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Venomics and Structural Proteomics LaboratoryMain Researcher
Juan José Calvete ChornetFull Professor; Head of the Structural Proteomics Laboratory EDUCATION/TRAINING/RESEARCH:
Research interestStructural Biology: Carbohydrate-binding proteins -spermadhesins (sperm surface-coating lectins involved in sperm physiology) and plant lectins. Non-conventional Proteomics; Snake venomics; antivenomics; venom phenotyping Snake envenoming constitutes a highly relevant public health issue in many tropical and subtropical countries, and has been recognised by the World Health Organization as a "neglected tropical disease". Adequate treatment of envenoming is critically dependent on the ability of antivenoms to neutralize the symptoms of systemic envenoming. A robust knowledge of the toxin composition and pathophysiological activities of venom proteomes is instrumental for the treatment of envenomed victims and for the selection of specimens for the generation of improved antidotes. A major research aim of our laboratoty is the development and application of proteomic tools (“venomics”, “antivenomics”, “venom phenotyping”) to study the natural history and composition of snake venoms and their interaction with antivenoms. Proteomic-guided identification of evolutionary and immunological trends among venoms may aid replacing the traditional geographic- and phylogenetic-driven hypotheses for antivenom production strategies by a more rationale approach based on venom proteome phenotyping and immunological profile similarities. Venoms comprise unique mixtures of deadly toxins tailored by Natural Selection in a prey-predator co-evolutionary arms race, and thus represent a sophisticated natural source of chemical and pharmacological novelty. Research on venoms (“venomics”) has emerged as a discovery science. In our laboratory we investigate structure-function correlations of the RTS-disintegrin jerdostatin, cloned from a venom gland cDNA library of the Chinese Jerdon's pitviper Protobothrops jerdonii, which selectively blocks the function of the α1β1 integrin both in vitro and in vivo. Jerdostatin may represent a valuable lead compound for the development of anti-angiogenic drugs. Members of research group
Dr. Juan J. Calvete (Profesor de Investigación, CSIC)
Dr. Libia Sanz (Titulado Superior Especializado, CSIC) Alicia Pérez (Técnico de Grado Medio, CSIC) Dr. Davinia Plá (Contrato Postdoctoral, MICINN) Jordi Durban (Becario FPI, MICINN) Gema Bolás (Becaria JAE-Pre CSIC) Raquel Sanz (Becaria FPI, MICINN) Carolina Llorente (Técnico JAE, CSIC) Beatriz Companys (Técnico FPII Prometeo) Grants as Projects Investigation 2002-2004: BCM2001-3337 Structural biology of molecular recognition systems: integrin-disintegrin, Spanish Ministry
of Education and Science. Total cost: 222.344 € 2003-2005: Programa de Cooperación Interuniversitaria hispano-tunecina 28p/02: Etude
protéomique des Venis de Serpents en Tunisie. Recherche des Disintégrines. Spanish-Tunisian Cooperation
