Approaching the golden age of natural product pharmaceuticals from venom libraries: an overview of toxins and toxin-derivatives currently involved in therapeutic or diagnostic applications.

Poisons and the toxins found in venomous and poisonous organisms have been the focus of much research over the past 70 years, most of which has been directed at understanding the biochemical and physiological mechanisms by which they elicit their dramatic pathological consequences. Much knowledge has been gained in terms of how poisons and venoms and their composite toxins give rise to the syndromes associated with envenoming and poisoning and in some isolated cases there have been a few such agents promoted for therapeutic use. However, it has only been in the past decade that an explosion of interest has occurred in mining these natural, highly evolved libraries of bioactive toxins and poisons for use in pharmacotherapeutics as drugs or drug leads as well as in diagnostic applications. We ascribe this recent phenomenon to advances in toxinology which have provided investigators with a relatively thorough understanding of the nature of venoms and their biologically active toxins: particularly with regard to the peptidomes and proteomes of venoms. This is in conjunction with our greatly improved understanding of the etiology of many human diseases and the identification of sites of potential therapeutic intervention. In this review we provide an overview of some of the toxins, toxin derivatives or poisons from animal venoms and secretions which are in various stages of development for use as pharmaceuticals or diagnostics in human diseases. As one will recognize, developments in this field suggest that toxinology is now entering a golden age in terms of the identification and use of toxins as potent novel pharmaceuticals.

[1]  Gail Murphy,et al.  Pharmacokinetics and pharmacodynamics of MK‐383, a selective non‐peptide platelet glycoprotein‐IIb/IIIa receptor antagonist, in healthy men , 1994, Clinical pharmacology and therapeutics.

[2]  D. Hoppensteadt,et al.  Emerging anticoagulant and thrombolytic drugs , 2001, Expert opinion on emerging drugs.

[3]  J. Daly,et al.  Epibatidine, a potent analgetic and nicotinic agonist. , 1994, Molecular pharmacology.

[4]  R. Gould,et al.  Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. , 1994, Journal of medicinal chemistry.

[5]  D. Phillips,et al.  Clinical pharmacology of eptifibatide. , 1997, The American journal of cardiology.

[6]  B. Olivera,et al.  Contulakin-G, an O-Glycosylated Invertebrate Neurotensin* , 1999, The Journal of Biological Chemistry.

[7]  J. Changeux,et al.  Rational understanding of nicotinic receptors drug binding. , 2004, Current topics in medicinal chemistry.

[8]  M. Read,et al.  Venom coagglutinin for detection of von Willebrand factor activity in animal plasmas. , 1983, The Journal of laboratory and clinical medicine.

[9]  M. Bonnet The toxicology of Heloderma suspectum: the Gila monster , 2000, British Homeopathic Journal.

[10]  A. Young,et al.  Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). , 1999, Diabetes.

[11]  B. Fry From genome to "venome": molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. , 2005, Genome research.

[12]  M. Trikha,et al.  Contortrostatin, a snake venom disintegrin, inhibits beta 1 integrin-mediated human metastatic melanoma cell adhesion and blocks experimental metastasis. , 1994, Cancer research.

[13]  R. C. Rodríguez de la Vega,et al.  Overview of scorpion toxins specific for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution. , 2005, Toxicon : official journal of the International Society on Toxinology.

[14]  L. Duong,et al.  Isolation, characterization, and cDNA cloning of a vampire bat salivary plasminogen activator. , 1989, The Journal of biological chemistry.

[15]  S. Niewiarowski,et al.  Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. , 1987, The Journal of biological chemistry.

[16]  C. Toombs Alfimeprase: Pharmacology of a Novel Fibrinolytic Metalloproteinase for Thrombolysis , 2001, Pathophysiology of Haemostasis and Thrombosis.

[17]  M. Esnouf,et al.  The Isolation and Properties of the Thrombin‐like Activity from Ancistrodon rhodostoma Venom , 1967, British journal of haematology.

