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-aminomethyl- d-mannose 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.