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Chem Biol. 2002 Aug;9(8):891-6.

A quick diversity-oriented amide-forming reaction to optimize P-subsite residues of HIV protease inhibitors.

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Department of Chemistry and The Skaggs Institute for Chemical Biology, La Jolla, CA 9203, USA.


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.

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