Specificity Mapping of HIV-1 Protease by Reduced Bond Inhibitors

Pavel Majer, Jan Urban, Eva Gregorová, Jan Konvalinka, Petr Novek, Jana Stehlíková, Martin Andreánsky, Juraj Sedláček, Petr Štrop

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


A series of 47 N-truncated reduced bond inhibitors, systematically modified at individual positions (P1, P'1, P'2, P'3, and P'4), were synthesized and used to map the subsite preferences of HIV-1 protease. The tight binding inhibitor of HIV-1 protease t-butoxycarbonyl-Phe[CH2NH]Phe-Glu-Phe-NH2 (K(i) = 0.2 nM) was chosen as the parent structure for further modifications. The P'2 glutamic acid was found to fit well into the S'2 subsite of the protease. The conformational restriction of any phenylalanine residue or saturation of more than one phenylalanine side chain in P'1 or P'3 lead is to a large K(i) increase. Introduction of tyrosine in the P1 position improves the binding by an order of magnitude. The S'4 subsite of the protease was shown to accommodate large structural changes in the inhibitor at this position. Therefore P'4 may serve as an ideal region for further modification in order to improve bioavailability of this type of compound. An improved method of direct comparison of tight binding inhibitors with subnanomolar K(i) values has been described.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalArchives of Biochemistry and Biophysics
Issue number1
StatePublished - 1993
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology


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