Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor

Kailash Singh; Vijayalakshmi Senthil; Aloysius Wilfred Raj Arokiaraj; Jérôme Leprince; Benjamin Lefranc; David Vaudry; Ahmed A Allam; Jamaan Ajarem; Billy K C Chow

doi:10.1371/journal.pone.0149359

Structure-Activity Relationship Studies of N- and C-Terminally Modified Secretin Analogs for the Human Secretin Receptor

PLoS One. 2016 Mar 1;11(3):e0149359. doi: 10.1371/journal.pone.0149359. eCollection 2016.

Authors

Kailash Singh¹, Vijayalakshmi Senthil¹, Aloysius Wilfred Raj Arokiaraj¹, Jérôme Leprince², Benjamin Lefranc², David Vaudry², Ahmed A Allam^{3

4}, Jamaan Ajarem³, Billy K C Chow¹

Affiliations

¹ School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.
² Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Neurotrophic Factors and Neuronal Differentiation Team, Inserm U982, Associated International Laboratory Samuel de Champlain, Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN), University of Rouen, Mont-Saint-Aignan, France.
³ Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.

Abstract

The pleiotropic role of human secretin (hSCT) validates its potential use as a therapeutic agent. Nevertheless, the structure of secretin in complex with its receptor is necessary to develop a suitable therapeutic agent. Therefore, in an effort to design a three-dimensional virtual homology model and identify a peptide agonist and/or antagonist for the human secretin receptor (hSR), the significance of the primary sequence of secretin peptides in allosteric binding and activation was elucidated using virtual docking, FRET competitive binding and assessment of the cAMP response. Secretin analogs containing various N- or C-terminal modifications were prepared based on previous findings of the role of these domains in receptor binding and activation. These analogs exhibited very low or no binding affinity in a virtual model, and were found to neither exhibit in vitro binding nor agonistic or antagonistic properties. A parallel analysis of the analogs in the virtual model and in vitro studies revealed instability of these peptide analogs to bind and activate the receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Cyclic AMP / metabolism
Drug Discovery
Humans
Molecular Docking Simulation
Molecular Sequence Data
Peptides / chemistry*
Peptides / pharmacology*
Protein Binding
Receptors, G-Protein-Coupled / agonists
Receptors, G-Protein-Coupled / antagonists & inhibitors
Receptors, G-Protein-Coupled / metabolism*
Receptors, Gastrointestinal Hormone / agonists
Receptors, Gastrointestinal Hormone / antagonists & inhibitors
Receptors, Gastrointestinal Hormone / metabolism*
Secretin / analogs & derivatives*
Secretin / pharmacology*
Structure-Activity Relationship

Substances

Peptides
Receptors, G-Protein-Coupled
Receptors, Gastrointestinal Hormone
secretin receptor
Secretin
Cyclic AMP

Grants and funding

The present study was supported by the Hong Kong Government Research Grant Council grant, Collaborative Research Fund CRFHKU6/CRF/11G and Hong Kong University 764812M to B.K.C.C. & Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no RGP- VPP- 240.