35. Antiviral Therapy Flashcards
what was the first anti-viral?
Iododeoxyuridine
how does iododeoxyuridine work?
NUCLEOSIDE analog
- inhibits viral nucleic acid synthesis via chain termination bc of iodine that distorts sugar
what virus is iododeoxyuridine for?
herpes
was iododeoxyuridine topical or oral?
topical
what was the first oral antiviral? what was it for?
Amantadine –> inhibits influenza M protein
3 COVID antivirals and route of administration
- remdesivir (injectable)
- nermatrelvir (oral)
- molnupiravir (oral)
what do HCV protease inhibitors inhibit?
NS3
what do HCV nucleoside analogs target?
NS5A (for replication) and NS5B (RdRP) –> blocks replication
2 types of HBV treatments
- IFN-alpha
- nucleoside/nucleotide analogs
difference btwn nucleotide and nucleoside analogs
nucleotide –> must add the phosphate
nucleoside –> given as prodrug with protecting group on 1st phosphate
what is HAART?
Highly Active AntiRetroviral Therapy
progression of antiretroviral therapy thru HIV pandemic
- started with nucleoside inhibitors only (monotherapy) but developed rapid resistance
- then added protease inhibitors (multidrug) to give much better outcomes
what was the first anti-HIV drug?
ZIDOVUDINE
What functional group is on zidovudine and what is its role?
has azide that replaces 3’ OH so acts as chain terminator bc cannot accept another triphosphate
2 general types of HIV RT inhibitors
- Nucleoside analogue RT inhibitors (NRTIs)
- Non-nucleoside analogue RT inhibitors (NNRTIs)
what type of HIV are NRTIs active against? why?
active against both HIV1 and HIV2
bc both RT have conserved active site
what type of HIV are NNRTIs active against? why?
only active against HIV1
they don’t bind at active site, just near active site with diff amino acids
another name for zidovudine
AZT
2 analogues of thymidine
- AZT
- d4T
1 analogue of cytidine
3TC aka Lamivudine
what 2 viruses is 3TC used for?
HIV and HBV
what does it mean for NRTIs to be prodrugs?
they must convert to triphosphate once in cell to be true inhibitor and join existing chain
difference btwn NRTIs and NNRTIs?
NRTIs block active site of RT
NNRTIs bind outside of active site to prevent proper dynamics of RT
what type of drugs are HIV1 protease inhibitors?
peptidomimetics
what type of protease is HIV protease?
aspartic acid protease
why are protease inhibitors not used as monotherapy?
have lowest barrier to resistance
how do HIV1 integrase inhibitors work?
prevent strand transfer to chromosome during integration
2 types of integrase inhibitors
- strand transfer inhibitors –> directly bind active site
- allosteric inhibitors –> don’t bind active site
another name for integrase inhibitors?
integrase strand transfer inhibitors
why are HIV1 capsid inhibitors especially helpful?
involved in early and late stages of viral life cycle so therapy can block early and late stages
3 types of entry inhibitors
- block CD4 attachment
- binds CCR5 on host
- block formation of 6-bundle helix for fusion
what is the name of the drug that blocks CCR5?
maraviroc
why is maraviroc unique?
one of the only drugs to target host component, not viral component
does HAART cure?
no
why does HAART not cure viral infection? (2)
- drug resistance
- virus latency
describe HIV virus latency
HIV integrates in CD4 memory cells which last a long time –> creates long-lived genome and allows latency
4 ways that HIV1 becomes resistant to antiviral drugs
- mutation
- RT is error-prone
- large number of HIV particles made
- low drug concentration in certain tissue compartments
what is NRTI resistance caused by?
amino acid changes which give diff levels of resistance
what happens to people on 3TC monotherapy?
on 3TC monotherapy, quickly gains resistance for 3TC but becomes MORE SENSITIVE to AZT
2 mechanisms for NRTI resistance
- cell becomes able to discriminate between natural dNTPs and NRTIs
- excision of NRTI from 3’ end of DNA chain
example of mutation that causes excision of NRTI from 3’ end
thymidine analogue mutation (TAM)
how does HIV gain resistance to AZT?
excision of AZT via reverse phosphopyrolysis
2 mechanisms of NNRTI resistance
- sterically prevent inhibitor binding
- destabilize inhibitor binding
unwanted interaction btwn drug resistance mechanisms
cross-resistance mutations / multi drug resistance virus
2 benefits of interactions btwn drug resistance mutations
- hypersensitivity
- resensitization of formerly resistant viruses (via background mutations)
which protein has the highest level of resistance?
protease
of the 99 aa in each protease monomer, how many are invariant, how many are involved in drug resistance
37 are invariant
45 are involved in drug resistance
of the 45 aa involved in drug resistance, how many have strong resistance to 1+ PIs
26
of the 26 drug resistant aa with strong resistance to 1+ PIs, what % are outside the active site region?
60%
besides mutated protease, what is another way to gain PI resistance
mutate the Gag and Gag-pol cleavage sites –> to increase Gag processing and viral replication to compensate for PI-resistance in protease
is integrase easily mutatable?
no, has highest barrier to resistance bc fewer aa can be changed and mutations are rare
