Rationally designed squaryldiamides - a novel class of sugar-nucleotide mimics?
Sugar-nucleotides such as GDP-mannose, GDP-fucose and UDP-glucose are important biomolecules with a central role in carbohydrate and glycoconjugate biosynthesis, metabolism and cell signalling. Analogues and mimics of naturally occurring sugar-nucleotides are sought after as chemical tools and inhibitor candidates for sugar-nucleotide-dependent enzymes including glycosyltransferases. Many sugar-nucleotides bind to their target glycosyltransferases via coordination of the diphosphate group to a divalent metal cofactor in the active site. The identification of uncharged, chemically stable surrogates for the diphosphate group, with the ability to coordinate to a divalent metal, is therefore an important design criteria for the development of sugar-nucleotide mimics. Here, we describe the rational design and synthesis of a novel class of sugar-nucleotide mimics based on a squaryldiamide scaffold, an uncharged phosphate isostere. We demonstrate by comprehensive NMR titration experiments that the new sugar-nucleotide mimics coordinate efficiently to Mg(2+), and provide results from biological studies with a therapeutically relevant mannosyltransferase from Trypanosoma brucei. Our findings suggest that squaryldiamides are a promising template for the development of sugar-nucleotide mimics, and illustrate the considerable potential of the squarylamide group as a fragment for inhibitor design.
School of Pharmacy, University of East Anglia, Norwich, UKNR4 7TJ.
Sven
S
Niewiadomski
Zeenat
Z
Beebeejaun
Helen
H
Denton
Terry K
TK
Smith
Richard J
RJ
Morris
Gerd K
GK
Wagner
D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008274:Magnesium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors; D009711:Nucleotides / Q000737:chemistry*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D000981:Antiprotozoal Agents; D003503:Cyclobutanes; D009711:Nucleotides; D013449:Sulfonamides; C527748:squaric acid amide; D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase; D008274:Magnesium