Synthesis of polyvalent inhibitors of controlled molecular weight: structure-activity relationship for inhibitors of anthrax toxin.
We describe a novel method to synthesize activated polymers of controlled molecular weight and apply this method to investigate the relationship between the structure and activity of polyvalent inhibitors of anthrax toxin. In particular, we observe an initial sharp increase in potency with increasing ligand density, followed by a plateau where potency is independent of ligand density. Our simple strategy for designing polyvalent inhibitors of controlled molecular weight and ligand density will be broadly applicable for designing inhibitors for a variety of pathogens and toxins, and for elucidating structure-activity relationships in these systems. Our results also demonstrate a role for kinetics in influencing inhibitory potency in polyvalent systems. Finally, our work presents a synthetic route to polyvalent inhibitors that are more structurally defined and effective in vivo. This control over inhibitor composition will be generally useful for the optimization of inhibitor potency and pharmacokinetics, and for the eventual application of these molecules in vivo.
Gujraty
Kunal V
KV
The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
Joshi
Amit
A
Saraph
Arundhati
A
Poon
Vincent
V
Mogridge
Jeremy
J
Kane
Ravi S
RS
D000818:Animals; D000881:Anthrax / Q000188:drug therapy / Q000821:virology; D000942:Antigens, Bacterial / Q000378:metabolism; D001408:Bacillus anthracis / Q000187:drug effects / Q000502:physiology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002850:Chromatography, Gel; D004195:Disease Models, Animal; D004986:Ether / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010455:Peptides; D011108:Polymers; C030325:anthrax toxin; D004986:Ether