Statistical pattern matching facilitates the design of polyvalent inhibitors of anthrax and cholera toxins

Abstract

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.

Polyvalent inhibitors of anthrax toxin that target host receptors

“…EF is an adenylate cyclase, and LF is a protease that cleaves mitogen-activated protein kinase kinases. The enzymatic activities of these proteins contribute to disease progression in several ways and at different stages of infection (16).Several anthrax-toxin inhibitors have been described that interfere with different steps in this intoxication pathway (8,11,12,16,(20)(21)(22)(23)(24)(25)(26), but none has targeted the host receptors. Here, we describe the development of a polyvalent receptor-directed anthrax-toxin inhibitor that binds both receptors and protects animals from toxin challenge.…”

Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin

“…[3] In previous work, phage display was used to identify a 12-mer peptide (HTSTYWWLDGAP) that binds to (PA 63 ) 7. [10] Polyvalent inhibitors have been created by attaching multiple copies of this peptide to a variety of scaffolds such as polymers, [12] liposomes, [13] and β-cyclodextrin. [14] Structure-based design is a particularly effective strategy to design polyvalent inhibitors of anthrax lethal toxin and other targets.…”

“…[14] Structure-based design is a particularly effective strategy to design polyvalent inhibitors of anthrax lethal toxin and other targets. [11][12][13][14][15][16] Ligand spacing and valency are key parameters that influence the efficacy of polyvalent molecules (Scheme 1A). [12][13][14]17] The ligand spacing is simply the distance separating adjacent ligands on a polyvalent molecule.…”

“…[11][12][13][14][15][16] Ligand spacing and valency are key parameters that influence the efficacy of polyvalent molecules (Scheme 1A). [12][13][14]17] The ligand spacing is simply the distance separating adjacent ligands on a polyvalent molecule. [5,13,14] Matching the ligand spacing on the polyvalent molecule to the distance between ligand binding sites on the target molecule has been shown to be an effective strategy to design potent polyvalent ligands.…”

“…[12][13][14]17] The ligand spacing is simply the distance separating adjacent ligands on a polyvalent molecule. [5,13,14] Matching the ligand spacing on the polyvalent molecule to the distance between ligand binding sites on the target molecule has been shown to be an effective strategy to design potent polyvalent ligands. [16,18] For a linear polymer or polypeptide, ligand spacing can be manipulated by choosing a linker of appropriate length to separate adjacent ligands on a polyvalent molecule.…”