Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679

S J deSolms; E A Giuliani; J P Guare; J P Vacca; W M Sanders; S L Graham; J M Wiggins; P L Darke; I S Sigal; J A Zugay

doi:10.1021/jm00113a025

Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679

J Med Chem. 1991 Sep;34(9):2852-7. doi: 10.1021/jm00113a025.

Authors

S J deSolms¹, E A Giuliani, J P Guare, J P Vacca, W M Sanders, S L Graham, J M Wiggins, P L Darke, I S Sigal, J A Zugay, et al.

Affiliation

¹ Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.

PMID: 1910089
DOI: 10.1021/jm00113a025

Abstract

A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.

MeSH terms

Antiviral Agents* / chemical synthesis
Drug Design
Gene Products, gag / analysis
HIV Antigens / analysis
HIV Core Protein p24
HIV Protease Inhibitors*
HIV-1 / drug effects
HIV-1 / enzymology
HIV-1 / isolation & purification
HIV-1 / physiology
Humans
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Protein Precursors / analysis
T-Lymphocytes / microbiology
Viral Core Proteins / analysis
Viral Proteins*
Virus Replication / drug effects
gag Gene Products, Human Immunodeficiency Virus

Substances

Antiviral Agents
Gene Products, gag
HIV Antigens
HIV Core Protein p24
HIV Protease Inhibitors
Oligopeptides
Protein Precursors
Viral Core Proteins
Viral Proteins
gag Gene Products, Human Immunodeficiency Virus
p17 protein, Human Immunodeficiency Virus Type 1
p55 gag precursor protein, Human immunodeficiency virus 1
L 682679