Statistical pattern matching facilitates the design of polyvalent inhibitors of anthrax and cholera toxins.
Numerous biological processes involve the recognition of a specific pattern of binding sites on a target protein or surface. Although ligands displayed by disordered scaffolds form stochastic rather than specific patterns, theoretical models predict that recognition will occur between patterns that are characterized by similar or "matched" statistics. Endowing synthetic biomimetic structures with statistical pattern matching capabilities may improve the specificity of sensors and resolution of separation processes. We demonstrate that statistical pattern matching enhances the potency of polyvalent therapeutics. We functionalized liposomes with an inhibitory peptide at different densities and observed a transition in potency at an interpeptide separation that matches the distance between ligand-binding sites on the heptameric component of anthrax toxin. Pattern-matched polyvalent liposomes inhibited anthrax toxin in vitro at concentrations four orders of magnitude lower than the corresponding monovalent peptide, and neutralized this toxin in vivo. Statistical pattern matching also enhanced the potency of polyvalent inhibitors of cholera toxin. This facile strategy should be broadly applicable to the detection and neutralization of toxins and pathogens.
Rai
Prakash
P
The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Ricketts 131, 110 8th Street, Troy, New York 12180, USA.
Padala
Chakradhar
C
Poon
Vincent
V
Saraph
Arundhati
A
Basha
Saleem
S
Kate
Sandesh
S
Tao
Kevin
K
Mogridge
Jeremy
J
Kane
Ravi S
RS
D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D015233:Models, Statistical; D008962:Models, Theoretical; D051381:Rats; D011916:Rats, Inbred F344; D013050:Spectrometry, Fluorescence
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008081:Liposomes; C030325:anthrax toxin; D002772:Cholera Toxin