[18]  P. Ho,et al.  Transcriptome analysis of expressed sequence tags from the venom glands of the fish Thalassophryne nattereri. , 2006, Biochimie.

[19]  R. Kini Venom phospholipase A2 enzymes , 1997 .

[20]  Harald Sontheimer,et al.  Chlorotoxin Inhibits Glioma Cell Invasion via Matrix Metalloproteinase-2* , 2003, The Journal of Biological Chemistry.

[21]  J. Fox,et al.  Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d). , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Maroun,et al.  Snake venom serine proteinases: sequence homology vs. substrate specificity, a paradox to be solved. , 2005, Toxicon : official journal of the International Society on Toxinology.

[23]  M. Watters Tropical marine neurotoxins: venoms to drugs. , 2005, Seminars in neurology.

[24]  G. Tucker Integrins: Molecular targets in cancer therapy , 2006, Current oncology reports.

[25]  Eric J Topol,et al.  Platelet GPIIb-IIIa blockers , 1999, The Lancet.

[26]  J. Brugge,et al.  Structurally distinct disintegrins contortrostatin and multisquamatin differentially regulate platelet tyrosine phosphorylation. , 1994, The Journal of biological chemistry.

[27]  J. Raufman,et al.  Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. , 1992, The Journal of biological chemistry.

[28]  L. Lorand,et al.  Methods in enzymology. Volume XIX. Proteolytic enzymes. Volume XIX. , 1970 .

[29]  M A Ondetti,et al.  Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation, elucidation of structure, and synthesis. , 1971, Biochemistry.

[30]  J. Stewart,et al.  Bradykinin potentiating peptide PCA-Lys-Trp-Ala-Pro. An inhibitor of the pulmonary inactivation of bradykinin and conversion of angiotensin I to II. , 1971, Biochemical pharmacology.

[31]  P. Ho,et al.  A survey of gene expression and diversity in the venom glands of the pitviper snake Bothrops insularis through the generation of expressed sequence tags (ESTs). , 2002, Gene.

[32]  C. Marcinkiewicz Functional characteristic of snake venom disintegrins: potential therapeutic implication. , 2005, Current pharmaceutical design.

[33]  I. Charo,et al.  Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. , 1993, The Journal of biological chemistry.

[34]  A. Harvey,et al.  Recent studies on dendrotoxins and potassium ion channels. , 1997, General pharmacology.

[35]  K. Garber Peptide leads new class of chronic pain drugs , 2005, Nature Biotechnology.

[36]  C. Roumestand,et al.  Scorpion toxins as natural scaffolds for protein engineering. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[37]  N. Marsh,et al.  The effects of snake venoms on the cardiovascular and haemostatic mechanisms. , 1978, International Journal of Biochemistry.

[38]  R. Luther,et al.  Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. , 1998, Toxicon : official journal of the International Society on Toxinology.

[39]  J. Fox,et al.  A multifaceted analysis of viperid snake venoms by two‐dimensional gel electrophoresis: An approach to understanding venom proteomics , 2005, Proteomics.

[40]  J. Ribeiro,et al.  Bitis gabonica (Gaboon viper) snake venom gland: toward a catalog for the full-length transcripts (cDNA) and proteins. , 2004, Gene.

[41]  J. Fox,et al.  Synthetic and endogenous inhibitors of snake venom metalloproteinases. , 1991, Biomedica biochimica acta.

[42]  J. Calvete,et al.  Snake venom disintegrins: evolution of structure and function. , 2005, Toxicon : official journal of the International Society on Toxinology.

[43]  B. Olivera,et al.  Conus venoms: a rich source of novel ion channel-targeted peptides. , 2004, Physiological reviews.

[44]  C. Moskaluk,et al.  Role of the snake venom toxin jararhagin in proinflammatory pathogenesis: in vitro and in vivo gene expression analysis of the effects of the toxin. , 2005, Archives of biochemistry and biophysics.

[45]  J. Vane,et al.  The Discovery of Captopril , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  A. Colevas,et al.  Clinical trials referral resource. Current clinical trials of cilengitide, an alpha(v) antagonist in clinical development as an anticancer agent. , 2004, Oncology.

