title: Reduced-bond tight-binding inhibitors of HIV-1 protease. Fine tuning of the enzyme subsite specificity.
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 P1' 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 of 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 -CH2-N(OH)-, has been synthesized. Binding of hydroxylamino inhibitor of HIV-1 protease is further improved with respect to reduced-bond inhibitor.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Praha.
authors.forename: J
authors.initials: J
authors.lastname: Urban
authors.forename: J
authors.initials: J
authors.lastname: Konvalinka
authors.forename: J
authors.initials: J
authors.lastname: Stehlíková
authors.forename: E
authors.initials: E
authors.lastname: Gregorová
authors.forename: P
authors.initials: P
authors.lastname: Majer
authors.forename: M
authors.initials: M
authors.lastname: Soucek
authors.forename: M
authors.initials: M
authors.lastname: Andreánsky
authors.forename: M
authors.initials: M
authors.lastname: Fábry
authors.forename: P
authors.initials: P
authors.lastname: Strop
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000187:drug effects; D017320:HIV Protease Inhibitors; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D017320:HIV Protease Inhibitors; D010455:Peptides; D011480:Protease Inhibitors