Synthesis of 2-C-branched derivatives of D-mannose: 2-C-aminomethyl-D-mannose binds to the human C-type lectin DC-SIGN with affinity greater than an order of magnitude compared to that of D-mannose

Abstract

2-C-Substituted branched D-mannose analogues are novel monosaccharides, readily obtained from a Kiliani-acetonation sequence on D-fructose, followed by subsequent functional group manipulation. 2-C-Azidomethyl-D-mannose and 2-C-aminomethylD-marmose bind to the C-type lectin DC-SIGN (CD209) with significantly greater affinity than mannose. In particular, 2-C-aminomethyl-D-mannose exhibits a comparative 48-fold increase in binding as determined using a surface plasmon resonance-based competition assay. DC-SIGN is an important cell-surface type II transmembrane protein that interacts with blood group antigens, endogenous glycoproteins such as ICAM-3, and also deadly pathogens such as the human immunodeficiency and hepatitis C viruses. The effective use of small compounds to block target binding by mannose-selective C-type lectins at sub-millimolar concentrations has not been shown previously; thus, these data represent a very attractive thoroughfare to novel antiviral and immunomodulatory drug development. @ 2007 Elsevier Ltd. All rights reserved