease inhibitors: suffix and mechanism

Answer 14

“-navir”
HIV needs proteases bc gene translated as long polyprotein that must be cleaved
Protease encoded by pol gene

Question 15

Protease resistance?

Answer 15

Mutations of pol gene; never use as monotherapy bc of this

Question 16

Protease SEs

Answer 16

Hyperglycemia due to insulin resistance, dyslipidemia, lipodystrophy
Ritonovir inhibits CYP450 strongly

Question 17

Interferons: what are they

Answer 17

Immunomodulatory cytokines released from virus infected cells; upregulated by interleukins

Question 18

Interferon alpha treats

Answer 18

Hep B and C, hairy cell leukemia, malignant melanoma, kaposi sarcoma, HPV condyloma accuminata, renal cell carcinoma

Question 19

Interferon alpha SEs

Answer 19

Flu like syndrome (can be very severe), retinopathy, confusion, myelosuppression, drug-induced lupus

Question 20

Interferon beta tx

Answer 20

multiple sclerosis

Question 21

Interferon gamma tx

Answer 21

Chronic granulomatous disease

Via activating macrophages

Question 22

Ribavarin mechanism

Answer 22

Guanosine nucleoside analogue; must be phosphorylated 3x into its active nucleotide form

Question 23

Ribavirin use

Answer 23

Hep C (not anymore)

Question 24

Sofosbuvir mechanism

Answer 24

Nucleoside analog, direct polymerase inhibitor

Question 25

Simeprevir mechanism

Answer 25

Protease inhibitor

Question 26

HSV, VZV drugs

Answer 26

Acyclovir, valacyclovir, famcyclovir

Question 27

Acyclovir mechanism

Answer 27

Guanosine nucleoside analog; must be activated by viral thymidine kinase (HSV virus specific) Absence of viral thymidine kinase confers resistance Acyclovir gets incorporated into replicating viral DNA, halting synthesis

Question 28

HSV antivirals that do not need to be activated by virus

Answer 28

Foscarnet and cidofovir | Directly inhibit viral DNA polymerase

Question 29

Acyclovir SE

Answer 29

``` CNS (delirium, confusion, hallucinations) Interstitial nephritis (prevent with hydration) ```

Question 30

CMV antivirals

Answer 30

gancyclovir, valgancyclovir, foscarnet, cidofovir

Question 31

Ganciclovir main toxicity

Answer 31

Myelosuppression

Question 32

When do people get CMV infections?

Answer 32

CD4<50

Question 33

Ganciclovir mechanism

Answer 33

Like acyclovir (guanosine analog, must be phosphor by viral kinase)

Question 34

Oseltamivir, zanamivir mechanism and tx for

Answer 34

inhibit influenza NA-->decrease release of progeny virus Tx and prevent influenza A and B (doesn't work if already widely replicated virus though, since only inhibits release of more progeny)

Question 35

Ganciclovir mech of resistance

Answer 35

Mutated viral kinase

Question 36

Foscarnet mechanism of resistance

Answer 36

Mutated DNA polymerase