[47]  H. Sontheimer,et al.  A role for ion channels in glioma cell invasion. , 2005, Neuron glia biology.

[48]  D. Missé,et al.  Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes , 2003, Nature Biotechnology.

[49]  J. Vane,et al.  Some Properties of Angiotensin Converting Enzyme in the Lung in vivo , 1970, Nature.

[50]  J. Rosing,et al.  Snake Venom Activators of Factor X: An Overview , 2001, Pathophysiology of Haemostasis and Thrombosis.

[51]  N. Whittaker,et al.  Further classification of skin alkaloids from neotropical poison frogs (Dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. , 1987, Toxicon : official journal of the International Society on Toxinology.

[52]  A. Camargo,et al.  The Bradykinin-potentiating peptides from venom gland and brain of Bothrops jararaca contain highly site specific inhibitors of the somatic angiotensin-converting enzyme. , 2005, Toxicon : official journal of the International Society on Toxinology.

[53]  W. Schleuning Vampire Bat Plasminogen Activator DSPA-Alpha-1 (Desmoteplase): A Thrombolytic Drug Optimized by Natural Selection , 2001, Pathophysiology of Haemostasis and Thrombosis.

[54]  P. Straub,et al.  Reptilase®‐R—A New Reagent in Blood Coagulation , 1971, British journal of haematology.

[55]  J. Fox,et al.  Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases. , 2005, Toxicon : official journal of the International Society on Toxinology.

[56]  M. Trikha,et al.  Purification and characterization of platelet aggregation inhibitors from snake venoms. , 1994, Thrombosis research.

[57]  S. Ferreira,et al.  Isolation of bradykinin-potentiating peptides from Bothrops jararaca venom. , 1970, Biochemistry.

[58]  S. Serrano,et al.  Sex-based individual variation of snake venom proteome among eighteen Bothrops jararaca siblings. , 2006, Toxicon : official journal of the International Society on Toxinology.

[59]  J. Motsch,et al.  Update in the prevention and treatment of deep vein thrombosis and pulmonary embolism , 2006, Current opinion in anaesthesiology.

[60]  W. Kisiel,et al.  The factor V-activating enzyme (RVV-V) from Russell's viper venom. Identification of isoproteins RVV-V alpha, -V beta, and -V gamma and their complete amino acid sequences. , 1988, The Journal of biological chemistry.

[61]  T. Tsuruo,et al.  Molecular cloning and functional analysis of apoxin I, a snake venom-derived apoptosis-inducing factor with L-amino acid oxidase activity. , 2000, Biochemistry.

[62]  T. Morita Structures and functions of snake venom CLPs (C-type lectin-like proteins) with anticoagulant-, procoagulant-, and platelet-modulating activities. , 2005, Toxicon : official journal of the International Society on Toxinology.

[63]  J. Fox,et al.  Comparison of indirect and direct approaches using ion-trap and Fourier transform ion cyclotron resonance mass spectrometry for exploring viperid venom proteomes. , 2006, Toxicon : official journal of the International Society on Toxinology.

[64]  G. Strichartz,et al.  Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. , 1993, The American journal of physiology.

[65]  A. Bosserhoff,et al.  Integrin signaling in malignant melanoma , 2005, Cancer and Metastasis Reviews.

[66]  J. Charles,et al.  A Sino-German λ 6 cm polarization survey of the Galactic plane I . Survey strategy and results for the first survey region , 2006 .

[67]  Julian White Snake venoms and coagulopathy. , 2005, Toxicon : official journal of the International Society on Toxinology.

[68]  S. Ferreira A Bradykinin-Potentiating Factor (BPF) present in the Venom of Bothrops jararaca. , 1965 .

[69]  C. M. Bogert,et al.  Gila monster: its biology, venom and bite--a review. , 1981, Toxicon : official journal of the International Society on Toxinology.

[70]  S. Arneric,et al.  ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization. , 1998, The Journal of pharmacology and experimental therapeutics.