A computational study of the resistance of HIV-1 aspartic protease to the inhibitors ABT-538 and VX-478 and design of new analogues.
PMID: 9464253
1998
Biochemical and biophysical research communications
Abstract: Reasons for the decrease in binding affinities with the two critical mutants (V82T/I84V and 4X) have also been elucidated in detail.
Abstract: Recent experimental findings with HIV-1 protease (HIV-1 PR) mutants containing variations at four residues, M46I, L63P, V82T and I84V, have shown that only mutants containing the latter two exhibit cross resistance to the inhibitors ABT-538 and VX-478.
Abstract: The V82T and I84V modifications in fact concern residues in the active site while the other two are in the flap (M46I) and hinge (L63P) domains of the enzyme.
In vitro selection and characterization of VX-478 resistant HIV-1 variants.
PMID: 9561202
1998
Advances in experimental medicine and biology
Abstract: By direct PCR analysis of selected viruses, a number of mutations were identified (L10F, M46I, I47V, I50V and I84V) in the protease gene.
Resistance to HIV protease inhibitors: a comparison of enzyme inhibition and antiviral potency.
Abstract: Four of the five mutations studied (V82F, V82A, I84V, and V82F/I84V) had been identified as conferring resistance during in vitro selection using a protease inhibitor.
Abstract: Much larger changes compared to wild type were observed for the double mutation V82F/I84V both for Ki (10-2000-fold) and for IC90 (0.7-377-fold).
Abstract: The single mutations V82F and I84V caused changes with various inhibitors ranging from 0.3- to 86-fold in Ki and from 0.1- to 11-fold in IC90.
Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues.
Abstract: However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses.
In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor.
Abstract: Selection of viral variants with increasing concentrations of ABT-378 revealed a sequential appearance of mutations in the protease gene: I84V-L10F-M46I-T91S-V32I-I47V.
Drug-resistant HIV-1 proteases identify enzyme residues important for substrate selection and catalytic rate.
Abstract: Mutants containing R8K, V32I, V82T, I84V, G48V/L90M, or V82T/I84V substitutions were analyzed for differences in substrate preference and catalytic efficiency using a set of single amino acid substituted HIV-1 CA-NCa cleavage site peptides.
Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities.
Abstract: We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P.
Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors.
Abstract: The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation.
An Escherichia coli expression assay and screen for human immunodeficiency virus protease variants with decreased susceptibility to indinavir.
PMID: 9835523
1998
Antimicrobial agents and chemotherapy
Abstract: The highly sensitive system detects the contributions of single substitutions such as I84V, L90M, and L63P.
Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors.
Abstract: Active-site mutations V32I and I84V/A were consistently observed in the protease of highly resistant viruses, along with up to six other mutations.
Abstract: Despite these observations, however, most mutations had little effect on viral replication except when the active-site mutations V32I and I84V/A were coexpressed in the protease.
Abstract: Furthermore, the double nucleotide mutation I84A rapidly reverted to I84V upon drug removal, confirming its impact on viral fitness.
HIV mutation literature information.
PMID: 
1998
Biochemical and biophysical research communications
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