Structure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venom

Autor(es)

Boaro, Andreia ; Ageitos, Lucia ; Torres, Marcelo Der Torossian ; Blasco, Esther Broset ; Oztekin, Sebahat ; de la Fuente-Nunez, Cesar

• Tipo de documento: Artigo Científico
• Fonte: CELL REPORTS PHYSICAL SCIENCE; v. 4, n. 7, p. 22-pg., 2023-07-19.

Resumo

Antimicrobial peptides (AMPs) derived from natural toxins and venoms offer a promising alternative source of antibiotics. Here, through structure-function-guided design, we convert two natural AMPs derived from the venom of the solitary eumenine wasp Eu-menes micado into a-helical AMPs with reduced toxicity that kill Gram-negative bacteria in vitro and in a preclinical mouse model. To identify the sequence determinants conferring antimicrobial ac-tivity, an alanine scan screen and strategic single lysine substitutions are made to the amino acid sequence of these natural peptides. These efforts yield a total of 34 synthetic derivatives, including alanine substituted and lysine-substituted sequences with stabilized a-helical structures and increased net positive charge. The resulting lead synthetic peptides kill the Gram-negative pathogens Escheri-chia coli and Pseudomonas aeruginosa (PAO1 and PA14) by rapidly permeabilizing both their outer and cytoplasmic membranes, exhibit anti-infective efficacy in a mouse model by reducing bacte-rial loads by up to three orders of magnitude, and do not readily select for bacterial resistance. (AU)

• Processo FAPESP: 16/10585-4 - Aspectos mecanísticos da decomposição induzida de hidroperóxidos e sililperóxidos derivados de lofina
• Beneficiário: Andréia Boaro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/15871-3 - Derivados de arginina emissores de luz como marcadores de peptídeos antimicrobianos
• Beneficiário: Andréia Boaro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado