Structure-guided design of sialic acid-based Siglec inhibitors and crystallographic analysis in complex with sialoadhesin.
The Siglec family of receptors mediates cell surface interactions through recognition of sialylated glycoconjugates. The crystal structure of the N-terminal immunoglobulin-like domain of the Siglec sialoadhesin (SnD1) in complex with 2,3-sialyllactose has informed the design of sialic acid analogs (sialosides) that bind Siglecs with significantly enhanced affinities and specificities. Binding assays against sialoadhesin (Sn; Siglec-1), CD22 (Siglec-2), and MAG (Siglec-4) show a 10- to 300-fold reduction in IC(50) values (relative to methyl-alpha-Neu5Ac) for three sialosides bearing aromatic group modifications of the glycerol side chain: Me-alpha-9-N-benzoyl-amino-9-deoxy-Neu5Ac (BENZ), Me-alpha-9-N-(naphthyl-2-carbonyl)-amino-9-deoxy-Neu5Ac (NAP), and Me-alpha-9-N-(biphenyl-4-carbonyl)-amino-9-deoxy-Neu5Ac (BIP). Crystal structures of these sialosides in complex with SnD1 suggest explanations for the differences in specificity and affinity, providing further ideas for compound design of physiological and potentially therapeutic relevance.
Zaccai
Nathan R
NR
CR-UK Receptor Structure Research Group, Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom.
Maenaka
Katsumi
K
Maenaka
Taeko
T
Crocker
Paul R
PR
Brossmer
Reinhard
R
Kelm
Sørge
S
Jones
E Yvonne
EY
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D037102:Lectins / Q000037:antagonists & inhibitors*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives*; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000378:metabolism*; D063267:Sialic Acid Binding Ig-like Lectin 1; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
D037102:Lectins; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D019158:N-Acetylneuraminic Acid