NCp7: targeting a multitasking protein for next-generation anti-HIV drug development part 1: covalent inhibitors

The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad-spectrum agents that are less prone to select for resistant strains. Here, we provide a comprehensive overview of the covalent NCp7 inhibitors that have emerged over the past 25 years of drug discovery campaigns, emphasising, where possible, their structure–activity relationships (SARs) and pharmacophoric features. Twenty years of drug discovery campaigns devoted to the identification of NCp7 covalent inhibitors are herein exhaustively reviewed from a medicinal chemistry perspective.