This short synthetic molecule has antitumoral activity against murine tumor cell lines, such as sarcoma, melanoma, mammary carcinoma, and others. The peptide p-AppK (KKYKAYFKLKCKK) is a specific example of that, inspired in the myotoxic C-terminal region of a Lys49-PLA 2 derived from the snake Agkistrodon piscivorus piscivorus. Thus, many lytic PLA 2-derived peptides with antitumor, leishmanicidal, and antibacterial effects have been synthesized to reproduce biological interactions between the C-terminal of the protein templates and biomembranes. Additionally, the membranes of pathogens and cancer cells are an attractive target for low-resistance therapeutic approaches. The PLA 2 family is extremely capable of interacting, modifying, and disrupting membrane lipids. In this connection, snake venom phospholipases A 2 (PLA 2) are a diverse group of great pharmaceutical relevance. An important precedent is Captopril, an antihypertensive synthetic analogue of one short molecule from Bothrops jaracaca, which is considered the first member of angiotensin-converting enzyme inhibitor medications. Biomedical products derived from toxins are a classical example of the pivotal contribution of natural products in the drug discovery process. This repertoire of molecules with subtle differences in the primary structure offers ample opportunity to find therapeutic applications and obtain relevant information to elaborate predictive models and synthesize more efficient molecules. In snake venoms, a diversity of protein isoforms is found. Toxins are natural products characterized by experiencing critical selective pressures for their action in pathways and cell structures of biomedical interest. However, 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. Yet, the design and refinement of these active structures are highly challenging, and several prediction models and tools are being proposed and have been made available in recent years. In the last years, more than 7% of Food and Drug Administration-approved drugs are peptide-based entities. 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.īioactive peptides have opened a new horizon in drug discovery and are currently considered a cornerstone in developing therapies for cancer and bacterial infections. 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. This phenomenon is expected to catalyze the permeation of solutes that otherwise could not cross the hydrophobic membrane core. The latter revealed that the peptides deform the membrane and increase its permeability by facilitating solvent penetration. Indeed, p-AppK and p-Acl did not disrupt erythrocyte membranes, in agreement with in silico predictions. Peptide-based treatment increased the uptake of a DNA-intercalating dye by bacteria, suggesting membrane damage. 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). RAMOS, K562, NB4, and CEM cells were the main leukemic targets of the peptides. All tested bacteria were susceptible to both peptides, Pseudomonas aeruginosa being the most affected. Briefly, both peptides have dual activity, i.e., they act against both bacteria, including multidrug-resistant strains and tumor cells. The mode of action was mainly studied by molecular dynamics simulations and membrane permeabilization assays. Toxicity to red blood cells was investigated via in silico and in vitro techniques. 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. 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. The membrane-active nature of phospholipase A 2-derived peptides makes them potential candidates for antineoplastic and antibacterial therapies.
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