Pharmacologic manipulation of nitric oxide signaling: targeting NOS dimerization and protein-protein interactions

Nitric oxide (NO) is an endogenously-produced small molecule that has critical roles in cellular signaling and a variety of physiological processes in many tissues, including the brain, the vasculature, and the immune system. In several medical disorders, NO has been implicated in disease pathology, in most cases due to persistent activation or overproduction of one of three NO synthase (NOS) isoforms. Although NOS inhibitors that are both potent and cell-permeable have been developed, none is currently used in the treatment of any disorder. One reason that NOS inhibitors fail to have therapeutic efficacy may be linked to their very low isoform-selectivity. An additional possibility is that NOS inhibitors, even if they exhibit isoform selectivity, might indiscriminately affect beneficial and pathological NO signaling pathways. In this review, we discuss emerging approaches in the development of isoform-specific NOS-directed therapeutics including dimerization inhibitors, novel L-arginine (L-Arg) binding site inhibitors, and dimer stabilization. Additionally, we suggest novel strategies for the future including targeting subcellular localization of NOS and protein-protein interactions with NOS effectors.