Synthesis of potent inhibitors of anthrax toxin based on poly-L-glutamic acid.
We report the synthesis of biodegradable polyvalent inhibitors of anthrax toxin based on poly-L-glutamic acid (PLGA). These biocompatible polyvalent inhibitors are at least 4 orders of magnitude more potent than the corresponding monovalent peptides in vitro and are comparable in potency to polyacrylamide-based inhibitors of anthrax toxin assembly. We have elucidated the influence of peptide density on inhibitory potency and demonstrated that these inhibitory potencies are limited by kinetics, with even higher activities seen when the inhibitors are preincubated with the heptameric receptor-binding subunit of anthrax toxin prior to exposure to cells. These polyvalent inhibitors are also effective at neutralizing anthrax toxin in vivo and represent attractive leads for designing biocompatible anthrax therapeutics.
Joshi
Amit
A
The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
Saraph
Arundhati
A
Poon
Vincent
V
Mogridge
Jeremy
J
Kane
Ravi S
RS
D020341:Absorbable Implants; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002460:Cell Line; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010455:Peptides; D011108:Polymers; C030325:anthrax toxin; D018698:Glutamic Acid