A novel constrained reduced-amide inhibitor of HIV-1 protease derived from the sequential incorporation of gamma-turn mimetics into a model substrate.
J Med Chem
; 36(16): 2321-31, 1993 Aug 06.
Article
em En
| MEDLINE
| ID: mdl-8360876
ABSTRACT
C7 mimetics, designed to lock three amino acid residues of a peptide chain into a gamma-turn conformation, were introduced sequentially between the P3 to P2' positions of a model HIV-1 protease substrate I (resulting in compounds II-IV) to probe its conformational requirements in binding to HIV-1 protease. Of these, compound IIIa with the C7 mimetic replacing Asn-Tyr-Pro, corresponding to the P2 through P1' positions of substrate, was found to be an inhibitor with a Ki of 147 microM. Reduction of the amide bond in the C7 mimetic of IIIa resulted in a novel constrained reduced-amide mimetic VIa with a Ki of 430 nM. This corresponds to over a 300-fold improvement in inhibitory activity over the original C7 mimetic. The inhibitory activity of mimetic VIa was in addition found to be 44-fold better than a similar linear reduced-amide containing inhibitor V. The synthesis of these mimetics are described.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simpatomiméticos
/
Inibidores da Protease de HIV
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
1993
Tipo de documento:
Article