The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function
Matthew R. Singer, Tung Dinh, Lev Levintov, Arun S. Annamalai, Juan S. Rey, Lorenzo Briganti, Nicola Cook, Valerie E. Pye, Ian A. Taylor, Kyungjin Kim, Alan Engelman, Baek Kim, Juan R. Perilla, Mamuka Kvaratskhelia, Peter Cherepanov
Abstract
Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens.