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

Ashraf Brik, Ying Chuan Lin, John Elder, Chi Huey Wong

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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 C2-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, Ki > 2 μM) to a potent inhibitor (AB1, Ki = 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.

Original languageEnglish
Pages (from-to)891-896
Number of pages6
JournalChemistry and Biology
Volume9
Issue number8
DOIs
StatePublished - 1 Aug 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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