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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

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

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.

Erratum in: PLoS One. 2016 Oct 26;11(10):e0165770. doi: 10.1371/journal.pone.0165770. (PMID: 27783654)

Nature. 2008 Jul 24;454(7203):486-91. (PMID: 18594507)
Nature. 2008 Jul 10;454(7201):183-7. (PMID: 18563085)
Biochem Pharmacol. 2009 Jul 1;78(1):11-20. (PMID: 19447219)
Nature. 2009 May 21;459(7245):356-63. (PMID: 19458711)
Trends Biochem Sci. 2009 Jun;34(6):303-10. (PMID: 19446460)
Adv Physiol Educ. 2009 Sep;33(3):165-8. (PMID: 19745041)
Trends Biochem Sci. 2009 Nov;34(11):540-52. (PMID: 19836958)
J Biol Chem. 2010 Jan 1;285(1):723-30. (PMID: 19861722)
Bioinformatics. 2010 Dec 15;26(24):3067-74. (PMID: 20947525)
Neuropsychopharmacology. 2011 Jan;36(2):459-71. (PMID: 20927047)
Kidney Int. 2011 Feb;79(3):280-7. (PMID: 20944548)
Biochim Biophys Acta. 2011 May;1814(5):724-30. (PMID: 21439408)
PLoS One. 2011;6(5):e19682. (PMID: 21625560)
J Med Chem. 2011 Jul 14;54(13):4283-311. (PMID: 21615150)
Nat Chem Biol. 2011 Aug;7(8):500-1. (PMID: 21769095)
J Chem Inf Model. 2011 Oct 24;51(10):2778-86. (PMID: 21919503)
Acta Pharmacol Sin. 2012 Mar;33(3):372-84. (PMID: 22266728)
Nucleic Acids Res. 2013 Jan;41(Database issue):D43-7. (PMID: 23161681)
Nature. 2013 Jul 25;499(7459):444-9. (PMID: 23863937)
Nature. 2013 Jul 25;499(7459):438-43. (PMID: 23863939)
J Lipid Res. 2014 Feb;55(2):190-200. (PMID: 24273196)
Neuropsychopharmacology. 2014 May;39(6):1460-8. (PMID: 24356714)
FASEB J. 2014 Aug;28(8):3494-505. (PMID: 24769669)
Eur J Biochem. 1970 Sep;15(3):513-9. (PMID: 5465996)
J Mol Biol. 1963 Jul;7:95-9. (PMID: 13990617)
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):618-21. (PMID: 15640351)
Drug Discov Today. 2005 Mar 15;10(6):417-27. (PMID: 15808821)
Mol Endocrinol. 2005 Jul;19(7):1821-36. (PMID: 15731172)
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16084-9. (PMID: 16236727)
Bioorg Med Chem. 2006 May 1;14(9):3160-73. (PMID: 16413785)
J Biol Chem. 2006 May 5;281(18):12792-8. (PMID: 16520374)
Mol Pharmacol. 2006 Jul;70(1):206-13. (PMID: 16531505)
Biochemistry. 2000 Aug 1;39(30):8878-87. (PMID: 10913300)
Science. 2000 Aug 4;289(5480):739-45. (PMID: 10926528)
World J Surg. 2001 Jul;25(7):835-9. (PMID: 11572020)
Biopolymers. 2002;66(4):218-35. (PMID: 12491536)
Receptors Channels. 2002;8(3-4):219-42. (PMID: 12529939)
Proteins. 2003 Feb 15;50(3):437-50. (PMID: 12557186)
Br J Pharmacol. 2003 Sep;140(2):339-46. (PMID: 12970080)
Protein Sci. 2003 Nov;12(11):2508-22. (PMID: 14573863)
J Biol Chem. 2003 Nov 28;278(48):48300-12. (PMID: 14500709)
Q Rev Biophys. 1973 Nov;6(4):341-87. (PMID: 4598034)
Immunol Commun. 1979;8(1):11-29. (PMID: 33892)
Science. 1991 Jul 12;253(5016):164-70. (PMID: 1853201)
Protein Sci. 1993 Sep;2(9):1511-9. (PMID: 8401235)
Acta Physiol Scand. 1996 Jul;157(3):343-5. (PMID: 8830889)
J Biomol NMR. 1996 Dec;8(4):477-86. (PMID: 9008363)
J Mol Biol. 1997 Sep 12;272(1):106-20. (PMID: 9299341)
Am J Physiol. 1998 Jul;275(1 Pt 1):G22-8. (PMID: 9655680)
J Med Chem. 1998 Nov 5;41(23):4433-8. (PMID: 9804683)
Mol Pharmacol. 2006 Jul;70(1):1-4. (PMID: 16632645)
Regul Pept. 2006 Nov 15;137(1-2):95-104. (PMID: 16930743)
Biochim Biophys Acta. 2007 Apr;1768(4):794-807. (PMID: 17188232)
Proc Natl Acad Sci U S A. 2007 May 8;104(19):7875-80. (PMID: 17470806)
Proteins. 2007 Jul 1;68(1):92-9. (PMID: 17393464)
Proteins. 2007 Aug 1;68(2):503-15. (PMID: 17444519)
Trends Pharmacol Sci. 2007 Aug;28(8):397-406. (PMID: 17629961)
Science. 2007 Nov 23;318(5854):1258-65. (PMID: 17962520)
J Biol Chem. 2008 Apr 25;283(17):11340-7. (PMID: 18287102)
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7439-44. (PMID: 18490656)
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W229-32. (PMID: 18424796)
Science. 2008 Nov 21;322(5905):1211-7. (PMID: 18832607)

0 (Peptides)
0 (Receptors, G-Protein-Coupled)
0 (Receptors, Gastrointestinal Hormone)
0 (secretin receptor)
1393-25-5 (Secretin)
E0399OZS9N (Cyclic AMP)

Date Created: 20160302 Date Completed: 20160721 Latest Revision: 20181113

20250114

PMC4773067

10.1371/journal.pone.0149359

26930505