A quick diversity-oriented amide-forming reaction to optimize P-subsite residues of HIV protease inhibitors.
We report a new simple method that allows rapid preparation in solution of a library of compounds for in situ high-throughput screening to identify new inhibitors of HIV-1 protease. The method is based on the amide-forming reaction of a C(2)-symmetrical diamino diol core with various carboxylic acids, followed by a direct assay of the inhibition activity without product isolation. Sixty-two compounds were made and screened in less than 1 hr. The utility of this method is demonstrated by the identification of new P3-P3' residues that convert a transition state analog core from a poor binding molecule (1, K(i) > 2 microM) to a potent inhibitor (AB1, K(i) = 2 nM) against the wild-type, and the inhibition activities against resistant mutants are better than those of two existing drugs. This method reduces the time required for synthesis and testing of a large number of characterized inhibitors and should find useful applications in other enzyme systems.
Department of Chemistry and The Skaggs Institute for Chemical Biology, La Jolla, CA 9203, USA.
Ashraf
A
Brik
Ying-Chuan
YC
Lin
John
J
Elder
Chi-Huey
CH
Wong
D000577:Amides; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004351:Drug Resistance / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D013329:Structure-Activity Relationship
D000577:Amides; D017320:HIV Protease Inhibitors