Targeting Human Immunodeficiency Virus Integrase Beyond the Active Site: The Discovery and Development of Allosteric Integrase Inhibitors

Abstract

Given its pivotal role in the viral life cycle, blocking integrase (IN) through IN strand transfer inhibitors (INSTIs) represented a breakthrough in the treatment of HIV infection, establishing these antiretroviral regimens as first‐line options against AIDS. However, the onset of drug‐resistant strains has challenged the efficacy of INSTIs, demanding new efforts in the search for therapeutic tools that work through alternative modes of action. In this context, the discovery of allosteric IN inhibitors (ALLINIs) has highlighted new opportunities to target IN beyond its active site, enhancing antiviral efficacy and the genetic barrier to resistance. Extensive drug discovery campaigns have resulted in the development of effective ALLINIs with both in vitro and in vivo efficacy, two of which are advancing in clinical trials as next‐generation therapeutic tools. Nevertheless, advancements in structural biology have critically aided in elucidating the underlying effects of ALLINIs, highlighting a complex, multimodal mode of action that ultimately yields defects in virion maturation. This review focuses on ALLINIs, providing a comprehensive overview of major drug discovery efforts devoted to this field, with an emphasis on the medicinal chemistry and structural biology findings that have revealed unprecedented opportunities for developing innovative and effective anti‐HIV drugs.