In:
International Journal of Peptide and Protein Research, Wiley, Vol. 40, No. 3-4 ( 1992-09), p. 274-281
Abstract:
This report details the structure‐activity relationships of the HIV gag substrate analog Val‐Ser‐Gln‐Asn‐Leu Ψ [CH(OH)CH 2 ]Val‐Ile‐Val (U‐85548E), an inhibitor exhibiting subnanomolar affinity towards HIV type‐1 aspartic proteinase (HIV‐1 PR). Our data show that the P 1 ‐P′ 2 tripeptidyl sequence provides the minimal chemical determinant for HIV‐1 PR binding. We describe the structure‐activity properties of Leui Ψ [CH(OH)CH2]Val substitution in other peptidyl ligands of nonviral substrate origin (e.g., angiotensinogen, insulin and pepstatin). Furthermore, the aspartic proteinase selectivities of a few key compounds are summarized relative to evaluation against human renin, human pepsin, and the fungal enzyme, rhizopuspepsin. These studies have led to the rational design of nanomolar potent inhibitors of both HIV‐1 and HIV‐2 PR. Finally, a 2.5 Å resolution X‐ray crystallographic structure of U–85548E complexed to synthetic HIV‐1 PR dimer (Jaskolski etal, Biochemistry 30, 1600 [1991]) provided a 3‐D picture of the inhibitor bound to the enzyme active site, and we performed computer‐assisted molecular modeling studies to explore the possible binding modes of the above series of Leu Ψ [CH(OH)CH2]Val substituted HIV‐1 PR inhibitors.
Type of Medium:
Online Resource
ISSN:
0367-8377
DOI:
10.1111/jpp.1992.40.issue-3-4
DOI:
10.1111/j.1399-3011.1992.tb00302.x
Language:
English
Publisher:
Wiley
Publication Date:
1992
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