TY - JOUR
T1 - Fucose-Functionalized Precision Glycomacromolecules Targeting Human Norovirus Capsid Protein
AU - Bücher, Katharina Susanne
AU - Yan, Hao
AU - Creutznacher, Robert
AU - Ruoff, Kerstin
AU - Mallagaray, Alvaro
AU - Grafmüller, Andrea
AU - Dirks, Jan Sebastian
AU - Kilic, Turgay
AU - Weickert, Sabrina
AU - Rubailo, Anna
AU - Drescher, Malte
AU - Schmidt, Stephan
AU - Hansman, Grant
AU - Peters, Thomas
AU - Uetrecht, Charlotte
AU - Hartmann, Laura
N1 - Funding Information:
The authors thank the German Research Foundation (DFG) for financial support (FOR2327, Virocarb; DFG Pe494/12-1, HA 5950/5-1, UE 183/1-1). H.Y. received funding through a doctoral stipend from the University of Hamburg. C.U. acknowledges funding via Leibniz grant SAW-2014-HPI-4. The Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit (BMG). L.H. thanks the DFG for support through the large equipment Grant INST 208/735-1.
Publisher Copyright:
© 2018 American Chemical Society.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/9/10
Y1 - 2018/9/10
N2 - Norovirus infection is the major cause of nonbacterial gastroenteritis in humans and has been the subject of numerous studies investigating the virus's biophysical properties and biochemical function with the aim of deriving novel and highly potent entry inhibitors to prevent infection. Recently, it has been shown that the protruding P domain dimer (P-dimer) of a GII.10 Norovirus strain exhibits two new binding sites for l-fucose in addition to the canonical binding sites. Thus, these sites provide a novel target for the design of multivalent fucose ligands as entry inhibitors of norovirus infections. In this current study, a first generation of multivalent fucose-functionalized glycomacromolecules was synthesized and applied as model structures to investigate the potential targeting of fucose binding sites in human norovirus P-dimer. Following previously established solid phase polymer synthesis, eight precision glycomacromolecules varying in number and position of fucose ligands along an oligo(amidoamine) backbone were obtained and then used in a series of binding studies applying native MS, NMR, and X-ray crystallography. We observed only one fucose per glycomacromolecule binding to one P-dimer resulting in similar binding affinities for all fucose-functionalized glycomacromolecules, which based on our current findings we attribute to the overall size of macromolecular ligands and possibly to steric hindrance.
AB - Norovirus infection is the major cause of nonbacterial gastroenteritis in humans and has been the subject of numerous studies investigating the virus's biophysical properties and biochemical function with the aim of deriving novel and highly potent entry inhibitors to prevent infection. Recently, it has been shown that the protruding P domain dimer (P-dimer) of a GII.10 Norovirus strain exhibits two new binding sites for l-fucose in addition to the canonical binding sites. Thus, these sites provide a novel target for the design of multivalent fucose ligands as entry inhibitors of norovirus infections. In this current study, a first generation of multivalent fucose-functionalized glycomacromolecules was synthesized and applied as model structures to investigate the potential targeting of fucose binding sites in human norovirus P-dimer. Following previously established solid phase polymer synthesis, eight precision glycomacromolecules varying in number and position of fucose ligands along an oligo(amidoamine) backbone were obtained and then used in a series of binding studies applying native MS, NMR, and X-ray crystallography. We observed only one fucose per glycomacromolecule binding to one P-dimer resulting in similar binding affinities for all fucose-functionalized glycomacromolecules, which based on our current findings we attribute to the overall size of macromolecular ligands and possibly to steric hindrance.
UR - http://www.scopus.com/inward/record.url?scp=85052313922&partnerID=8YFLogxK
U2 - 10.1021/acs.biomac.8b00829
DO - 10.1021/acs.biomac.8b00829
M3 - Journal articles
C2 - 30071731
AN - SCOPUS:85052313922
VL - 19
SP - 3714
EP - 3724
JO - Biomacromolecules
JF - Biomacromolecules
SN - 1525-7797
IS - 9
ER -