HIV-Integrase (IN) is an important enzyme that is responsible for integrating the viral genome into a host cell’s DNA. Although several drugs, including Raltegravir and Dolutegravir, have been developed and approved to target the active site of IN, mutations of the enzyme’s active site have necessitated the continued discovery and design of novel antiviral agents. A complementary approach to targeting the active site involves interaction with an IN allosteric binding site which is utilized by the endogenous cofactor LEDGF/p75, a host cell protein that promotes integrase activity. The binding of small molecule drugs to this allosteric site at the IN catalytic core domain (CCD) dimer interface results in the inactivation of integrase enzymes due to the formation of aberrant multimers in the late-stage formation of newly formed viral capsules. This hyper-multimerization occurs because of interactions between the C-terminal domain (CTD) subunit of another integrase protein with the CCD dimer interface. The goal of these studies has been to explore key binding motifs necessary for integrase inhibition and overcoming known integrase drug resistance through binding to the LEDGF/p75 site. To this end, we have synthesized novel inhibitors based on the well-studied quinoline core scaffold and also extended these studies with similarly functionalized indoles. The quinoline analogs were developed to validate computational models suggesting that key interactions could be captured between both the ligand and CCD and ligand and CTD subunits. The indole scaffold was chosen due to its facile synthesis, ease of functionalization, and native binding geometry within the allosteric binding pocket that orients the compound away from known mutation-prone amino acids.

Synthesis and functionalization of allosteric integrase inhibitors that promote HIV-1 integrase inhibition through aberrant multimerization

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