What can toxins tell us for drug discovery?

Harvey, Alan L.; Bradley, Karen N.; Cochran, S.; Rowan, Edward G.; Pratt, Judith A.; Quillfeldt, Jorge Alberto; Jerusalinsky, Diana

doi:10.1016/s0041-0101(98)00156-1

Cited by 76 publications

(43 citation statements)

References 9 publications

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“…Thus, the isolation and functional characterization of venom components provides a basis for understanding the mechanisms and/or future molecular models of venom action (21,22).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial activity of an L-amino acid oxidase isolated from Bothrops leucurus snake venom

Torres¹,

Dantas²,

Menezes³

et al. 2010

J. Venom. Anim. Toxins incl. Trop. Dis

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Some snake venom proteins present enzymatic activities, such as L-amino acid oxidase (LAAO). The aim of this paper was to investigate the effect of Bothrops leucurus total venom (BleuTV) and its fraction LAAO (BleuLAAO) on bacteria, yeast, and promastigote forms of Leishmania amazonensis and Leishmania chagasi, and epimastigote forms of Trypanosoma cruzi. BleuTV was isolated with a Protein Pack 5PW® (Waters Corporation, USA), and several fractions were obtained. BleuLAAO was purified to high molecular homogeneity, and its N-terminal amino acid sequence shared a high degree of amino acid conservation with other LAAOs. BleuTV inhibited Staphylococcus aureus growth in a dose-dependent manner, with a minimum inhibitory concentration (MIC) of 25 μg/mL, which corresponded to its minimum lethal concentration (MLC). BleuTV also inhibited the growth of promastigote forms of L. chagasi and L. amazonensis, with respective IC50 values of 1.94 μg/mL and 5.49 μg/mL. Furthermore, it repressed T. cruzi growth with an IC50 of 1.14 μg/mL. However, BleuLAAO did not inhibit the growth of the microorganisms studied and was not toxic to macrophages. BleuTV had low toxicity against macrophages at the concentrations studied. In conclusion, whole venom from Bothrops leucurus inhibited the growth of some microorganisms, including S. aureus, Leishmania sp., and T. cruzi

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“…Thus, the isolation and functional characterization of venom components provides a basis for understanding the mechanisms and/or future molecular models of venom action (21,22).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial activity of an L-amino acid oxidase isolated from Bothrops leucurus snake venom

Torres¹,

Dantas²,

Menezes³

et al. 2010

J. Venom. Anim. Toxins incl. Trop. Dis

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“…Subtle functional differences in some venoms components, which may confer distinct pharmacological activities to proteins from the same family but distinctly expressed in L. muta and L. stenophrys, may be responsible for speciesspecific effects. Our proteomic analysis may serve as a starting point for studying structure-function correlations of individual toxins aiming at the development of new research tools and drugs of potential clinical use [61][62][63]. It is also worth to notice that though intraspecific variation in venom toxins may inform us about evolutionary processes acting at the species or population level, it represents also a source of Numbers refer to the reverse-phase HPLC separation shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Snake venomics of the South and Central American Bushmasters. Comparison of the toxin composition of Lachesis muta gathered from proteomic versus transcriptomic analysis

Sanz

Escolano

Ferretti

et al. 2008

Journal of Proteomics

125

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. were identified in L. muta and L. stenophrys venoms. In addition, both venoms contained a large number of bradykinin-potentiating peptides (BPP) and a C-type natriuretic peptide (C-NP). BPPs and C-NP comprised around 15% of the total venom proteins. In both species, the most abundant proteins were Zn 2+ -metalloproteinases (32-38%) and serine proteinases (25-31%), followed by PLA 2 s (9-12%), galactose-specific C-type lectin (4-8%), L-amino acid oxidase (LAO, 3-5%), CRISP (1.8%; found in L. muta but not in L. stenophrys), and NGF (0.6%).On the other hand, only six L. muta venom-secreted proteins matched any of the previously reported 11 partial or full-length venom gland transcripts, and venom proteome and transcriptome depart in their relative abundances of different toxin families. As expected from their close phylogenetic relationship, the venoms of L. muta and L. stenophrys share (or contain highly similar) proteins, in particular BPPs, serine proteinases, a galactose-specific C-type lectin, and LAO. However, they dramatically depart in their respective PLA 2 complement. Intraspecific quantitative and qualitative differences in the expression of PLA 2 molecules were found when the venoms of five L. muta specimens (3 from Bolivia and 2 from Peru) and the venom of the same species purchased from Sigma were compared.These observations indicate that these class of toxins represents a rapidly-evolving Author's personal copy gene family, and suggests that functional differences due to structural changes in PLA 2 s molecules among these snakes may have been a hallmark during speciation and adaptation of diverging snake populations to new ecological niches, or competition for resources in existing ones. Our data may contribute to a deeper understanding of the biology and ecology of these snakes, and may also serve as a starting point for studying structure-function correlations of individual toxins.

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“…Other mutations can include the selective expression of a particular domain, such as the expression of the disintegrin domain from snake venom metalloprotease, ADAM-type (SVMP/ADAM) toxins in viperid venoms (21). These toxins have an unusual combination of precise specificity and extreme potency, characteristics that make them particularly amenable for use as investigational ligands or as leads for drug design and development (22)(23)(24).…”

Section: Molecular and Cellular Proteomics 7:215-246 2008mentioning

confidence: 99%

Evolution of an Arsenal

Fry

Scheib²,

Weerd³

et al. 2008

Molecular & Cellular Proteomics

309

145

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Venom is a key innovation underlying the evolution of advanced snakes (Caenophidia). Despite this, very little is known about venom system structural diversification, toxin recruitment event timings, or toxin molecular evolution. A multidisciplinary approach was used to examine the diversification of the venom system and associated toxins across the full range of the ϳ100 million-year-old advanced snake clade with a particular emphasis upon families that have not secondarily evolved a front-fanged venom system (ϳ80% of the 2500 species). Analysis of cDNA libraries revealed complex venom transcriptomes containing multiple toxin types including three finger toxins, cobra venom factor, cysteine-rich secretory protein, hyaluronidase, kallikrein, kunitz, lectin, matrix metalloprotease, phospholipase A 2 , snake venom metalloprotease/a disintegrin and metalloprotease, and waprin. High levels of sequence diversity were observed, including mutations in structural and functional residues, changes in cysteine spacing, and major deletions/truncations. Morphological analysis comprising gross dissection, histology, and magnetic resonance imaging also demonstrated extensive modification of the venom system architecture in nonfront-fanged snakes in contrast to the conserved structure of the venom system within the independently evolved front-fanged elapid or viperid snakes. Further, a reduction in the size and complexity of the venom system was observed in species in which constriction has been secondarily evolved as the preferred method of prey capture or dietary preference has switched from live prey to eggs or to slugs/snails. Investigation of the timing of toxin recruitment events across the entire advanced snake radiation indicates that the evolution of advanced venom systems in three front-fanged lineages is associated with recruitment of new toxin types or explosive diversification of existing toxin types. These results support the role of venom as a key evolutionary innovation in the diversification of advanced snakes and identify a potential role for non-front-fanged venom toxins as a rich source for lead compounds for drug design and development.

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What can toxins tell us for drug discovery?

Cited by 76 publications

References 9 publications

Antimicrobial activity of an L-amino acid oxidase isolated from Bothrops leucurus snake venom

Antimicrobial activity of an L-amino acid oxidase isolated from Bothrops leucurus snake venom

Snake venomics of the South and Central American Bushmasters. Comparison of the toxin composition of Lachesis muta gathered from proteomic versus transcriptomic analysis

Evolution of an Arsenal

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