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 Andreansky, Milan Fábrys, Petr Štrop

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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
Pages (from-to)9-13
Number of pages5
JournalFEBS Letters
Volume298
Issue number1
DOIs
StatePublished - Feb 17 1992
Externally publishedYes

Fingerprint

Peptide Hydrolases
Tuning
Peptides
Enzymes
Amino Acids
Hydroxylamine
Amides
Amino Acid Sequence
Substrates
Human immunodeficiency virus 1 p16 protease
phenylalanylphenylalanine methyl ester

Keywords

  • Enzyme subsite specificity
  • HIV-1 protease
  • Inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Urban, J., Konvalinka, J., Stehliková, J., Gregorová, E., Majer, P., Souček, M., ... Štrop, P. (1992). Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity. FEBS Letters, 298(1), 9-13. https://doi.org/10.1016/0014-5793(92)80010-E

Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity. / Urban, Jan; Konvalinka, Jan; Stehliková, Jana; Gregorová, Eva; Majer, Pavel; Souček, Milan; Andreansky, Martin; Fábrys, Milan; Štrop, Petr.

In: FEBS Letters, Vol. 298, No. 1, 17.02.1992, p. 9-13.

Research output: Contribution to journalArticle

Urban, J, Konvalinka, J, Stehliková, J, Gregorová, E, Majer, P, Souček, M, Andreansky, M, Fábrys, M & Štrop, P 1992, 'Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity', FEBS Letters, vol. 298, no. 1, pp. 9-13. https://doi.org/10.1016/0014-5793(92)80010-E
Urban J, Konvalinka J, Stehliková J, Gregorová E, Majer P, Souček M et al. Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity. FEBS Letters. 1992 Feb 17;298(1):9-13. https://doi.org/10.1016/0014-5793(92)80010-E
Urban, Jan ; Konvalinka, Jan ; Stehliková, Jana ; Gregorová, Eva ; Majer, Pavel ; Souček, Milan ; Andreansky, Martin ; Fábrys, Milan ; Štrop, Petr. / Reduced-bond tight-binding inhibitors of HIV-1 protease Fine tuning of the enzyme subsite specificity. In: FEBS Letters. 1992 ; Vol. 298, No. 1. pp. 9-13.
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