A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide. Issue 15 (1st August 2017)

• Record Type: Journal Article
• Authors: Nishizawa, Naoki; Nakamura, Goshi; Noguchi, Yoko; Nakagawa, Hideyuki; Shimizu, Ayako; Nakayama, Masaharu; Takekawa, Shiro; Asami, Taiji
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 15(2017)
• Page Start: 3542
• Page End: 3545
• Publication Date: 2017-08-01
• Subjects: ANP atrial natriuretic peptide -- Arg(Me) Nω-methylarginine -- cGMP cyclic guanosine monophosphate -- Cha 3-cyclohexylalanine -- GC guanylate cyclase -- hANP human ANP -- Hyp trans-4-hydroxyproline -- LC/MS/MS liquid chromatography–tandem mass spectrometry -- mANP mutant ANP -- NPR3 natriuretic peptide receptor-3 -- PBS phosphate buffered saline; Natriuretic peptide receptor-3 -- Blocker -- Peptide -- A-type natriuretic peptide (ANP) -- Musclin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.061
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha 8 ]-ANP(7-16)-NH2 (1 ), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9 ) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d -Phe 5, d -Hyp 7, Cha 8, d -Ser 9, Hyp 11, Arg(Me) 14 ]-ANP(5-15)-NHCH3 (23 ), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application.