Arg-substituted VmCT1 analogs reveals promising candidate for the development of new antichagasic agent

Author(s)

Pedron, Cibele Nicolaski ^{[1, 2]} ; Freire, Katielle Albuquerque ^[1] ; Torres, Marcelo Der Torossian ^{[1, 3, 4, 5]} ; Lima, Danya Bandeira ^[6] ; Monteiro, Marilia Lopes ^[6] ; Pessoa Bezerra de Menezes, Ramon Roseo Paula ^[6] ; Costa Martins, Alice Maria ^[6] ; Oliveira Junior, Vani Xavier ^{[1, 2]}

Affiliation

^[1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Biofis, BR-04044020 Sao Paulo, SP - Brazil

^[3] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 - USA

^[4] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Inst Biomed Informat, Machine Biol Grp, Dept Psychi, Philadelphia, PA 19104 - USA

^[5] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Inst Biomed Informat, Dept Microbiol, Philadelphia, PA 19104 - USA

^[6] Univ Fed Ceara, Fac Farm, Dept Anal Clin & Toxicol, BR-60430372 Fortaleza, Ceara - Brazil

• Document type: Journal article
• Source: Parasitology; v. 147, n. 14, p. 1810-1818, DEC 2020.
• Web of Science Citations: 1

Abstract

VmCT1 is an antimicrobial peptide (AMP) isolated from the venom of the scorpion Vaejovis mexicanus with antimicrobial, anticancer and antimalarial activities, which the rational design with Arg-substitution has yielded AMPs with higher antimicrobial activity than VmCT1. Chagas is a neglected tropical disease, becoming the development of new antichagasic agents is urgent. Thus, we aimed to evaluate the antichagasic effect of VmCT1 and three Arg-substituted analogues, as well their action mechanism. Peptides were tested against the epimastigote, trypomastigote, amastigote forms of Trypanossoma cruzi Y strain and against LLC-MK2 mammalian cells. The mechanism of action of these peptides was evaluated by means of flow cytometry and scanning electron microscopy. VmCT1 presented activity against all three forms of T. cruzi, with EC50 against trypomastigote forms of 1.37 mu mol L-1 and selectivity index (SI) of 58. {[}Arg](3)-VmCT1, {[}Arg](7)-VmCT1 and {[}Arg](11)-VmCT1 also showed trypanocidal effect, but {[}Arg](11)-VmCT1 had the best effect, being able to decrease the EC50 against trypomastigote forms to 0.8 mu mol L-1 and increase SI to 175. Necrosis was cell death pathway of VmCT1, as well {[}Arg](7)-VmCT1 and {[}Arg](11)-VmCT1, such as observed by membrane damage in flow cytometry analyses and scanning-electron-microscopy. In conclusion, {[}Arg](11)-VmCT1 revealed promising as a candidate for new antichagasic therapeutics. (AU)

• FAPESP's process: 17/03046-2 - Biologically active peptides against pathogenic microorganisms and cancer cells
• Grantee: Vani Xavier de Oliveira Junior
• Support Opportunities: Regular Research Grants