Programme. Total cost: 17.909 € 2003-2005: C03701 Factores de riesgo, evolución y tratamiento de las enfermedades cardiovasculares y sus mecanismos moleculares y celulares, Red temática "Cardiovascular", Instituto de Salud Carlos III. Spanish Ministry of Health. Total cost: 464.175,1 € 2003-2005: GRUPOS03/072 Proteomics and Functional and Structural Genomics of Human Pathologies, Valencian Agency of Science and Technology). Total cost: 93.989, 6 € 2004-2005: 2004UY0006 Parasitic glycobiology: characterization of Tn-bearing O-glycoproteins, Spanish Uruguayan Research Programme. Total cost: 4.000 € 2005-2007: BFU2004-01432 Venomics: structural and functional proteomics of disintegrins and other snake venom proteins of potential biomedical relevance, Spanish Ministry of Education and Science Total cost: 323.000 € 2006-2009: 206AC0281 Antivenenos en Iberoamérica: fortalecimiento de las tecnologías para producción y control de calidad en laboratorios públicos de la región Red Temática CYTED (Coordinador: J.M. Gutiérrez, Instituto Clodomiro Picado, Universidad de San José, Costa Rica) 2008-2009 2007CR0004: Venómica y antivenómica de serpientes de interés biomédico en Costa Rica y en la región Centroamericana. Convenio CRUSA-CSIC (I.I.P.P. José María Gutiérrez, Instituto Clodomiro Picado, Universidad de San José, Costa Rica, J.J. Calvete) Total cost: 20.000 € 2007-2010 BFU2007-61563 Top-down snake venomics. Evolution of the disintegrin family and evaluation of the use of the RTS-disintegrin jerdostatin for in vivo imaging of integrin α1β1-dependent tumor angiogenesis, Spanish Ministry of Education and Science. Total cost: 359. 370 € 2010-2011 2009CR0021: Antivenómica de venenos de serpientes de Centroamerica: uso de la proteómica en el mejoramiento de los antivenenos. Convenio CRUSA-CSIC (I.I.P.P. José María Gutiérrez, Instituto Clodomiro Picado, Universidad de San José, Costa Rica, J.J. Calvete) Total cost: 20.000 € 2010-2014 PROMETEO/2010/005: Identificación de nuevas dianas terapéuticas en angiogénesis y apoptosis basadas en interacciones proteína-proteína Generalitat Valenciana (IIPP., Enrique Pérez-Payá (CIPF, IBV), Ismael Mingarro (UV), Manuel M. Sánchez del Pino (CIPF), J.J. Calvete (IBV-CSIC)) Total cost: 64.700 € (2010); 78.000 € (2011) 2011-2013 BFU2010-17373: Venómica Traslacional Ministerio de Ciencia e Innovación (IP. J.J. Calvete) Total cost: 459.800 € 2011 C/032069/10: Venómica y antivenómica de venenos de serpientes de interés médico en Marruecos Agencia Española de Cooperación Internacional (AECID) (IIPP: Juan J. Calvete (CSIC), Noreddine Ghalim (Institut Pasteur du Maroc) Total cost: 21.950 € Selected publications2005Conformation and concerted dynamics of the integrin binding site and the C-terminal region of echistatin revealed by homonuclear NMR Monleón, D., Esteve, V., Kovacs, H., Calvete, J.J. & Celda, B. Biochem. J. 387 (2005) 57-66 Structure-function correlations of snake venom disintegrins Calvete, J.J. Curr. Pharm. Design 11 (2005) 829-835 Snake venom disintegrins: evolution of structure and function Calvete, J.J., Marcinkiewicz, C., Monleón, D., Esteve, V., Celda, B., Juárez, P. & Sanz, L. Toxicon 45 (2005) 1063-1074 Snake venomics: comparative analysis of the venom proteomes of the Tunisian snakes Cerastes cerastes, Cerastes vipera and Macrovipera lebetina Bazaa, A., Marrakchi, N., El Ayeb, M., Sanz, L. & Calvete, J.J. Proteomics 5 (2005) 4223-4235 cDNA cloning and functional expression of jerdostatin, a novel RTS-disintegrin from Trimeresurus jerdonii and a
specific inhibitor of the α1β1 integrin 2006Molecular cloning of disintegrins from Cerastes vipera and Macrovipera lebetina transmediterranea venom gland
