Lessons Learned: HIV Points the Way Towards Precision Treatment of Mixed-Lineage Leukemia

Protein–protein interactions are involved in most if not all pathogenic and pathophysiological processes and represent attractive therapeutic targets. Extensive biological and clinical research efforts have led to the identification and validation of several cellular hubs that are crucially involved in disease pathogenesis. An interesting example of such a hub is the lens epithelium-derived growth factor (LEDGF/p75), a protein that tethers multiple unrelated proteins and protein complexes to the chromatin. Its chromatin-tethering ability is linked to at least two unrelated diseases–HIV infection and MLL-rearranged acute leukemia. In this review we discuss recent progress in our understanding of the interaction of LEDGF/p75 with its binding partners and focus on the first steps towards therapies targeting protein–protein interactions of LEDGF/p75.

TrendsProtein–protein interactions provide an unmined supply of new therapeutic targets.LEDGF/p75–MLL–MENIN and LEDGF/p75–HIV IN interaction inhibitors are excellent examples of protein–protein interactions inhibitors resulting from a drug discovery process ranging from target validation through structural characterization to the development of small-molecule lead inhibitors.Both HIV and MLL research lines emphasize the role of academic drug discovery.MLL treatment increasingly focuses on the development of precision therapies. Because the LEDGF/p75–MLL–MENIN interaction is most probably present in all fusions, it is receiving increasing attention.LEDGINs have a dual effect on HIV replication (early and late steps of replication) and do not show cross-resistance to the current clinical integrase catalytic inhibitors, making them a promising new class of HIV inhibitors.