Lec 26 - Antiviral therapies Flashcards
What is a good antiviral and what are the best targets?
Binds target viral protein more tightly than human and has good pharmacological properties
Targets = unique and essential proteins for virus
List some challenges associated with developing antivirals
- Fewer targets in viruses vs bacteria
- Viruses rep intracellularly
- Latency with some viruses = curing active doesn’t cure entire disease
- Difficult diagnosis from similar symptoms by different viruses
- Presents only at peak viraemia = small window for treatment
- Escape from immunity
- Resistance
What is the structure of RT and how does it relate to NRTIs and NNRTIs?
RT = heterodimer of p66 with pol active site and p51 with binding cleft
NRTIs bind pol active site in cleft
NNRTIs bind close to active site in cleft
Describe the mechanism of NRTIs and give an example
Competitive inhibitors of viral polymerases and lack 3’ OH for extension
Eg AZT with azido/NH3 group on 3’ C
Describe the mechanism of NNRTIs and give an example
Non-competitive inhibitors of viral polymerases by conformational change to alter and limit active site
Eg Nevirapine for reducing mother-child transmission
Eg Etravirine
How do viruses resist NRTIs and NNRTIs?
NRTIs = discriminatory mutations = RT selects natural dNTPS
NNRTIs = 7 residues with possible mutations = etravirine flexible with multiple binding conformations
What is the function of HIV’s integrase? What are the 2 reactions needed? How do INSTIs inhibit integrase?
Integrase = transports and attaches proviral DNA to host-cell chromosomes
1. 3’ processing in host cytoplasm to prep provirus for attachment
2. Strand transfer to covalently link provirus to host DNA
INSTIs = competitively inhibit strand transfer reaction by binding metallic ions in active site; removes dNTP from 3’ end before integration
How do fusion inhibitors work? Use example drugs
Temsavir = binds and prevents gp120 conformational change needed for attachment
Maraviroc CCR5 inhibitor
What was the issue of resistance with Maraviroc CCR5 inhibitor? What were the resulting variants produced?
- Mutations allowing gp120-CCR5 binding and conformational change despite drug binding
- Existing X4-tropic variants being selected or newly emerging X4 variants
Give an example of a post-attachment inhibitor
Ibalizumab = monoclonal antibody binding D2 domain of CD4 to prevent normal conformational change required for attachment
What does HIV’s protease do? How do protease inhibitors combat this function? Give a drug example
- Protease = cleave gag and gag-pol polyproteins to capsid subunits = mature virion
- Protease inhibitors = competitive inhibitors directly binding HIV-1 protease’s active site to prevent polypeptide cleavage
- Eg Squanivir
What is virologic rebound? What are the reasons for it?
Confirmed detectable HIV RNA >200 copies/mL plasma after virologic suppression due to resistance and/or drug compliance
What happens when patients stop ART with HIV?
No more selective pressure = reverts back to wild type (WT) virus with more fitness
How does acyclovir inhibit HSV and VZV?
- Guanosine analog = selectively phosphorylated by viral thymidine kinase (TK) and inhibits DNA polymerase by chain termination
- Works with visceral, disseminated and CNS diseases
How does gancyclovir inhibit CMV?
Acyclic guanosine analogue = competitive inhibitor of deoxyguanosine triphosphate and inhibits viral DNA polymerases over host ones
