The drug-induced interface that drives HIV-1 integrase hypermultimerization and loss of function

DOI: 10.1128/mbio.03560-22

Authors: Matthew Singer (The Francis Crick Institute (Midland Road)) , Tung Dinh (University of Colorado) , Lev Levintov (University of Delaware) , Arun S. Annamalai (University of Colorado) , Juan S. Rey (University of Delaware) , Lorenzo Briganti (University of Colorado) , Nicola J. Cook (The Francis Crick Institute) , Valerie E. Pye (The Francis Crick Institute (Midland Road)) , Ian A. Taylor (The Francis Crick Institute) , Kyungjin Kim (ST Pharm Co. Ltd) , Alan N. Engelman (Dana-Farber Cancer Institute; Harvard Medical School) , Baek Kim (Children’s Healthcare of Atlanta; Emory University) , Juan R. Perilla (University of Delaware) , Mamuka Kvaratskhelia (University of Colorado) , Peter Cherepanov (The Francis Crick Institute; Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 13775

Abstract: Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 08/02/2023 10:21

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)