From micromolar to nanomolar affinity: a systematic approach to identify the binding site of CGRP at the human calcitonin gene-related peptide 1 receptor

Journal of Medicinal Chemistry
B RistA G Beck-Sickinger

Abstract

CGRP Y0-28-37 is known as a selective CGRP1 receptor antagonist. In order to elucidate the essential requirements for its receptor interaction, we performed a variety of systematic approaches by modifying the C-terminal segments CGRP Y0-28-37 and CGRP 27-37. N-Terminal and C-terminal segments have been synthesized, as well as chimeras which combine segments of CGRP, adrenomedullin, and amylin. Furthermore, we carried out an Ala scan, a Phe scan, a D-amino acid scan and a Pro scan of CGRP 27-37. Additionally, single amino acids were replaced by those with similar biophysical properties. Receptor binding studies of all analogs were performed at human neuroblastoma cells SK-N-MC, which selectively express the hCGRP1 receptor. On the basis of the obtained results, we synthesized a series of ligands with multiple amino acid replacements in order to optimize the exchange at each position. This approach yielded to a series of high affinity ligands, including [D31,P34,F35] CGRP 27-37 which exhibits a 100-fold increased affinity compared to the unmodified segment. So far, this is the smallest CGRP analog that shows affinity in the nanomolar range.

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Citations

Aug 23, 2002·Pharmacology & Therapeutics·Paul L Durham, Andrew F Russo
Dec 21, 2000·Trends in Pharmacological Sciences·C JuanedaR Quirion
Mar 11, 2000·British Journal of Pharmacology·H DoodsW Eberlein
Aug 22, 2000·European Journal of Biochemistry·M FabryA G Beck-Sickinger
Oct 31, 2015·Annual Review of Pharmacology and Toxicology·Debbie L Hay, Augen A Pioszak
Jan 29, 2013·British Journal of Pharmacology·H A WatkinsD L Hay
Mar 18, 2011·Journal of Peptide Science : an Official Publication of the European Peptide Society·Liang Zeng YanJohn P Mayer
Nov 29, 2012·British Journal of Pharmacology·Harriet A WatkinsDavid R Poyner
Oct 12, 2013·Protein Science : a Publication of the Protein Society·Heather E Moad, Augen A Pioszak
Aug 17, 2000·The Journal of Biological Chemistry·C CabreleA G Beck-Sickinger
Jan 22, 2008·ChemMedChem·Robert RennertAnnette G Beck-Sickinger
Feb 25, 2010·Dalton Transactions : an International Journal of Inorganic Chemistry·Katrin SplithUlrich Schatzschneider
Jun 1, 2019·PloS One·Chia Lin Chang, Sheau Yu Teddy Hsu
Oct 24, 2017·British Journal of Pharmacology·Debbie L HayChristopher S Walker
Apr 14, 2016·Biochemical Society Transactions·Debbie L HayDavid R Poyner
Feb 15, 2001·Bioconjugate Chemistry·K HoffmannM Jung

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