Small Molecule HIV-1 Capsid Inhibitor Design using Hybrid Structure Based Methods

Abstract

Protein-protein interactions (PPI) are fundamental to almost all biological and pathological processes and therefore represent an important class of therapeutic targets that can be utilized against multi-drug resistant pathogens such as HIV-1. The HIV-1 capsid (CA) protein has recently emerged as an attractive target as it performs essential roles, both regulatory and structural in early and late stages of the viral life cycle. Hence, small-molecule inhibitors of capsid assembly would be attractive and novel antiretroviral medications. With the latest crystal structure of the hexameric arrangement of CA monomers, atomic level details of the CA hexamer interface are now available. The HIV-1 capsid shell is composed of ∼250 CA hexamers and 12 CA pentamers which are arranged in the form of a fullerene cone. Crystal structure analysis shows a weak association between the monomers and hence the interfaces formed between the N-terminal (NTD) and C-terminal domains (CTD) seem attractive as drug targets. In this study, we targeted the NTD-NTD interface region as a novel PPI to design inhibitors using the hybrid structure based method. Our preliminary results show that we have identified two compounds (CK026 and CK422) that display significant antiretroviral activity against HIV-1. Importantly, these compounds belong to two distinct inhibitory classes: early-stage inhibitors and late-stage inhibitors. Compound CK026 represents the first CA-targeted small molecule that works by disruption of pre-integration events in HIV-1 replication. Further chemical modification has led to identification of other analogs that retain the antiviral activity with improved drug like properties.