The present application aims to discover multimeric HIV-1 integrase (IN) inhibitors or MINIs. HIV-1 IN multimerization presents an important therapeutic target as the ordered multimeric state is essential for virus replication. The principal objective of our studiesis to impair IN function by stabilizing rather than destabilizing interacting IN subunits to promote aberrant protein multimerization. Our initial proof-of-concept experiments have laid a strong foundation for the feasibility of our approach. We have demonstrated that a small molecule can inhibit IN catalytic activity in vitro by binding at the protein dimer interface, stabilizing the interacting subunits and promoting formation of higher-order oligomers. More recent studies with multifunctional quinoline compounds have demonstrated that these compounds potently target IN multimerization in infected cells. However, the application of quinoline compounds as investigational probes is limited due to the fact that they promote aberrant IN multimerization and inhibit the IN-LEDGF/p75 binding with similar potency. Therefore, new more selective compounds are needed to explore the roles of HIV-1 IN multimerization in the virus life cycle. Accordingly, we propose the following three aims: Aim 1 will rationally develop MINIs and elucidate their antiviral mechanism of action; Aim 2 will investigate IN resistance mutations that arise from treatment of HIV-1 in cell culture with MINIs and develop second generation inhibitors; Aim 3 will focus on discovery of new MINIs through high-throughput screening (HTS) of a library of 365,000 compounds and subsequent hit-to-lead optimization. The proposed studies will develop novel, powerful investigational probes (MINIs) to study HIV-1 molecular biology by selectively targeting IN multimerization. In addition, MINIs are expected to target previously unexploited sites on HIV-1 IN and potently inhibit HIV-1 phenotypes resistant to all currently used HAART. Thus, our studies will facilitate the development of clinically useful new types of allosteric IN inhibitors.

R01AI110310

2014-05-01

2020-04-30