Synthetic Peptide Derived from Scorpion Venom Displays Minimal Toxicity and Anti-infective Activity in an Animal Model

Autor(es)

Oliveira, Cyntia Silva ^[1] ; Torres, Marcelo Der Torossian ^{[2, 3, 4, 5, 6]} ; Pedron, Cibele Nicolaski ^[1] ; Andrade, Viviane Brito ^[7] ; Silva Jr, Pedro Ismael ; Silva, Fernanda Dias ^[7] ; de la Fuente-Nunez, Cesar ^{[2, 3, 4, 5, 6]} ; Oliveira Jr, Vani Xavier

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Programa Posgrad Biol Mol, Escola Paulista Med, BR-04044020 Sao Paulo, SP - Brazil

^[2] Univ Penn, Penn Inst Computat Sci, Philadelphia, PA 19104 - USA

^[3] Univ Penn, Machine Biol Grp, Sch Engn & Appl Sci, Dept Bioengn, Dept Psychiat, Perelman Sch Med, Inst Translat Med & Therapeut, In, Philadelphia, PA 19104 - USA

^[4] Univ Penn, Machine Biol Grp, Sch Engn & Appl Sci, Dept Bioengn, Dept Microbiol, Perelman Sch Med, Inst Translat Med & Therapeut, In, Philadelphia, PA 19104 - USA

^[5] Univ Penn, Machine Biol Grp, Sch Engn & Appl Sci, Dept Psychiat, Dept Chem & Bio, Perelman Sch Med, Inst Translat Med & Therapeut, In, Philadelphia, PA 19104 - USA

^[6] Univ Penn, Machine Biol Grp, Sch Engn & Appl Sci, Dept Microbiol, Dept Chem & Bi, Perelman Sch Med, Inst Translat Med & Therapeut, In, Philadelphia, PA 19104 - USA

^[7] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS INFECTIOUS DISEASES; v. 7, n. 9, p. 2736-2745, SEP 10 2021.
• Citações Web of Science: 0

Resumo

Multidrug-resistant bacteria represent a global health problem increasingly leading to infections that are untreatable with our existing antibiotic arsenal. Therefore, it is critical to identify novel effective antimicrobials. Venoms represent an underexplored source of potential antibiotic molecules. Here, we engineered a peptide (IsCT1-NH2) derived from the venom of the scorpion Opisthacanthus madagascariensis, whose application as an antimicrobial had been traditionally hindered by its high toxicity. Through peptide design and the knowledge obtained in preliminary studies with single and double-substituted analogs, we engineered IsCT1 derivatives with multiple amino acid sub-stitutions to assess the impact of net charge on antimicrobial activity and toxicity. We demonstrate that increased net charge (from +3 to +6) significantly reduced toxicity toward human erythrocytes. Our lead synthetic peptide, {[}A](1){[}K](3){[}F](5){[}K](8)-IsCT1-NH2 (net charge of +4), exhibited increased antimicrobial activity against Gram-negative and Gram-positive bacteria in vitro and enhanced anti-infective activity in a mouse model. Mechanism of action studies revealed that the increased antimicrobial activity of our lead molecule was due, at least in part, to its enhanced ability to permeabilize the outer membrane and depolarize the cytoplasmic membrane. In summary, we describe a simple method based on net charge tuning to turn highly toxic venom-derived peptides into viable therapeutics. (AU)

• Processo FAPESP: 17/03046-2 - Peptídeos biologicamente ativos em micro-organismos patogênicos e em células tumorais
• Beneficiário: Vani Xavier de Oliveira Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular