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

FEBS Letters

Gregorová, Eva¹  Majer, Pavel¹  Konvalinka, Jan¹  Stehliková, Jana¹  Souček, Milan¹  Štrop, Petr¹  Fábrys, Milan²  Andreánsky, Martin²  Urban, Jan¹ 

[1] Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Flemingovo n. 2, CS 166 10 Praha 6, Czechoslovakia;Institute of Molecular Genetics, Czechoslovak Academy of Science, Flemingovo. n. 2, CS 166 37 Praha 6, Czechoslovakia

关键词: Inhibitor;    HIV-1 protease;    Enzyme subsite specificity;    DMSO;    dimethylsulfoxide;    Et;    total enzyme concentration;    K i;    inhibition constant;    dissociation constant of enzyme-inhibitor complex;    PR;    protease;    HIV;    human immunodeficiency virus;    Nle;    norleucine;    Nph;    p-nitro-phenylalanine;    Me;    methyl;    Ac;    acetyl;    Boc;    tert-butoxycarbonyl;    Z;    benzyloxycarbonyl protecting group;    PIV;    pivaloyl;    (t-butylcarbonyl);    [CH2–NH];    reduced peptide bond. The nomenclature system of Schechter and Berger [1];    i.e. P2-P1*P1′-P2′-P3′ is used to depict residues adjacent to the scissile (or reduced) bond situated between P1 and P1′ marked by an asterisk;   

DOI  :  10.1016/0014-5793(92)80010-E

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 K _i 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 -CH₂-N(OH)-, has been synthesized. Binding of hydroxylamino inhibitor of HIV-1 protease is further improved with respect to reduced-bond inhibitor.

【 授权许可】

Unknown