Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A(2)-Derived Peptides

• Tipo: Artigo em Revista Científica Internacional
• Data: 2022

Autores

Almeida, JR (Autor) Outra; Mendes, B (Autor) Outra; Lancellotti, M (Autor) Outra; Franchi, GC (Autor) Outra; Passos, O (Autor) Outra; Ramos, MJ (Autor) FCUP; Pedro A Fernandes (Autor) FCUP; Alves, C (Autor) Outra; Nuno Vale (Autor) FMUP; Paula Gomes (Autor) FCUP; da Silva, SL (Autor) Outra

Revista

Título: Current Issues in Molecular Biology

Vol. 44

Páginas: 46-62

ISSN: 1467-3037

Indexação

ISI Web of Knowledge - 16 Citações

Scopus - 17 Citações

Outras Informações

ID Authenticus: P-00V-W9Z

DOI: 10.3390/cimb44010004

Abstract (EN): The membrane-active nature of phospholipase A(2)-derived peptides makes them potential candidates for antineoplastic and antibacterial therapies. Two short 13-mer C-terminal fragments taken from snake venom Lys49-PLA(2) toxins (p-AppK and p-Acl), differing by a leucine/phenylalanine substitution, were synthesized and their bioactivity was evaluated. Their capacity to interfere with the survival of Gram-positive and Gram-negative bacteria as well as with solid and liquid tumors was assessed in vitro. Toxicity to red blood cells was investigated via in silico and in vitro techniques. The mode of action was mainly studied by molecular dynamics simulations and membrane permeabilization assays. Briefly, both peptides have dual activity, i.e., they act against both bacteria, including multidrug-resistant strains and tumor cells. All tested bacteria were susceptible to both peptides, Pseudomonas aeruginosa being the most affected. RAMOS, K562, NB4, and CEM cells were the main leukemic targets of the peptides. In general, p-Acl showed more significant activity, suggesting that phenylalanine confers advantages to the antibacterial and antitumor mechanism, particularly for osteosarcoma lines (HOS and MG63). Peptide-based treatment increased the uptake of a DNA-intercalating dye by bacteria, suggesting membrane damage. Indeed, p-AppK and p-Acl did not disrupt erythrocyte membranes, in agreement with in silico predictions. The latter revealed that the peptides deform the membrane and increase its permeability by facilitating solvent penetration. This phenomenon is expected to catalyze the permeation of solutes that otherwise could not cross the hydrophobic membrane core. In conclusion, the present study highlights the role of a single amino acid substitution present in natural sequences towards the development of dual-action agents. In other words, dissecting and fine-tuning biomembrane remodeling proteins, such as snake venom phospholipase A(2) isoforms, is again demonstrated as a valuable source of therapeutic peptides.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 17