The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

The wasp venom‐derived antimicrobial peptide polybia‐CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical‐guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia‐CP and derivatives, namely their ability to target Plasmodium sporozoites and cancer cells. We leverage a physicochemical‐guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity‐related properties of polybia‐CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia‐CP and analogs. Additionally, we demonstrate that a physicochemical‐guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure–function to generate novel and potent new‐to‐nature therapies.