In search of small molecules blocking interactions between HIV proteins and intracellular cofactors

One of the major obstacles to pursue the discovery of small molecule inhibitors targeting protein-protein interactions is the. at nature of their interface. X-Ray structures have indeed shown that a large part of the interaction area is buried with atoms closely packed together, implying a lack of available cavities for small molecule binding. Yet, it has become clear that some protein-protein interfaces have a well-defined compact area, commonly referred to as a hot spot, that plays a major role in the affinity of the interaction. These hot spots de. ne potential targets for the development of small molecule protein-protein interaction inhibitors ( SMPPIIs). In this review we discuss the interactions between viral and host proteins that have the potential for the future development of SMPPIIs. In light of the current anti-HIV therapy a short overview of protein-protein interactions that may serve as targets for novel drugs is provided. Our hypothesis will exemplify and discuss the interaction between HIV-1 integrase and its cellular cofactor LEDGF/p75, which, as evidenced by crystallography and site directed mutagenesis, displays favourable properties needed for the development of interaction inhibitors.