35. Antiviral Therapy

Question 1

what was the first anti-viral?

Answer 1

Iododeoxyuridine

Question 2

how does iododeoxyuridine work?

Answer 2

NUCLEOSIDE analog
- inhibits viral nucleic acid synthesis via chain termination bc of iodine that distorts sugar

Question 3

what virus is iododeoxyuridine for?

Answer 3

herpes

Question 4

was iododeoxyuridine topical or oral?

Answer 4

topical

Question 5

what was the first oral antiviral? what was it for?

Answer 5

Amantadine –> inhibits influenza M protein

Question 6

3 COVID antivirals and route of administration

Answer 6

1. remdesivir (injectable)
2. nermatrelvir (oral)
3. molnupiravir (oral)

Question 7

what do HCV protease inhibitors inhibit?

Answer 7

NS3

Question 8

what do HCV nucleoside analogs target?

Answer 8

NS5A (for replication) and NS5B (RdRP) –> blocks replication

Question 9

2 types of HBV treatments

Answer 9

1. IFN-alpha
2. nucleoside/nucleotide analogs

Question 10

difference btwn nucleotide and nucleoside analogs

Answer 10

nucleotide –> must add the phosphate

nucleoside –> given as prodrug with protecting group on 1st phosphate

Question 11

what is HAART?

Answer 11

Highly Active AntiRetroviral Therapy

Question 12

progression of antiretroviral therapy thru HIV pandemic

Answer 12

1. started with nucleoside inhibitors only (monotherapy) but developed rapid resistance
2. then added protease inhibitors (multidrug) to give much better outcomes

Question 13

what was the first anti-HIV drug?

Answer 13

ZIDOVUDINE

Question 14

What functional group is on zidovudine and what is its role?

Answer 14

has azide that replaces 3’ OH so acts as chain terminator bc cannot accept another triphosphate

Question 15

2 general types of HIV RT inhibitors

Answer 15

1. Nucleoside analogue RT inhibitors (NRTIs)
2. Non-nucleoside analogue RT inhibitors (NNRTIs)

Question 16

what type of HIV are NRTIs active against? why?

Answer 16

active against both HIV1 and HIV2

bc both RT have conserved active site

Question 17

what type of HIV are NNRTIs active against? why?

Answer 17

only active against HIV1

they don’t bind at active site, just near active site with diff amino acids

Question 18

another name for zidovudine

Answer 18

AZT

Question 19

2 analogues of thymidine

Answer 19

1. AZT
2. d4T

Question 20

1 analogue of cytidine

Answer 20

3TC aka Lamivudine

Question 21

what 2 viruses is 3TC used for?

Answer 21

HIV and HBV

Question 22

what does it mean for NRTIs to be prodrugs?

Answer 22

they must convert to triphosphate once in cell to be true inhibitor and join existing chain

Question 23

difference btwn NRTIs and NNRTIs?

Answer 23

NRTIs block active site of RT

NNRTIs bind outside of active site to prevent proper dynamics of RT

Question 24

what type of drugs are HIV1 protease inhibitors?

Answer 24

peptidomimetics

Question 25

what type of protease is HIV protease?

Answer 25

aspartic acid protease

Question 26

why are protease inhibitors not used as monotherapy?

Answer 26

have lowest barrier to resistance

Question 27

how do HIV1 integrase inhibitors work?

Answer 27

prevent strand transfer to chromosome during integration

Question 28

2 types of integrase inhibitors

Answer 28

1. strand transfer inhibitors --> directly bind active site 2. allosteric inhibitors --> don't bind active site

Question 29

another name for integrase inhibitors?

Answer 29

integrase strand transfer inhibitors

Question 30

why are HIV1 capsid inhibitors especially helpful?

Answer 30

involved in early and late stages of viral life cycle so therapy can block early and late stages

Question 31

3 types of entry inhibitors

Answer 31

1. block CD4 attachment 2. binds CCR5 on host 3. block formation of 6-bundle helix for fusion

Question 32

what is the name of the drug that blocks CCR5?

Answer 32

maraviroc

Question 33

why is maraviroc unique?

Answer 33

one of the only drugs to target host component, not viral component

Question 34

does HAART cure?

Answer 34

no

Question 35

why does HAART not cure viral infection? (2)

Answer 35

1. drug resistance 2. virus latency

Question 36

describe HIV virus latency

Answer 36

HIV integrates in CD4 memory cells which last a long time --> creates long-lived genome and allows latency

Question 37

4 ways that HIV1 becomes resistant to antiviral drugs

Answer 37

1. mutation 2. RT is error-prone 3. large number of HIV particles made 4. low drug concentration in certain tissue compartments

Question 38

what is NRTI resistance caused by?

Answer 38

amino acid changes which give diff levels of resistance

Question 39

what happens to people on 3TC monotherapy?

Answer 39

on 3TC monotherapy, quickly gains resistance for 3TC but becomes MORE SENSITIVE to AZT

Question 40

2 mechanisms for NRTI resistance

Answer 40

1. cell becomes able to discriminate between natural dNTPs and NRTIs 2. excision of NRTI from 3' end of DNA chain

Question 41

example of mutation that causes excision of NRTI from 3' end

Answer 41

thymidine analogue mutation (TAM)

Question 42

how does HIV gain resistance to AZT?

Answer 42

excision of AZT via reverse phosphopyrolysis

Question 43

2 mechanisms of NNRTI resistance

Answer 43

1. sterically prevent inhibitor binding 2. destabilize inhibitor binding

Question 44

unwanted interaction btwn drug resistance mechanisms

Answer 44

cross-resistance mutations / multi drug resistance virus

Question 45

2 benefits of interactions btwn drug resistance mutations

Answer 45

1. hypersensitivity 2. resensitization of formerly resistant viruses (via background mutations)

Question 46

which protein has the highest level of resistance?

Answer 46

protease

Question 47

of the 99 aa in each protease monomer, how many are invariant, how many are involved in drug resistance

Answer 47

37 are invariant 45 are involved in drug resistance

Question 48

of the 45 aa involved in drug resistance, how many have strong resistance to 1+ PIs

Answer 48

26

Question 49

of the 26 drug resistant aa with strong resistance to 1+ PIs, what % are outside the active site region?

Answer 49

60%

Question 50

besides mutated protease, what is another way to gain PI resistance

Answer 50

mutate the Gag and Gag-pol cleavage sites --> to increase Gag processing and viral replication to compensate for PI-resistance in protease

Question 51

is integrase easily mutatable?

Answer 51

no, has highest barrier to resistance bc fewer aa can be changed and mutations are rare