Peptide Design Enables Reengineering of an Inactive Wasp Venom Peptide into Synthetic Antiplasmodial Agents

Abstract

Malaria, caused by Plasmodium protozoa, is responsible for ∼0.5 million deaths annually. Decoralin is a wasp‐derived peptide with activity against a number of microorganisms but no antiplasmodial function. In its unmodified form, it cannot be used as an anti‐infective because of its hemolytic activity. We have generated decoralin analogs with potent antiplasmodial function. Our results provide insight into antiplasmodial sequence requirements and identify single mutations that confer novel biological and therapeutic properties to this peptide, demonstrating the utility of rational peptide design.

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

“…6 Generally, naturally occurring small cationic peptides that are active against bacteria are not as active against Plasmodium. 13 In fact, Pol-CP-NH 2 did not exhibit antiplasmodial activity at the range of concentrations tested. However, the synthetic peptides designed displaying increased net positive charge showed higher antiplasmodial activity compared to other synthetic peptides described in the literature 13,15,[27][28][29][30][31][32] (Figure 2b).…”

“…For example, recent reports have described the design of AMPs with broadspectrum activity, particularly amphipathic cationic peptides. 11 Exploring the multifunctional properties of these molecules may lead to candidate molecules that simultaneously kill resistant microorganisms, viruses, 12 parasite infections, [13][14][15][16] and cancer cells. 17,18 Torres et al 6 using a physicochemical feature-guided design of polybia-CP (Pol-CP-NH 2 : Ile-Leu-Gly-Thr-Ile-Leu-Gly-Leu-Leu-Lys-Ser-Leu-NH 2 ), identified functional determinants that were key for converting a toxic wasp venom peptide into nontoxic variants with enhanced antimicrobial activity against fungi, Gram-positive and Gram-negative bacteria by destabilizing the membrane of those microorganisms.…”

Reprogramming biological peptides to combat infectious diseases

“…41,42 The decoralin derivatives also inhibited the growth of MCF-7 human breast cancer cells 43 and Plasmodium sporozoites. 44 High-throughput peptide synthesis, by enabling the correlation of the most important biological descriptors with the biological activities of the peptides, 45 is another powerful tool for mutagenesis studies. 45,46 The systematic substitution within a native sequence of all possible options for each amino acid generates a synthetic library and a large amount of data that can guide the design of peptides with enhanced activity.…”

“…The use of D-enantiomeric amino acids for mutagenesis studies is a well-known approach for preventing peptide degradation in the presence of proteolytic enzymes. 44 D-Enantiomeric amino acids have greater bioavailability than L-enantiomers, and their use makes it possible to avoid abrupt changes in structural and physicochemical properties, which may have unforeseen functional effects. Thus, peptides consisting of D-amino acids are powerful tools for mutagenesis studies.…”

“…Features such as positive net charge and hydrophobicity were fine-tuned in the N-terminal extremity, yielding the selective antiplasmodial agents. 44 Decoralin was also repurposed into a selective anticancer agent through rational design, leading to the formation of necrotic pathways in breast cancer cells. Changes in hydrophobicity favoring the amphipathic structure, and helical conformations were described as being responsible for the anticancer activity of the decoralin analogs.…”