Antitumor effects of snake venom chemically modified Lys49 phospholipase A2-like BthTX-I and a synthetic peptide derived from its C-terminal region

Gebrim, Luiz Carlos; Marcussi, Silvana; Menaldo, Danilo L.; Menezes, Carla S.R. de; Nomizo, Auro; Hamaguchi, Amélia; Silveira-Lacerda, Elisângela de Paula; Homsi-Brandeburgo, Maria Inês; Sampaio, Suely Vilela; Soares, Andreimar M.; Rodrigues, Veridiana M.

doi:10.1016/j.biologicals.2009.01.010

Cited by 62 publications

(47 citation statements)

References 38 publications

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“…Peptides derived from the C‐terminal region of PLA 2 homologues have been the focus of many studies to elucidate their contribution in the mechanism of myotoxic action of these proteins and/or in their use as possible antimicrobial and antitumour agents .…”

Section: Discussionmentioning

confidence: 99%

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Diniz-Sousa

Caldeira

Kayano

et al. 2017

Basic Clin Pharma Tox

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Snake venom phospholipases A (PLA s) are responsible for numerous pathophysiological effects in snakebites; however, their biochemical properties favour antimicrobial actions against different pathogens, thus constituting a true source of potential microbicidal agents. This study describes the isolation of a Lys49 PLA homologue from Lachesis muta muta venom using two chromatographic steps: size exclusion and reverse phase. The protein showed a molecular mass of 13,889 Da and was devoid of phospholipase activity on an artificial substrate. The primary structure made it possible to identify an unpublished protein from L. m. muta venom, named LmutTX, that presented high identity with other Lys49 PLA s from bothropic venoms. Synthetic peptides designed from LmutTX were evaluated for their cytotoxic and antimicrobial activities. LmutTX was cytotoxic against C2C12 myotubes at concentrations of at least 200 μg/mL, whereas the peptides showed a low cytolytic effect. LmutTX showed antibacterial activity against Gram-positive and Gram-negative bacteria; however, S. aureusATCC 29213 and MRSA strains were more sensitive to the toxin's action. Synthetic peptides were tested on S. aureus, MRSA and P. aeruginosaATCC 27853 strains, showing promising results. This study describes for the first time the isolation of a Lys49 PLA from Lachesis snake venom and shows that peptides from specific regions of the sequence may constitute new sources of molecules with biotechnological potential.

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Section: Discussionmentioning

confidence: 99%

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Diniz-Sousa

Caldeira

Kayano

et al. 2017

Basic Clin Pharma Tox

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“…Gebrim et al [110] evaluated both in vitro and in vivo antitumor activity of BPB-modified BthTX-I (PLA 2 Lys49) and its cationic synthetic peptide derived from the 115–129 C-terminal region. BPB-BthTX-I presented 70 and 90% cytotoxicity upon Jurkat, B16F10, and S180 tumor cell lines, which were also susceptible to the lytic action of the synthetic peptide.…”

Section: Snake Venom Phospholipases A2 (Svpla2s)mentioning

confidence: 99%

“…Several articles state the affinity of secretory PLA 2 s for different membrane receptors and lipids, but since those related to Bothrops myotoxins are still unknown, two mechanisms have been proposed to explain Lys49 myotoxin cytotoxicity: a fatty acid-dependent lysis by means of an interaction with a receptor able to activate the myotoxin and the activation of intracellular lipase unleashed by the binding of the myotoxin to the receptor [110–112]. …”

Section: Snake Venom Phospholipases A2 (Svpla2s)mentioning

confidence: 99%

Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

Calderon

Sobrinho

Zaqueo

et al. 2014

BioMed Research International

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142

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For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP), disintegrins, L-amino acid oxidases (LAAOs), C-type lectins, and phospholipases A2 (PLA2s). Their mechanisms of action include direct toxic action (PLA2s), free radical generation (LAAOs), apoptosis induction (PLA2s, MP, and LAAOs), and antiangiogenesis (disintegrins and lectins). Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development.

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“…This C-terminal region was identified as a structural determinant of this effect [45]. Short synthetic peptides representing the C-terminal region of PLA 2 myotoxins showed cytolytic and muscle damaging activities similar to their parent proteins, although they display a lower potency [46–48]. Significant decrease of myotoxic activity after incubation with heparin confirms the involvement of C-terminal region of PhTX-I which is a basic myotoxin with high content of Lys residues [20].…”

Section: Discussionmentioning

confidence: 99%

Chemical Modifications of PhTX-I Myotoxin fromPorthidium hyoproraSnake Venom: Effects on Structural, Enzymatic, and Pharmacological Properties

Huancahuire-Vega

Corrêa²,

Hollanda³

et al. 2013

BioMed Research International

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We recently described the isolation of a basic PLA2 (PhTX-I) from Porthidium hyoprora snake venom. This toxin exhibits high catalytic activity, induces in vivo myotoxicity, moderates footpad edema, and causes in vitro neuromuscular blockade. Here, we describe the chemical modifications of specific amino acid residues (His, Tyr, Lys, and Trp), performed in PhTX-I, to study their effects on the structural, enzymatic, and pharmacological properties of this myotoxin. After chemical treatment, a single His, 4 Tyr, 7 Lys, and one Trp residues were modified. The secondary structure of the protein remained unchanged as measured by circular dichroism; however other results indicated the critical role played by Lys and Tyr residues in myotoxic, neurotoxic activities and mainly in the cytotoxicity displayed by PhTX-I. His residue and therefore catalytic activity of PhTX-I are relevant for edematogenic, neurotoxic, and myotoxic effects, but not for its cytotoxic activity. This dissociation observed between enzymatic activity and some pharmacological effects suggests that other molecular regions distinct from the catalytic site may also play a role in the toxic activities exerted by this myotoxin. Our observations supported the hypothesis that both the catalytic sites as the hypothetical pharmacological sites are relevant to the pharmacological profile of PhTX-I.

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Antitumor effects of snake venom chemically modified Lys49 phospholipase A2-like BthTX-I and a synthetic peptide derived from its C-terminal region

Cited by 62 publications

References 38 publications

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

Chemical Modifications of PhTX-I Myotoxin fromPorthidium hyoproraSnake Venom: Effects on Structural, Enzymatic, and Pharmacological Properties

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Antitumor effects of snake venom chemically modified Lys49 phospholipase A2-like BthTX-I and a synthetic peptide derived from its C-terminal region

Cited by 62 publications

References 38 publications

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A2 Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A2 Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

Chemical Modifications of PhTX-I Myotoxin fromPorthidium hyoproraSnake Venom: Effects on Structural, Enzymatic, and Pharmacological Properties

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Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)

Identification of the Molecular Determinants of the Antibacterial Activity of LmutTX, a Lys49 Phospholipase A₂ Homologue Isolated from Lachesis muta muta Snake Venom (Linnaeus, 1766)