Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity

Jan Urban, Jan Konvalinka, Jana Stehliková, Eva Gregorová, Pavel Majer, Milan Souček, Martin Andreánsky, Milan Fábrys, Petr Štrop

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Truncation of a peptide substrate in the N-terminus and replacement of its scissile amide bond with a non-cleavable reduced bond results in a potent inhibitor of HIV-1 protease. A series of such inhibitors has been synthesized, and S2-S3′ subsites of the protease binding cleft mapped. The S2 pocket requires bulky Boc or PIV groups, large aromatic Phe residues are preferred in P1 and P′ and Glu in P2′. The S3′ pocket prefers Phe over small Ala or Val. Introduction of a Glu residue into the P2′ position yields a tight-binding inhibitor or HIV-1 protease, Boc-Phe-[CH2-NH]-Phe-Glu-Phe-OMe, with a subnanomolar inhibition constant. The relevant peptide derived from the same amino acid sequence binds to the protease with a Ki of 110 nM, thus still demonstrating a good fit of the amino acid residues into the protease binding pockets and also the importance of the flexibility of P1-P1′ linkage for proper binding. A new type of peptide bond mimetic, N-hydroxylamine CH2N(OH), has been synthesized. Binding of hydroxylamino inhibitor of HIV-1 protease is further improved with respect to reduced-bond inhibitor.

Original languageEnglish (US)
Pages (from-to)9-13
Number of pages5
JournalFEBS letters
Issue number1
StatePublished - Feb 17 1992
Externally publishedYes


  • Enzyme subsite specificity
  • HIV-1 protease
  • Inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology


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