Rapid synthesis and in situ screening of potent HIV-1 protease dimerization inhibitors.
A library of dimerization inhibitors of HIV-1 protease is described based on crosslinked interfacial peptides. The 54 component library was designed to contain two modifications to the starting structure, one each in the Northern and Southern fragments. A rapid synthesis and in situ screening method in microtiter plates was developed to facilitate the generation and evaluation of the library members. More than 90% of the doubly modified agents were more potent than their respective singly mutated parent compounds, and five of the most potent dimerization inhibitors of HIV-1 protease described to date were identified. The free energy of binding for the combined two modifications was generally found to be additive, demonstrating the predictive value of earlier libraries.
Lee
Song-Gil
SG
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Chmielewski
Jean
J
D019281:Dimerization; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D020836:Protein Structure, Quaternary / Q000187:drug effects
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D019151:Peptide Library