Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators

• Published in: PNAS nexus Vol. 3; no. 6; p. pgae225
• Main Authors: Ma, Xiao, Peddibhotla, Satyamaheshwar, Zheng, Ye, Pan, Shuchong, Mehta, Alka, Moroni, Dante G, Chen, Qi-Yin, Ma, Xiaoyu, Burnett, Jr, John C, Malany, Siobhan, Sangaralingham, S Jeson
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-06-2024
• Subjects: Allosteric proteins; B cells; Biological, Health, and Medical Sciences; Collagen; Guanylate cyclase; Health aspects; Homeopathy; Identification and classification; Materia medica and therapeutics; Mortality; Natriuretic peptides; Properties; Therapeutics; United States; guanylyl cyclase B receptor; cGMP; small molecule
• ISSN: 2752-6542; 2752-6542
• DOI: 10.1093/pnasnexus/pgae225

Myocardial fibrosis is a pathological hallmark of cardiovascular disease (CVD), and excessive fibrosis can lead to new-onset heart failure and increased mortality. Currently, pharmacological therapies for myocardial fibrosis are limited, highlighting the need for novel therapeutic approaches. The particulate guanylyl cyclase B (GC-B) receptor possesses beneficial antifibrotic actions through the binding of its natural ligand C-type natriuretic peptide (CNP) and the generation of the intracellular second messenger, cyclic guanosine 3',5'-monophosphate (cGMP). These actions include the suppression of fibroblast proliferation and reduction in collagen synthesis. With its abundant expression on fibroblasts, the GC-B receptor has emerged as a key molecular target for innovative CVD therapeutics. However, small molecules that can bind and potentiate the GC-B/cGMP pathway have yet to be discovered. From a cell-based high-throughput screening initiative of the NIH Molecular Libraries Small Molecule Repository and hit-to-lead evolution based on a series of structure-activity relationships, we report the successful discovery of MCUF-42, a GC-B-targeted small molecule that acts as a positive allosteric modulator (PAM). Studies herein support MCUF-42's ability to enhance the binding affinity between GC-B and CNP. Moreover, MCUF-42 potentiated cGMP levels induced by CNP in human cardiac fibroblasts (HCFs) and notably also enhanced the inhibitory effect of CNP on HCF proliferation. Together, our findings highlight that MCUF-42 is a small molecule that can modulate the GC-B/cGMP signaling pathway, potentially enhancing the antifibrotic actions of CNP. Thus, these data underscore the continued development of GC-B small molecule PAMs as a novel therapeutic strategy for targeting cardiac fibrosis and CVD.