{"doi":"10.1093/pnasnexus/pgae225","title":"Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators","abstract":"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.","journal":"PNAS Nexus","year":2024,"id":478825,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":258564,"name":"Satyamaheshwar Peddibhotla","orcid":"0000-0001-5381-0507","position":1,"is_corresponding":false},{"id":1317526,"name":"Ye Zheng","orcid":"0000-0003-4587-8100","position":2,"is_corresponding":false},{"id":1317838,"name":"Shuchong Pan","orcid":null,"position":3,"is_corresponding":false},{"id":1129454,"name":"Alka Mehta","orcid":"0000-0002-4417-8041","position":4,"is_corresponding":false},{"id":1317527,"name":"Dante Moroni","orcid":"0000-0002-0963-0346","position":5,"is_corresponding":false},{"id":523148,"name":"Qi-Yin Chen","orcid":null,"position":6,"is_corresponding":false},{"id":992444,"name":"Xiaoyu Ma","orcid":"0000-0002-9347-3565","position":7,"is_corresponding":false},{"id":290758,"name":"John C. Burnett","orcid":"0000-0002-3414-1659","position":8,"is_corresponding":false},{"id":424905,"name":"Siobhan Malany","orcid":"0000-0003-0710-7460","position":9,"is_corresponding":false},{"id":413596,"name":"S. Jeson Sangaralingham","orcid":"0000-0002-3967-8703","position":10,"is_corresponding":false},{"id":672837,"name":"Xiao Ma","orcid":"0000-0001-9940-8468","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:06:46.330532Z","pmid":"38894878","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}