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.