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MIMM 324 > 35. Antiviral Therapy > Flashcards

35. Antiviral Therapy Flashcards

1
Q

what was the first anti-viral?

A

Iododeoxyuridine

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2
Q

how does iododeoxyuridine work?

A

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

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3
Q

what virus is iododeoxyuridine for?

A

herpes

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4
Q

was iododeoxyuridine topical or oral?

A

topical

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5
Q

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

A

Amantadine –> inhibits influenza M protein

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6
Q

3 COVID antivirals and route of administration

A
  1. remdesivir (injectable)
  2. nermatrelvir (oral)
  3. molnupiravir (oral)
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7
Q

what do HCV protease inhibitors inhibit?

A

NS3

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8
Q

what do HCV nucleoside analogs target?

A

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

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9
Q

2 types of HBV treatments

A
  1. IFN-alpha
  2. nucleoside/nucleotide analogs
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10
Q

difference btwn nucleotide and nucleoside analogs

A

nucleotide –> must add the phosphate

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

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11
Q

what is HAART?

A

Highly Active AntiRetroviral Therapy

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12
Q

progression of antiretroviral therapy thru HIV pandemic

A
  1. started with nucleoside inhibitors only (monotherapy) but developed rapid resistance
  2. then added protease inhibitors (multidrug) to give much better outcomes
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13
Q

what was the first anti-HIV drug?

A

ZIDOVUDINE

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14
Q

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

A

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

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15
Q

2 general types of HIV RT inhibitors

A
  1. Nucleoside analogue RT inhibitors (NRTIs)
  2. Non-nucleoside analogue RT inhibitors (NNRTIs)
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16
Q

what type of HIV are NRTIs active against? why?

A

active against both HIV1 and HIV2

bc both RT have conserved active site

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17
Q

what type of HIV are NNRTIs active against? why?

A

only active against HIV1

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

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18
Q

another name for zidovudine

A

AZT

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19
Q

2 analogues of thymidine

A
  1. AZT
  2. d4T
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20
Q

1 analogue of cytidine

A

3TC aka Lamivudine

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21
Q

what 2 viruses is 3TC used for?

A

HIV and HBV

22
Q

what does it mean for NRTIs to be prodrugs?

A

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

23
Q

difference btwn NRTIs and NNRTIs?

A

NRTIs block active site of RT

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

24
Q

what type of drugs are HIV1 protease inhibitors?

A

peptidomimetics

25
Q

what type of protease is HIV protease?

A

aspartic acid protease

26
Q

why are protease inhibitors not used as monotherapy?

A

have lowest barrier to resistance

27
Q

how do HIV1 integrase inhibitors work?

A

prevent strand transfer to chromosome during integration

28
Q

2 types of integrase inhibitors

A
  1. strand transfer inhibitors –> directly bind active site
  2. allosteric inhibitors –> don’t bind active site
29
Q

another name for integrase inhibitors?

A

integrase strand transfer inhibitors

30
Q

why are HIV1 capsid inhibitors especially helpful?

A

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

31
Q

3 types of entry inhibitors

A
  1. block CD4 attachment
  2. binds CCR5 on host
  3. block formation of 6-bundle helix for fusion
32
Q

what is the name of the drug that blocks CCR5?

A

maraviroc

33
Q

why is maraviroc unique?

A

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

34
Q

does HAART cure?

A

no

35
Q

why does HAART not cure viral infection? (2)

A
  1. drug resistance
  2. virus latency
36
Q

describe HIV virus latency

A

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

37
Q

4 ways that HIV1 becomes resistant to antiviral drugs

A
  1. mutation
  2. RT is error-prone
  3. large number of HIV particles made
  4. low drug concentration in certain tissue compartments
38
Q

what is NRTI resistance caused by?

A

amino acid changes which give diff levels of resistance

39
Q

what happens to people on 3TC monotherapy?

A

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

40
Q

2 mechanisms for NRTI resistance

A
  1. cell becomes able to discriminate between natural dNTPs and NRTIs
  2. excision of NRTI from 3’ end of DNA chain
41
Q

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

A

thymidine analogue mutation (TAM)

42
Q

how does HIV gain resistance to AZT?

A

excision of AZT via reverse phosphopyrolysis

43
Q

2 mechanisms of NNRTI resistance

A
  1. sterically prevent inhibitor binding
  2. destabilize inhibitor binding
44
Q

unwanted interaction btwn drug resistance mechanisms

A

cross-resistance mutations / multi drug resistance virus

45
Q

2 benefits of interactions btwn drug resistance mutations

A
  1. hypersensitivity
  2. resensitization of formerly resistant viruses (via background mutations)
46
Q

which protein has the highest level of resistance?

A

protease

47
Q

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

A

37 are invariant
45 are involved in drug resistance

48
Q

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

A

26

49
Q

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

A

60%

50
Q

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

A

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

51
Q

is integrase easily mutatable?

A

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

MIMM 324 (37 decks)

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