Synthetic Covalently Linked Dimeric Form of H2 Relaxin Retains Native RXFP1 Activity and Has Improved In Vitro Serum StabilityReportar como inadecuado




Synthetic Covalently Linked Dimeric Form of H2 Relaxin Retains Native RXFP1 Activity and Has Improved In Vitro Serum Stability - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BioMed Research International - Volume 2015 2015, Article ID 731852, 9 pages -

Research Article

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia

School of Chemistry, University of Melbourne, Parkville, VIC 3010, Australia

Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia

Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia

Received 9 September 2014; Accepted 11 October 2014

Academic Editor: Andrei Surguchov

Copyright © 2015 Vinojini B. Nair et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Human H2 relaxin is a two-chain peptide member of the insulin superfamily and possesses potent pleiotropic roles including regulation of connective tissue remodeling and systemic and renal vasodilation. These effects are mediated through interaction with its cognate G-protein-coupled receptor, RXFP1. H2 relaxin recently passed Phase III clinical trials for the treatment of congestive heart failure. However, its in vivo half-life is short due to its susceptibility to proteolytic degradation and renal clearance. To increase its residence time, a covalent dimer of H2 relaxin was designed and assembled through solid phase synthesis of the two chains, including a judiciously monoalkyne sited B-chain, followed by their combination through regioselective disulfide bond formation. Use of a bisazido PEG7 linker and “click” chemistry afforded a dimeric H2 relaxin with its active site structurally unhindered. The resulting peptide possessed a similar secondary structure to the native monomeric H2 relaxin and bound to and activated RXFP1 equally well. It had fewer propensities to activate RXFP2, the receptor for the related insulin-like peptide 3. In human serum, the dimer had a modestly increased half-life compared to the monomeric H2 relaxin suggesting that additional oligomerization may be a viable strategy for producing longer acting variants of H2 relaxin.





Autor: Vinojini B. Nair, Ross A. D. Bathgate, Frances Separovic, Chrishan S. Samuel, Mohammed Akhter Hossain, and John D. Wade

Fuente: https://www.hindawi.com/



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