Abstract
The membrane-active nature of phospholipase A2-derived peptides makes them potential candidates for antineoplastic and antibacterial therapies. Two short 13-mer C-terminal fragments taken from snake venom Lys49-PLA2 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 A2 isoforms, is again demonstrated as a valuable source of therapeutic peptides.
Highlights
Bioactive peptides have opened a new horizon in drug discovery and are currently considered a cornerstone in developing therapies for cancer and bacterial infections [1].In the last years, more than 7% of Food and Drug Administration-approved drugs are peptide-based entities [2]
Peptide p-AppK is inspired in a membrane disrupting protein from Agkistrodon piscivorus piscivorus, and has been previously reported to exert cytotoxic effects on tumors
Peptide p-Acl is derived from a membrane-damaging toxin, a Lys49-PLA2 from Agkistrodon contortrix laticinctus
Summary
Bioactive peptides have opened a new horizon in drug discovery and are currently considered a cornerstone in developing therapies for cancer and bacterial infections [1].In the last years, more than 7% of Food and Drug Administration-approved drugs are peptide-based entities [2]. The design and refinement of these active structures are highly challenging [3], and several prediction models and tools are being proposed and have been made available in recent years [4,5]. Despite these bioinformatics and statistical advances, the isolation of peptides from natural sources, the identification by genomic and transcriptomic investigations, or the synthesis of molecular region mimics of target proteins remain useful both to discover new structures and to understand functional aspects that are crucial for the selection of more potent and selective molecules [6,7]. An important precedent is Captopril, an antihypertensive synthetic analogue of one short molecule from
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