cDNA libraries. Insight into the evolution of the snake venom´s integrin inhibition system Molecular cloning of disintegrin-like transcript BA-5A from Bitis arietans venom gland cDNA library: a putative intermediate in the evolution of the long chain disintegrin bitistatin Juárez, P., Wagstaff, S.C., Oliver, J., Sanz, L., Harrison, R.A. & Calvete, J.J. J. Mol. Evol. 63 (2006) 142-152 Molecular cloning of Echis ocellatus disintegrins reveals non-venom-secreted proteins and a pathway for the evolution of ocellatusin Juárez, P., Wagstaff, S.C., Sanz, L., Harrison, R.A. & Calvete, J.J. J. Mol. Evol. 63 (2006) 183-193 Venom proteomes of closely-related Sistrurus rattlesnakes with divergent diets Sanz, L., Gibbs, H.L., Mackessy, S.P. & Calvete, J.J. J. Prot. Res. 5 (2006) 2098-2112 2007KTS- and RTS-disintegrins: anti-angiogenic viper venom peptides specifically targeting the α1β1 integrin Calvete, J.J., Marcinkiewicz, C. & Sanz, L. Curr. Pharm. Des. 13 (2007) 2853-285 Loss of introns along the evolutionary diversification pathway of snake venom disintegrins bevidenced by sequence analysis of genomic DNA from Macrovipera lebetina transmediterranea and Echis ocellatus Bazaa, A., Juárez, P., Marrakchi, N., Bel Lasfer, Z., El Ayeb, M., Harrison, R.A., Calvete, J.J. & Sanz, L. J. Mol. Evol. 64 (2007) 261-271 Snake venomics of Bitis gabonica gabonica. Protein family composition, subunit organization of venom toxins, and characterization of dimeric disintegrins bitisgabonin-1 and bitisgabonin-2 Calvete, J.J., Marcinkiewicz, C. & Sanz, L. J. Proteome Res. 6 (2007) 326-336 Proteomic mass profiling of a snake venom using high-mass detection MALDI-TOF mass spectrometry Yanes, O., Wenzel, R., Calvete, J.J., Nazabal, A., Avilés, F.X., Zenobi, R. J. Am. Soc. Mass Spectrom. 18 (2007) 600-609 Snake venomics. Protocols and applications Calvete, J.J., Juárez, P. & Sanz, L. J. Mass Spectrom. 42 (2007) 1405-1414 Snake venomics of Bitis species reveals large intragenus venom toxin composition variation. Application to taxonomy of congeneric taxa Calvete, J.J., Escolano, J. & Sanz, L. J. Proteome Res. 6 (2007) 2732-2745 VEGF-related protein isolated from Vipera palestinae venom, promotes angiogenesis Brown, M.C., Calvete, J.J., Staniszewska, I., Walsh, E.M., Perez-Liz, G., Del Valle, L.D., Lazarovici, P. & Marcinkiewicz, C. Growth Factors 25 (2007) 108-117 2008Snake venomics of Central American pitvipers. Clues for rationalizing the distinct envenomation profiles of Atropoides nummifer and Atropoides picadoi Angulo, Y., Escolano, J., Lomonte, B., Gutiérrez, J.M., Sanz, L. & Calvete, J.J. J. Proteome Res. 7 (2008) 708-719 Snake venomics of the South and Central American Bushmasters. Comparison of the toxin composition of Lachesis muta gathered from proteomic versus transcriptomic analysis Sanz, L., Escolano, J., Ferretti, M., Biscoglio, M.J., Rivera, E., Crescenti, E.J., Angulo, Y., Lomonte, B., Gutiérrez, J.M. & Calvete, J.J. J. Proteomics 71 (2008) 46-60 Snake venomics and antivenomics of the arboreal neotropical pitvipers Bothriechis lateris and Bothriechis schlegelii Lomonte, B., Escolano, J., Fernández, J., Sanz, L., Angulo, Y., Gutiérrez, J.M. & Calvete, J.J. J. Proteome Res.7 (2008) 2445-2457 Snake venomics of the lancehead pitviper Bothrops asper. Geographic, individual and ontogenetic variations Alape-Girón, A., Sanz, L., Escolano, J., Flores-Díaz, M., Madrigal, M., Sasa, M. & Calvete, J.J. J. Proteome Res. 7 (2008) 3556-3571 Snake venomics of the Armenian mountain