HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oikonomakos, N. G. Articles by Defossa, E. Search for Related Content PubMed PubMed Citation Articles by Oikonomakos, N. G. Articles by Defossa, E. Social Bookmarking                   What's this?

Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs

¹ Institute of Organic and Pharmaceutical Chemistry, ² Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, Athens 11635, Greece
³ Aventis Pharma Deutschland GmbH, a company of the Sanofi-Aventis Group, D-65926 Frankfurt am Main, Germany

(RECEIVED February 25, 2005; FINAL REVISION April 7, 2005; ACCEPTED April 7, 2005)

Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC₅₀ of 2.0 µM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26Å resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.

Keywords: type 2 diabetes; glycogen phosphorylase; acyl ureas; inhibition; X-ray crystallography

Abbreviations: GP, glycogen phosphorylase, 1,4--D-glucan:orthophosphate -glucosyltransferase (EC 2.4.1.1) • rmGPb, rabbit muscle glycogen phosphorylase b • rmGPa, rabbit muscle glycogen phosphorylase a • hlGPa, human liver glycogen phosphorylase a • PLP, pyridoxal 5'-phosphate • glucose, -D-glucose • Glc-1-P, -D-glucose 1-phosphate • Glc-6-P, D-glucose 6-phosphate • W1807, (–)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarboxylate • CP320626, 5-chloro-1H-indole-2-carboxylic acid [1-(4-fluorobenzyl)- 2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]amide • compound 1, 6-{2,6-dichloro-4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid • compound 2, 4-{3-chloro-4-[3-(2,4-dichloro-benzoyl)-ureido]- phenoxy}-butyric acid • compound 3, 4-{4-[3-(2,4-dichloro-benzoyl)-ureido]-2,3-dimethyl-phenoxy}-butyric acid • compound 4, 5-{3-[3- (2,4-dichloro-benzoyl)-ureido]-2-methyl-phenoxy}-pentanoic acid • r.m.s. deviation, root-mean-square deviation.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051432405.

Reprint requests to: Nikos G. Oikonomakos, Institute of Organic and Pharmaceutical Chemistry, The National Hellenic Research Foundation, 48, Vassileos Constantinou Avenue, 11635, Athens, Greece; e-mail: ngo{at}eie.gr; fax: 30-210-7273-831.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Tiraidis, K.-M. Alexacou, S. E. Zographos, D. D. Leonidas, T. Gimisis, and N. G. Oikonomakos FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase Protein Sci., August 1, 2007; 16(8): 1773 - 1782. [Abstract] [Full Text] [PDF]