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Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors.

ABSTRACT: Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

SUBMITTER: Dinh LP

PROVIDER: S-EPMC9324412 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors.

Dinh Long Phi LP Sun Jian J Glenn Courtney D CD Patel Krunal K Pigza Julie A JA Donahue Matthew G MG Yet Larry L Kessl Jacques J JJ

Viruses 20220702 7

Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found th ...[more]

PMID: 35891446

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