vipers Macrovipera lebetina obtusa and Vipera raddei Sanz, L., Ayvazyan, N. & Calvete J.J. J. Proteomics 71 (2008) 198-209 Snake venomics of the Brazilian pitvipers Bothrops cotiara and Bothrops fonsecai. Identification of taxonomy markers Tashima, A.K., Sanz, L., Camargo, A.C.M., Serrano, S.M.T. & Calvete, J.J. J. Proteomics 71 (2008) 473-485 Evolution of snake venom disintegrins by positive Darwinian selection Juárez, P., Comas, I., González-Candelas, F. & Calvete, J.J. Mol. Biol. Evol. 25 (2008) 2391-2407 Snake venomics of the Lesser Antillean pit vipers Bothrops caribbaeus and Bothrops lanceolatus. Correlation with toxicological activities and immunoreactivity of a heterologous antivenom Gutierrez, J., Sanz, L., Escolano, J., Fernandez, J., Lomonte, B., Angulo, Y., Rucavado, A., Warrell, D.A. & Calvete, J.J. J. Proteome Res. 7 (2008) 4396-4408 2009Snake population venomics: proteomics-based analyses of individual variation reveals gene regulation effects on venom protein expression in Sistrurus rattlesnakes Gibbs, H.L., Sanz, L. & Calvete, J.J. J. Mol. Evol. 68 (2009) 113-125 Combined snake venomics and venom gland transcriptomic analysis of the ocellated carpet viper, Echis ocellatus Wagstaff, S.C., Sanz, L., Juárez, P., Harrison, R.A. & Calvete, J.J. J. Proteomics 71 (2009) 609-623 Structural requirements of KTS-disintegrin for inhibition of α1β1 integrin Brown, M.C., Eble, J.A., Calvete, J.J. & Marcinkiewicz, C. Biochem. J. 417 (2009) 95-101 Snake venomics and antivenomics of Bothrops colombiensis, a medically important pitviper of the Bothrops atroxasper complex endemic to Venezuela: Contributing to its taxonomy and snakebite management Calvete, J.J., Borges, A., Segura, A., Flores-Diaz, M., Alape-Girón, A., Gutiérrez, J.M., Diez, N., De Sousa, L., Kiriakos, D., Sánchez, E., Faks, J.G., Escolano, J. & Sanz, L. J. Proteomics 72 (2009) 227-240 Snake venomics and antivenomics: proteomic tools in the design and control of antivenoms for the treatment of snakebite envenoming Gutiérrez, J.M., Lomonte, B., León, G., Alape-Girón, A., Flores-Diaz, M., Sanz, L., Angulo, Y. & Calvete, J.J. J. Proteomics 72 (2009) 165-182 Venoms, venomics, antivenomics Calvete, J.J., Sanz, L., Angulo, Y., Lomonte, B. & Gutiérrez, J.M. FEBS Lett 583 (2009) 1736-1743 Exploring the venom proteome of the western diamond rattlesnake, Crotalus atrox, via snake venomics and combinatorial peptide ligand approaches Calvete, J.J., Fasoli, E., Sanz, L., Boschetti, E. & Righetti, P.G. J. Proteome Res. 8 (2009) 3055-3067 Studies on the venom proteome of Bothrops asper: perspectives and applications Alape-Girón, A., Sanz, L., Escolano, J., Flores-Díaz, M., Madrigal, M., Sasa, M. & Calvete, J.J. Toxicon 54 (2009) 938-948 Effect of VP12 and viperistatin on inhibition of collagen receptors-dependent melanoma metastasis Staniszewska, I., Walsh, E.M., Rothman, V.L., Lazarovici, P., Calvete, J.J., Tuszynski, G.P., Gaathon, A. & Marcinkiewicz, C. Cancer Biol. Therapy 8 (2009) 1507-1516 Snake venomics and antivenomics of Bothrops atrox venoms from Colombia and the Amazon regions of Brazil, Perú and Ecuador suggest the occurrence of geographic variation of venom phenotype by a trend towards paedomorphism Núñez, V., Cid, P., Sanz, L., De La Torre, P., Angulo, Y., Lomonte, B., Gutiérrez, J.M. & Calvete, J.J. J. Proteomics 73 (2009) 57-78 Snake venomics and disintegrins. Portrait and evolution of a family