N-Methylated sst2 Selective Somatostatin Cyclic Peptide Analogue as a Potent Candidate for Treating Neurogenic Inflammation

Jayanta Chatterjee; Burkhardt Laufer; Johannes G Beck; Zsuzsanna Helyes; Erika Pintér; János Szolcsányi; Aniko Horvath; Jozsef Mandl; Jean C Reubi; György Kéri; Horst Kessler

doi:10.1021/ml200032v

N-Methylated sst2 Selective Somatostatin Cyclic Peptide Analogue as a Potent Candidate for Treating Neurogenic Inflammation

ACS Med Chem Lett. 2011 Apr 4;2(7):509-14. doi: 10.1021/ml200032v. eCollection 2011 Jul 14.

Affiliations

¹ Institute for Advanced Study and Center for Integrated Protein Science at the Department Chemie, Technische Universität München , Lichtenbergstrasse 4, Garching 85747, Germany.
² Department of Pharmacology and Pharmacotherapy, University of Pécs , H-7624, Hungary.
³ Pathobiochemistry Research Group of Hungarian Academy of Sciences in Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University , Budapest, H-1094, Hungary.
⁴ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern , Bern, CH-3010 Switzerland.

Abstract

A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and on acute neurogenic inflammatory response in vivo. The analogue shows selectivity toward somatostatin receptor subtype 2 (sst2). Extensive 2D NMR spectroscopy and molecular dynamics simulation revealed the solution conformation of the analogue, which can be adopted as a lead for the further structure-activity relationship studies targeting neurogenic inflammation.

Keywords: N-methylated peptide; Somatostatin; cyclic peptide; multiple N-methylation; neurogenic inflammation; sst.