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Mutational analysis of HIV protease residues interacting with the inhibitor L-735,524.


Natl Conf Hum Retroviruses Relat Infect (1st). 1993 Dec 12-16;:129.

The aspartyl protease of HIV-1 catalyzes the cleavage of the viral polyprotein, is essential for viral infectivity and is, therefore, an attractive target for antiviral intervention. L-735,524 is a potent and selective competitive inhibitor of the enzyme and is currently undergoing clinical evaluation. However, the long-term efficacy of antiviral therapies is often compromised by the emergence of resistant viral variants. In an effort to assess the potential for clinical resistance to L-735,525, we have attempted to derive resistant mutant enzymes and virus in vitro. Guided by molecular modeling, amino acid substitutions were introduced at specific residues within the protease's active site. Several mutant enzymes resistant to the inhibitor were identified. However, introduction of the responsible mutations into proviral clones yielded virus variants that were fully susceptible to L-735,524. Attempts at direct cell culture selection for resistant variants have also been unsuccessful. Hence, mutations conferring resistance to this inhibitor do not appear readily in vitro.

Antiviral Agents/*PHARMACOLOGY Cells, Cultured Chromatography, High Pressure Liquid Enzyme-Linked Immunosorbent Assay HIV Protease Inhibitors/CHEMISTRY/*PHARMACOLOGY HIV-1/DRUG EFFECTS/METABOLISM Kinetics Solubility Structure-Activity Relationship Water ABSTRACT


Information in this article was accurate in December 30, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.