of snake venom integrin antagonists Calvete, J.J., Juárez, P. & Sanz, L. Handbook of Venoms and Toxins of Reptiles Mackessy, S.P. (ed.) CRC Press, Taylor & Francis, Boca Ratón Chapter 17, pp. 337-357 (2009), ISBN: 978-0-8493-9165-1 Venomics Calvete, J.J. (ed.) J. Proteomics 72 (2), pp. 121-282, Elsevier, BV (2009) doi:10.1016/S1874-3919(09)00082-7 2010Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP®) for the treatment of viper envenoming in sub-Saharan Africa Segura, A., Villalta, M., Herrera, M., León, G., Harrison, R., Durfa, N., Nasidi, A., Calvete, J.J., Theakston, R.D.G., Warrell, D.A. & Gutiérrez, J.M. Toxicon 55 (2010) 369-374 Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America Calvete, J.J., Sanz, L., Cid, P., De La Torre, P., Flores-Díaz, M., Dos Santos, M.C., Borges, A., Bremo, A., Angulo, Y., Lomonte, B., Alape-Girón, A. & Gutiérrez, J.M. J. Proteome Res.9 (2010) 528-544 Impact of regional variation in Bothrops asper snake venom on the design of antivenoms: integrating antivenomics and neutralization approaches Gutiérrez, J.M., Sanz, L., Flores-Díaz, M., Figueroa, L., Madrigal, M., Herrera, M., Villalta, M., León, G., Estrada, R., Borges, A., Alape-Girón, A. & Calvete, J.J. J. Proteome Res. 9 (2010) 564-577 Antivenomics and venom phenotyping: a marriage of convenience to address the performance and range of clinical use of antivenoms Calvete, J.J. Toxicon 56 (2010) 1284–1291 Exploring the venom proteome of the African puff adder, Bitis arietans, using a combinatorial peptide ligand library approach at different pHs Fasoli, E., Sanz, L., Wagstaff, S., Harrison, R.A., Righetti, P.G. & Calvete, J.J. J. Proteomics 73 (2010) 932-942 Isolation of an acidic phospholipase A2 from the venom of the snake Bothrops asper of Costa Rica: biochemical and toxicological characterization Fernández, J., Gutiérrez, J.M, Angulo, Y., Sanz, L., Juárez, P., Calvete, J.J. & Lomonte, B. Biochimie 92 (2010) 273-283 Antivenomic Assessment of the Immunological Reactivity of EchiTAb-Plus-ICP®, an Antivenom for the Treatment of Snakebite Envenoming in sub-Saharan Africa Calvete, J.J., Cid, P., Sanz, L., Segura, A., Villalta, M., León, G., Harrison, R., Durfa, N., Nasidi, A., Theakston, R.D.G., Warrell, D.A., Gutiérrez, J.M. Am. J. Trop. Med. Hyg. 82 (2010) 1194-201 Snake venomics and antivenomics of Crotalus durissus subspecies from Brazil: assessment of geographic variation and its implication on snakebite management Boldrini-França, J., Corrêa-Netto, C., Silva, M.M.S., Rodrigues, R.S., De La Torre, P., Pérez, A., Soares, A.M., Zingali, R.B., Nogueira, R.A., Rodrigues, V.M., Sanz, L. & Calvete, J.J. J. Proteomics 73 (2010) 1758-1776 Isolation and biological characterization of Batx-I, a weak hemorrhagic and fibrinogenolytic PI metalloproteinase from Colombian Bothrops atrox venom Patiño, A.C., Pereañez, J.A., Núñez, V., Benjumea, D.M., Fernández, M., Rucavado, A., Sanz, L. & Calvete, J.J. Toxicon 56 (2010) 936-943 Snake venomics of Bothriechis nigroviridis reveals extreme variability among palm pitviper venoms: different evolutionary solutions for the same trophic purpose Fernández, J., Lomonte, B., Sanz, L., Angulo, Y., Gutiérrez, J.M. & Calvete, J.J. J. Proteome Res. 9 (2010) 4234-4241 Recombinant expression in human cells of active integrin α1β1-blocking RTS-disintegrin jerdostatin Juárez, P., Bolás, G., de Rezende, F.F., Calvete, J.J. & Eble, J.A. Toxicon 