title: Rapid synthesis and in situ screening of potent HIV-1 protease dimerization inhibitors.
abstract: 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.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Song-Gil
authors.initials: SG
authors.lastname: Lee
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
mesh_terms: 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
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D019151:Peptide Library