Multimerization of HIV-1 integrase hinges on conserved SH3-docking platforms

Abstract

New anti-AIDS treatments must be continually developed in order to overcome resistance mutations including those emerging in the newest therapeutic target, the viral integrase (IN). Multimerization of IN is functionally imperative and provides a forthcoming therapeutic target. Allosteric inhibitors of IN bind to non-catalytic sites and prevent correct multimerization not only restricting viral integration but also the assembly and maturation of viral particles. Here, we report an allosteric inhibitor peptide targeting an unexploited SH3-docking platform of retroviral IN. The crystal structure of the peptide in complex with the HIV-1 IN core domain reveals a steric interference that would inhibit conserved docking of SH3-containing domain with the core domain vital for IN multimerization, providing a template for the development of novel anti-IN allosteric inhibitors.