A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase

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The administration of highly active-antiretroviral therapy (HAART) has changed what was once a terminal disease into a manageable chronic infection. The success of HAART is manifested by reduced mortality and morbidity of HIV-1 infected patients. However, evolution of HIV-1 strains resistant to current therapies is a major clinical problem in the fight against AIDS. Therefore, new inhibitors with novel mechanisms of action are needed. One such mechanism is to target multimerization of HIV-1 integrase. In the present study, we report the design of pyridine-based small molecules that contain a rotatable single bond to allow optimal bridging between interacting integrase subunits. As a result, pyridine-based compounds stabilized interacting IN subunits and promoted aberrant, higher order integrase multimerization. The most potent compound, KF116, potently inhibited HIV-1 replication by interfering with proper maturation of HIV-1 particles, whereas KF116 at therapeutically relevant (submicromolar) concentrations had no detectable effects on LEDGF/p75 mediated HIV-1 integration. Our findings highlight HIV-1 integrase multimerization as a plausible therapeutic target and offer a path for designing improved inhibitors for potential clinical use.

Vyšlo v časopise: A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004171
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004171

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