Polyvalent inhibitors of anthrax toxin that target host receptors.
Resistance of pathogens to antimicrobial therapeutics has become a widespread problem. Resistance can emerge naturally, but it can also be engineered intentionally, which is an important consideration in designing therapeutics for bioterrorism agents. Blocking host receptors used by pathogens represents a powerful strategy to overcome this problem, because extensive alterations to the pathogen may be required to enable it to switch to a new receptor that can still support pathogenesis. Here, we demonstrate a facile method for producing potent receptor-directed antitoxins. We used phage display to identify a peptide that binds both anthrax-toxin receptors and attached this peptide to a synthetic scaffold. Polyvalency increased the potency of these peptides by >50,000-fold in vitro and enabled the neutralization of anthrax toxin in vivo. This work demonstrates a receptor-directed anthrax-toxin inhibitor and represents a promising strategy to combat a variety of viral and bacterial diseases.
Basha
Saleem
S
The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, NY 12180, USA.
Rai
Prakash
P
Poon
Vincent
V
Saraph
Arundhati
A
Gujraty
Kunal
K
Go
Mandy Y
MY
Sadacharan
Skanda
S
Frost
Mia
M
Mogridge
Jeremy
J
Kane
Ravi S
RS
D000107:Acetylation; D000818:Animals; D000881:Anthrax / Q000188:drug therapy / Q000821:virology; D000942:Antigens, Bacterial / Q000378:metabolism; D001408:Bacillus anthracis / Q000187:drug effects; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D019793:Fluorescein; D005456:Fluorescent Dyes; D020128:Inhibitory Concentration 50; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D018000:Receptors, Peptide / Q000737:chemistry / Q000378:metabolism*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D005456:Fluorescent Dyes; D008081:Liposomes; D019151:Peptide Library; D010455:Peptides; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors; D019793:Fluorescein