Natriuretic Peptide Receptor A (NPRA) is a receptor widely distributed in the human kidney, vasculature and myocardium. The peptide hormone atrial natriuretic peptide (ANP, 28 AA) and B-type natriuretic peptide (BNP, 32 AA), secreted from heart, and their homolog urodilatin, secreted from vasculature and kidney, all activate NPRA to stimulate the production of cGMP. Their biologic effects range from acute vessel dilation, diuresis and natriuresis to long lasting effects of anti-proliferation, tissue remodeling, and energy metabolism. Recombinant ANP (Carperitide) and BNP (Nesiritide) have been used as treatments for acute decompensated heart failure. However, the very short half-lives of these peptide hormones (2 to 20 min), is part of the difficulties in studying the impact of sustained activation of NPRA over long period in clinical settings. Thus small molecule NPRA agonists that can offer sustained activation are of high interest. On the other hand, using small molecule to fill the large ANP (28 AA) binding pocket posed a significant challenge on discovering small molecule NPRA agonist.<br/><br/>Here we report our small molecule NPRA agonists that bind to the receptor in a unique way with two ligands per receptor dimer. The two ligands form a dimer and occupy the large binding receptor pocket, and the binding induces changes in receptor conformation and results in receptor activation. The challenges and strategies on the discovery and optimization of this unique approach will be discussed. Both in vitro and in vivo, this class of NPRA activator behaves like ANP or BNP. The discovery of small molecule NPRA agonists opens the possibility of sustained NPRA activation and offers therapeutic value that is not possible with the peptide ligands ANP and BNP.<br/><br/>

Small molecule homo dimers mimic large peptide hormone and activate natriuretic peptide receptor A (NPRA) for the potential treatment of heart failure

2019 Fall National Meeting

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