Antiviral Chemotherapy 2 - Blocking HIV Entry + Integrase Inhibitors Flashcards
(24 cards)
Describe membrane fusion
Between enveloped viruses (HIV) + host cell = obligatory in viral infection
Mediated by viral glycoproteins
What is gp41?
Transmembrane protein responsible for membrane fusion
What is gp120?
Surface proteins responsible for host recognition
Describe the process of membrane fusion
Binding of viral gp120 to CD4
= changes conformation of gp120
= protein binds to CCR5/CXCR4
What drugs block entry?
Fusion inhibitors
Entry inhibitors
Attachment inhibitors
Describe fusion inhibitors
Blocks gp41
eg. Albuviride
Describe attachment inhibitors
Post-attachment = blocks binding of co-receptor = Ibalizumab
Attachment inhibitors = Temsavir
Describe entry inhibitors
CCR5 co-receptor antagonists
= Maraviroc
How does fusion inhibitors work?
Binding of gp120 = conformational change = exposes fusion peptide gp41 = allows insertion into membrane = fusion
Fuzeon binds to gp41 = blocks binding of fusion of membranes
Describe Fuzeon
S/C injection (90mg BD)
Hypersensitivity reactions = rash, fever, N+V, low BP + raised liver enzymes
Describe Albuvirtide
Covalently links to serum albumin
= increases t1/2 = maintains activity
Describe inhibition of HIV entry
Process by which HIV attaches to cells is mediated by viral envelope protein (gp120/gp41)
gp41 = glycine rich fusion peptide = mediated membrane fusion
gp120 = subunit required for binding to host cell
Co-receptors = CXR4 + CCR5
How does Fostemsavir work?
Prodrug = Temsavir active agent
Binds to gp120 in highly conserved region (‘Phe 43 pocket - hydrophobic)
Alters conformation = inhibits binding to CD4
Describe Ibalizumab (post-attachment inhibitor)
Treatment of heavily experienced patients with multi-drug resistance
How does Maraviroc (CCR5 antagonist) work?
Bind to allosteric site on CCR5 receptor
= conformational change
= disrupts binding of virus
How does HIV integrase work?
Binds to viral double-stranded viral DNA + mediates its integration into cellular genomic DNA
Final step before irreversible + productive HIV infection
Describe structure of integrase
N-terminal domain = zinc ion = stabilise fold of N-terminal domain
Catalytic core domain = 3 negatively charged amino acids = coordinate Mg2+
Ions are essential for 3’-processing + strand transfer
C-terminal domain = binds to DNA non-specifically
What is the function of integrase?
Contains 2Mg2+ = Lewis acids
= interact with Lewis base = facilitate bond breaking/making reactions
RT and IN moderate each other
Removes bases = sticky ends
IN = cut into host DNA + add in viral DNA
What does LEDGF/p75 do?
Binds to CCD-CCD (catalytic core domain) interface of one dimer whilst simultaneously binding to N-terminal of another dimer
= stabilising tetramer
Describe the intasome
3’-processing in cytoplasm
Strand transfer rection in nucleus
Describe the intasome chemistry
Put viral DNA into host cell DNA
Stable synaptic complex (SSC) - cleavage of phosphodiester bond
Interaction with Mg2+ essential
Target capture complex (TCC) - cleavage of phosphodiester bond
Strand transfer complex - bond forms
Describe the structure of integrase inhibitors
Oxygen = key bit of pharmacophore
= planar arrangement
Other bit = holds in correct orientation = hydrophobic rings = in contact with hydrophobic residues
Metal chelators
How does integrase inhibitors work?
By blocking ST reaction
All chelate to Mg2+ via Lewis acid-Lewis base interaction
What is the new model?
Dual therapy
= better safety profile
= increased adherence
= high residence time
LATTE = key study for this = Cabotegravir + Rilpivirine
Cabotegravir = sub-nanomolar + high barrier to resistance
Rilpivirine = nano-formulation with sustained release + NO drug-drug interaction
