Selective reaction of conjugated polymers with basic proteins for broad-spectrum antivirulence therapy

Abstract

Antivirulence therapy has proven to be an attractive method for the treatment of bacterial infections and venomous injuries; however, the approaches for neutralizing multiple types of virulence through one platform are limited. To address this challenge, we have developed a reactive conjugated polymer, PPV–NHS, which functions as a broad-spectrum antidote for directly inactivating basic toxins. The antivirulence is achieved via multivalent electrostatic recognition and subsequent amidation reactions between PPV–NHS and toxins. The resultant bioconjugates significantly reduced neurotoxicity and cytotoxicity. In the mouse model, PPV–NHS effectively inhibited the toxicity of cardiotoxin (CTX) and improved the survival rate of toxin-challenged mice. This work represents the rational design of functionalized conjugated polymers for antivirulence therapy with both high efficiency and broad applicability. A new material that can selectively bind to multiple types of toxins while leaving other protein biomolecules and blood cells untouched has undergone successful animal trials. Baoyang Hu, Shu Wang, and colleagues from the Chinese Academy of Sciences in Beijing report that aromatic polymers containing amine-based rings active esters and carboxylic acid groups recognize and attach to proteins carrying high densities of surface positive charges. Gel electrophoresis and measurements of enzyme activity demonstrated that this polymer binding could also deactivate the functions of the positively charged proteins found in many snake venoms. Polymer treatments of mice injected with cardiotoxins improved survival rates significantly compared to control groups. In addition, the polymer’s naturally bright fluorescent emissions enabled the team to examine its distribution into internal organs using bioimaging techniques. Toxin proteins can cause physical damage, biochemical degradation and signaling interruption in mammals, leading to disabilities and even death. Most of the current antitoxins are developed against specific toxins. The broad-spectrum antitoxic platforms are still rare. Here, we developed a reactive conjugated polymer, PPV-NHS, which selectively reacted with basic proteins and reduced the activity of these attached proteins. PPV-NHS showed excellent inhibition effect on neurotoxicity and hemolysis caused by α-bungarotoxin and cardiotoxin in vitro and in vivo. This work represents the rational design of functionalized conjugated polymers for anti-virulence therapy with both high efficiency and broad applicability.