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Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents.

Abstract

Phospholipase A2 toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA2 from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications.

Authors+Show Affiliations

Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.Universidad Regional Amazónica Ikiam, Km 7 Via Muyuna, Tena, Napo, Ecuador.Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia da Universidade do Porto, Portugal; IPATIMUP/Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Portugal.LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Portugal.Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.Facultad de Ciencias Químicas, Universidad de Cuenca, Cuenca/Azuay, Ecuador.; Centro de Innovación de la Salud - EUS/EP, Cuenca/Azuay, Ecuador.Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil. Electronic address: dcmiguel@unicamp.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31454702

Citation

Mendes, Bruno, et al. "Potential Use of 13-mer Peptides Based On Phospholipase and Oligoarginine as Leishmanicidal Agents." Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP, vol. 226, 2019, p. 108612.
Mendes B, Almeida JR, Vale N, et al. Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents. Comp Biochem Physiol C Toxicol Pharmacol. 2019;226:108612.
Mendes, B., Almeida, J. R., Vale, N., Gomes, P., Gadelha, F. R., Da Silva, S. L., & Miguel, D. C. (2019). Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents. Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP, 226, 108612. https://doi.org/10.1016/j.cbpc.2019.108612
Mendes B, et al. Potential Use of 13-mer Peptides Based On Phospholipase and Oligoarginine as Leishmanicidal Agents. Comp Biochem Physiol C Toxicol Pharmacol. 2019;226:108612. PubMed PMID: 31454702.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potential use of 13-mer peptides based on phospholipase and oligoarginine as leishmanicidal agents. AU - Mendes,Bruno, AU - Almeida,José R, AU - Vale,Nuno, AU - Gomes,Paula, AU - Gadelha,Fernanda R, AU - Da Silva,Saulo L, AU - Miguel,Danilo C, Y1 - 2019/08/24/ PY - 2019/07/19/received PY - 2019/08/21/revised PY - 2019/08/22/accepted PY - 2019/8/28/pubmed PY - 2020/2/25/medline PY - 2019/8/28/entrez KW - Leishmanicidal activity KW - Oligoarginine KW - Peptide KW - Phospholipase SP - 108612 EP - 108612 JF - Comparative biochemistry and physiology. Toxicology & pharmacology : CBP JO - Comp. Biochem. Physiol. C Toxicol. Pharmacol. VL - 226 N2 - Phospholipase A2 toxins present in snake venoms interact with biological membranes and serve as structural models for the design of small peptides with anticancer, antibacterial and antiparasitic properties. Oligoarginine peptides are capable of increasing cell membrane permeability (cell penetrating peptides), and for this reason are interesting delivery systems for compounds of pharmacological interest. Inspired by these two families of bioactive molecules, we have synthesized two 13-mer peptides as potential antileishmanial leads gaining insights into structural features useful for the future design of more potent peptides. The peptides included p-Acl, reproducing a natural segment of a Lys49 PLA2 from Agkistrodon contortrix laticinctus snake venom, and its p-AclR7 analogue where all seven lysine residues were replaced by arginines. Both peptides were active against promastigote and amastigote forms of Leishmania (L.) amazonensis and L. (L.) infantum, while displaying low cytotoxicity for primary murine macrophages. Spectrofluorimetric studies suggest that permeabilization of the parasite's cell membrane is the probable mechanism of action of these biomolecules. Relevantly, the engineered peptide p-AclR7 was more active in both life stages of Leishmania and induced higher rates of ethidium bromide incorporation than its native template p-Acl. Taken together, the results suggest that short peptides based on phospholipase toxins are potential scaffolds for development of antileishmanial candidates. Moreover, specific amino acid substitutions, such those herein employed, may enhance the antiparasitic action of these cationic peptides, encouraging their future biomedical applications. SN - 1532-0456 UR - https://www.unboundmedicine.com/medline/citation/31454702/Potential_use_of_13-mer_peptides_based_on_phospholipase_and_oligoarginine_as_leishmanicidal_agents L2 - https://linkinghub.elsevier.com/retrieve/pii/S1532-0456(19)30328-X DB - PRIME DP - Unbound Medicine ER -