56 (2010) 1052-1058 Envenenamiento por mordedura de serpiente: La proteómica facilita el desarrollo de tratamientos para el ofidismo, una patología desatendida Calvete, J.J. Investigación y Ciencia 405 (2010) 9-11 Antivenomics of Atropoides mexicanus and Atropoides picadoi snake venoms: relationship to the neutralization of toxic and enzymatic activities Antúnez, J., Fernández, J., Lomonte, B., Angulo, Y., Sanz, L., Pérez, A., Calvete, J.J. & Gutiérrez, J.M. J. Venom Res. 1 (2010) 8-17 Snake venomics, antivenomics, and venom phenotyping: ménage à trois of proteomic tools aimed at understanding
the biodiversity of venoms Brief history and molecular determinants of snake venom disintegrin evolution Calvete, J.J. Toxins and Hemostasis: from Bench to Bedside (Kini, R.M., Clemetson, K., Markland, F., McLane, M.A., Morita, T., eds.) Springer, Dordrecht (The Netherlands) Chapter 18, pp. 285-300 (2010), ISBN 9789048192946 2011Snake venomics of African spitting cobras: Toxin composition and assessment of congeneric cross-reactivity of the Pan-African EchiTAb-Plus-ICP® antivenom by antivenomics and neutralization approaches Petras, D., Sanz, L., Segura, A., Herrera, M., Villalta, M., Solano, D., Vargas, M., León, G., Warrell, D.A., Theakston, R.D.G., Harrison, R.A., Durfa, N., Nasidi, A., Gutiérrez, J.M. & Calvete, J.J. J. Proteome Res. 10 (2011) 1266-1280 Snake population venomics and antivenomics of Bothrops atrox: paedomorphism along its transamazonian dispersal and implications of geographic venom variability on snakebite management Calvete, J.J., Sanz, L., Pérez, A., Borges, A., Vargas, A.M., Lomonte, B., Angulo, Y., Gutiérrez, J.M., Chalkidis, H.M., Mourão, R.H.V., Furtado, M.F.D. & Moura da Silva, A.M. J. Proteomics 74 (2011) 510-527 Venomic and antivenomic analyses of the Central American coral snake, Micrurus nigrocinctus (Elapidae) Fernández, J., Alape-Girón, A., Angulo, Y., Sanz, L., Gutiuérrez, J., Calvete, J.J. & Lomonte, B. J. Proteome Res. 10 (2011) 1816–1827 Snake venomics and venom gland tranacriptomic analysis of Brazilian coral snakes, Micrurus altirostris and M. corallinus Corrêa-Netto, C., Junqueira de Azevedo, I.L.M., Silva, D.A., Ho, P.L., Leitão de Araujo, M., Alves, M.L.M., Sanz, L., Foguel, D., Zingali, R.B. & Calvete, J.J. J. Proteomics 74 (2011) Profiling venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing Durban, J., Juárez, P., Angulo, Y., Lomonte, B., Flores-Diaz, M., Alape-Girón, A., Sasa, M., Sanz, L., Gutiérrez, J.M., Dopazo, J., Conesa, A. & Calvete, J.J. BMC Genomics (2011) NMR structure and dynamics of recombinant wild-type and mutated jerdostatin, a selective inhibitor of integrin α1β1 Carbajo, R.J., Sanz, L., Mosulén S., Pérez, A., Marcinkiewicz, C., Pineda-Lucena, A. & Calvete, J.J. PROTEINS: Structure, Function, and Bioinformatics (2011) Ending the drought: new strategies for improving the flow of affordable, effective antivenoms in Asia and Africa Williams, D.J., Gutiérrez, J.M., Calvete, J.J., Wüster, W., Ratanabanangkoon, K., Paiva, O., Brown, N.I., Casewell, N.R., Harrison, R.A., Rowley, P.D., O’Shea, M., Jensen, S.D., Winkel, K.D. & Warrell, D. A. J. Proteomics (2011) Proteomic tools against the neglected pathology of snakebite envenoming Calvete J.J. Exp. Rev. Proteomics (2011) Contact Information
Instituto de Biomedicina de Valencia, Teléfono: +34 96 339 1778; Fax:+34 96 369 0800; Email: jcalvete@ibv.csic.es |
