Structure-Activity Relationship of Chlorotoxin-Like Peptides

Ali, Syed Abid; Alam, Mehtab; Abbasi, Atiya; Undheim, Eivind A. B.; Fry, Bryan G.; Kalbacher, Hubert; Voelter, Wolfgang

doi:10.3390/toxins8020036

Cited by 24 publications

(13 citation statements)

References 56 publications

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“…Indeed, the analogs presented herein retained the structure, low toxicity, and stability of CTX. Looking beyond CTX, there are many venom‐derived peptides that have been recently reported to have high sequence similarity to CTX . These chlorotoxin‐like peptides might also serve as tunable drug design scaffolds with potential for use in drug delivery.…”

Section: Resultsmentioning

confidence: 99%

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

et al. 2017

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Chlorotoxin (CTX), a disulfide-rich peptide from the scorpion Leiurus quinquestriatus, has several promising biopharmaceutical properties, including preferential affinity for certain cancer cells, high serum stability, and cell penetration. These properties underpin its potential for use as a drug design scaffold, especially for the treatment of cancer; indeed, several analogs of CTX have reached clinical trials. Here, we focus on its ability to internalize into cells-a trait associated with a privileged subclass of peptides called cell-penetrating peptides-and whether it can be improved through conservative substitutions. Mutants of CTX were made using solid-phase peptide synthesis and internalization into human cervical carcinoma (HeLa) cells was monitored by fluorescence and confocal microscopy. CTX_M1 (ie, [K15R/K23R]CTX) and CTX_M2 (ie, [K15R/K23R/Y29W]CTX) mutants showed at least a twofold improvement in uptake compared to CTX. We further showed that these mutants internalize into HeLa cells largely via an energy-dependent mechanism. Importantly, the mutants have high stability, remaining intact in serum for over 24 h; thus, retaining the characteristic stability of their parent peptide. Overall, we have shown that simple conservative substitutions can enhance the cellular uptake of CTX, suggesting that such type of mutations might be useful for improving uptake of other peptide toxins.

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Section: Resultsmentioning

confidence: 99%

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

et al. 2017

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“…This peptide inhibits thechlorotoxin (ClTx) and CFTR channels (GaTx1) by 66% and 82%, respectively, and an amino acid sequence analysis of Bs-Tx7 has identified a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in malignant tumors. This finding suggests that Bs-Tx7 inhibits tumor proliferation by decreasing MMP2 activity (142).…”

Section: Amphibiansmentioning

confidence: 89%

Anticancer potential of bioactive peptides from animal sources

Wang

Dong

et al. 2017

Oncology Reports

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Cancer is the most common cause of human death worldwide. Conventional anticancer therapies, including chemotherapy and radiation, are associated with severe side effects and toxicities as well as low specificity. Peptides are rapidly being developed as potential anticancer agents that specifically target cancer cells and are less toxic to normal tissues, thus making them a better alternative for the prevention and management of cancer. Recent research has focused on anticancer peptides from natural animal sources, such as terrestrial mammals, marine animals, amphibians, and animal venoms. However, the mode of action by which bioactive peptides inhibit the proliferation of cancer cells remains unclear. In this review, we present the animal sources from which bioactive peptides with anticancer activity are derived and discuss multiple proposed mechanisms by which these peptides exert cytotoxic effects against cancer cells.

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“…Scorpion venoms contain hundreds of different compounds that target membranes, ion channels and receptors [ 22 , 23 ]. One class of compounds, known as “non-disulfide-bridged peptides”, comprises short peptides with diverse properties including antimicrobial activity, lytic activity and the potentiation of bradykinin and cell signaling [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Bioactivity of Natural and Engineered Antimicrobial Peptides from Venom of the Scorpions Urodacus yaschenkoi and U. manicatus

Luna-Ramirez

Tonk

Rahnamaeian

et al. 2017

Toxins

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The spread of multidrug-resistant human pathogens has drawn attention towards antimicrobial peptides (AMPs), which are major players in the innate immune systems of many organisms, including vertebrates, invertebrates, plants and microbes. Scorpion venom is an abundant source of novel and potent AMPs. Here, we investigated natural and engineered AMPs from the scorpions Urodacus yaschenkoi and U. manicatus to determine their antimicrobial spectra as well as their hemolytic/cytotoxic activity. None of the AMPs were active against fungi, but many of them were active at low concentrations (0.25–30 µM) against seven different bacteria. Hemolytic and cytotoxic activities were determined using pig erythrocytes and baby hamster kidney cells, respectively. The amino acid substitutions in the engineered AMPs did not inhibit cytotoxicity, but reduced hemolysis and therefore increased the therapeutic indices. The phylogenetic analysis of scorpion AMPs revealed they are closely related and the GXK motif is highly conserved. The engineered scorpion AMPs offer a promising alternative for the treatment of multidrug-resistant bacterial infections and could be modified further to reduce their hemolytic/cytotoxic activity.

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Structure-Activity Relationship of Chlorotoxin-Like Peptides

Cited by 24 publications

References 56 publications

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

Anticancer potential of bioactive peptides from animal sources

Bioactivity of Natural and Engineered Antimicrobial Peptides from Venom of the Scorpions Urodacus yaschenkoi and U. manicatus

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