HIV-1 Integrase Drug Discovery Comes of Age

Abstract

Insertion of the viral genome into host cell chromatin is a pivotal step in the replication cycle of the human immunodeficiency virus and other retroviruses. Blocking the viral integrase enzyme that catalyzes this reaction therefore provides an attractive therapeutic strategy. Nevertheless, many years lie between the initial discovery of integrase and the clinical approval of the first integrase strand transfer inhibitor, raltegravir, in 2007. Recently, elvitegravir was second to make it into the clinic, while dolutegravir, a second-generation integrase inhibitor, is close to receiving the green light as well. Viral resistance and cross-resistance among these strand transfer inhibitors however warrant the search for compounds targeting HIV integration through different mechanisms of action. The most advanced class of allosteric integrase inhibitors, coined LEDGINs or non-catalytic integrase inhibitors (NCINIs), has shown remarkable antiviral activity that extends beyond the viral integration step. Time will tell however if they will stand the test of clinical development. Notably, the development of LEDGINs and other integrase inhibitors is aided by recent structural and mechanistic insights into the retroviral integration apparatus. Here we provide an overview of the development of integrase strand transfer and allosteric inhibitors while exploring their mechanisms of action and patterns of viral resistance.