Advances in targeting nucleocapsid-nucleic acid interactions in HIV-1 therapy

•The nucleocapsid protein is required for the HIV life cycle.•The nucleocapsid protein is conserved among all viral clades.•Functional disruption of nucleocapsid may be an effective antiviral strategy.•The biology and requirements for nucleocapsid in the HIV life cycle are discussed.•Small molecule targeting strategies to disrupt nucleocapsid function are highlighted.

The continuing challenge of HIV-1 treatment resistance in patients creates a need for the development of new antiretroviral inhibitors. The HIV nucleocapsid (NC) protein is a potential therapeutic target. NC is necessary for viral RNA packaging and in the early stages of viral infection. The high level of NC amino acid conservation among all HIV-1 clades suggests a low tolerance for mutations. Thus, NC mutations that could arise during inhibitor treatment to provide resistance may render the virus less fit. Disruption of NC function provides a unique opportunity to strongly dampen replication at multiple points during the viral life cycle with a single inhibitor. Although NC exhibits desirable features for a potential antiviral target, the structural flexibility, size, and the presence of two zinc fingers makes small molecule targeting of NC a challenging task. In this review, we discuss the recent advances in strategies to develop inhibitors of NC function and present a perspective on potential novel approaches that may help to overcome some of the current challenges in the field.