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Design and development of novel non-peptide agonists at NPR-C
BMC Pharmacology volume 11, Article number: P54 (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.
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Quinteiro, F.M., Gane, P., Rebstock, A. et al. Design and development of novel non-peptide agonists at NPR-C. BMC Pharmacol 11, P54 (2011). https://doi.org/10.1186/1471-2210-11-S1-P54
- Molecular Modelling
- Mesenteric Artery
- Chemical Synthesis
- Vascular Tone