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Zhang S , Xiao Q , Sherman SE , Muncan A , Ramos Vicente AD , Wang Z , Hammer DA , Williams D , Chen Y , Pochan DJ , Vertesy S , Andre S , Klein ML , Gabius HJ , Percec V
Glycodendrimersomes from Sequence-Defined Janus Glycodendrimers Reveal High Activity and Sensor Capacity for the Agglutination by Natural Variants of Human Lectins
J Am Chem Soc. 2015 Oct 21;137(41) :13334-44
PMID: 26421463 URL: http://www.ncbi.nlm.nih.gov/pubmed/26421463
AbstractA library of eight amphiphilic Janus glycodendrimers (Janus-GDs) presenting D-lactose (Lac) and a combination of Lac with up to eight methoxytriethoxy (3EO) units in a sequence-defined arrangement was synthesized via an iterative modular methodology. The length of the linker between Lac and the hydrophobic part of the Janus-GDs was also varied. Self-assembly by injection from THF solution into phosphate-buffered saline led to unilamellar, monodisperse glycodendrimersomes (GDSs) with dimensions predicted by Janus-GD concentration. These GDSs provided a toolbox to measure bioactivity profiles in agglutination assays with sugar-binding proteins (lectins). Three naturally occurring forms of the human adhesion/growth-regulatory lectin galectin-8, Gal-8S and Gal-8L, which differ by the length of linker connecting their two active domains, and a single amino acid mutant (F19Y), were used as probes to study activity and sensor capacity. Unpredictably, the sequence of Lac on the Janus-GDs was demonstrated to determine bioactivity, with the highest level revealed for a Janus-GD with six 3EO groups and one Lac. A further increase in Lac density was invariably accompanied by a substantial decrease in agglutination, whereas a decrease in Lac density resulted in similar or lower bioactivity and sensor capacity. Both changes in topology of Lac presentation of the GDSs and seemingly subtle alterations in protein structure resulted in different levels of bioactivity, demonstrating the presence of regulation on both GDS surface and lectin. These results illustrate the applicability of Janus-GDs to dissect structure-activity relationships between programmable cell surface models and human lectins in a highly sensitive and physiologically relevant manner.
NotesZhang, Shaodong Xiao, Qi Sherman, Samuel E Muncan, Adam Ramos Vicente, Andrea D M Wang, Zhichun Hammer, Daniel A Williams, Dewight Chen, Yingchao Pochan, Darrin J Vertesy, Sabine Andre, Sabine Klein, Michael L Gabius, Hans-Joachim Percec, Virgil Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. United States J Am Chem Soc. 2015 Oct 21;137(41):13334-44. doi: 10.1021/jacs.5b08844. Epub 2015 Oct 7.