Design and development of novel non-peptide agonists at NPR-C
© Quinteiro et al; licensee BioMed Central Ltd. 2011
Published: 1 August 2011
Endothelium-derived C-type natriuretic peptide (CNP) possesses cytoprotective and anti-atherogenic functions that regulate vascular tone and smooth-muscle relaxation and might be key in protecting against ischaemia-reperfusion injury . The finding that many of the vasoprotective effects of CNP are mediated by the natriuretic peptide receptor type-C (NPR-C) suggests that this receptor might represent a novel therapeutic target for the treatment of cardiovascular diseases. Thus, we have designed and developed small molecule drug-like mimetics of CNP agonists at NPRC.
Methods and results
We employ a multi-disciplinary approach that comprises molecular modelling, chemical synthesis and biological and functional assays. The crystal structure of NPR-C was used as the starting point for the design of peptidic and subsequently non-peptidic ligands to the receptor . We have determined which fragments of CNP are crucial for binding to NPR-C and modified the NPR-C antagonist AP-811 using pharmacophore searches to replace the peptide component, which led to the design of a library of compounds that were subsequently synthesised, tested and optimised .
Novel and selective non-peptide NPR-C agonists have been identified that relax rat isolated mesenteric arteries in vitro. We foresee that such molecules will facilitate the development of potential therapeutic agents for cardiovascular diseases.
- Ahluwalia A, Hobbs AJ: Endothelium-derived C-type natriuretic peptide: more than just a hyperpolarizing factor. Trends Pharmacol Sci. 2005, 26: 162-167. 10.1016/j.tips.2005.01.005.View ArticlePubMedGoogle Scholar
- He XL, Chow DC, Martick MM, Garcia KC: Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone. Science. 2001, 293: 1657-1662. 10.1126/science.1062246.View ArticleGoogle Scholar
- Veale CA, Alford VC, Aharony D, Banville DL, Bialecki RA, Brown FJ, Damewood JR, Dantzman CL, Edwards PD, Jacobs RT, Mauger RC, Murphy MM, Palmer WE, Pine KK, Rumsey WL, Garcia-Davenport LE, Shaw A, Steelman GB, Surian JM, Vacek EP: The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. Bioorg Med Chem Lett. 2000, 10: 1949-1952. 10.1016/S0960-894X(00)00387-5. Part 1View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.