New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine.

摘要

During the last thirty years since the discovery of endothelin-1,the therapeutic strategy that has evolved in the clinic, mainly inthe treatment of pulmonary arterial hypertension, is to block theaction of the peptide either at the ETA subtype or both receptorsusing orally active small molecule antagonists. Recently, therehas been a rapid expansion in research targeting ET receptorsusing chemical entities other than small molecules, particularlymonoclonal antibody antagonists and selective peptide agonistsand antagonists. While usually sacrificing oral bio-availability,these compounds have other therapeutic advantages with thepotential to considerably expand drug targets in the endothelinpathway and extend treatment to other pathophysiologicalconditions. Where the small molecule approach has beenretained, a novel strategy to combine two vasoconstrictortargets, the angiotensin AT1 receptor as well as the ETA receptorin the dual antagonist sparsentan has been developed.A second emerging strategy is to combine drugs that have twodifferent targets, the ETA antagonist ambrisentan with thephosphodiesterase inhibitor tadalafil, to improve the treatment ofpulmonary arterial hypertension. The solving of the crystalstructure of the ETB receptor has the potential to identifyallosteric binding sites for novel ligands. A further key advance isthe experimental validation of a single nucleotide polymorphismthat has genome wide significance in five vascular diseases andthat significantly increases the amount of big endothelin-1precursor in the plasma. This observation provides a rationale fortesting this single nucleotide polymorphism to stratify patients forallocation to treatment with endothelin agents and highlights thepotential to use personalized precision medicine in the endothelinfield.