Rational approach for searching molecular targets involved in inflammatory events and cell survival

• Processo: 15/50040-4
• Linha de fomento: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia
• Vigência: 01 de dezembro de 2015 - 30 de novembro de 2020
• Área do conhecimento: Ciências Biológicas - Bioquímica - Biologia Molecular
• Convênio/Acordo: GlaxoSmithKline
• Pesquisador responsável: Ana Marisa Chudzinski-Tavassi
• Beneficiário: Ana Marisa Chudzinski-Tavassi
• Instituição-sede: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brasil
• Empresa: Glaxosmithkline Brasil Ltda
• Pesquisadores principais: Catarina de Fatima Pereira Teixeira ; Denise Vilarinho Tambourgi ; Irina Kerkis ; Olga Celia Martinez Ibanez ; Yara Cury
• Auxílios(s) vinculado(s): 18/08434-3 - Descoberta de drogas, tendo como alvo a poliglutamilação, em doenças neurodegenerativas, AP.R; 16/19391-8 - EMU concedido no processo 15/50040-4: microscópio confocal TCs SP8 DLS Hyvolution, AP.EMU; 16/19176-0 - EMU concedido no processo: 15/50040-4: sistema de análise fluorescente multiparamétrica, AP.EMU; 16/06027-6 - EMU: aquisição de Amnis image stream para citometria de fluxo com imagem, AP.EMU; 16/06026-0 - EMU: aquisição de QExactive Plus, thermo scientific para espectrometria de massas, AP.EMU
• Bolsa(s) vinculada(s): 19/09498-8 - Vias de sinalização envolvidas na resposta inflamatória em modelos celulares de osteoartrite, BP.PD; 18/20677-9 - Tumor equino: análise proteômica, BP.PD; 18/20469-7 - Usos de moléculas citoprotetoras (hemolina, lipocalina e peptídeos) como ferramentas para a pesquisa de novos alvos moleculares em condrócitos osteoartríticos, BP.PD; + mais bolsas vinculadas 18/20998-0 - Análises de resultados digitalizados dos experimentos de ômicas desenvolvidos no CENTD, em especial transcriptômica e proteômica, BP.PD; 18/10937-3 - Cálulas satélite: efeitos da lipocalina, hemolina e peptídeos derivados, na proliferação e diferenciação de células quiescentes de músculo esquelético, BP.PD; 18/01370-0 - Investigação da ação de toxinas na osteoclastogênese e na ativação de linfócitos: busca dos possíveis alvos terapêuticos, BP.PD; 17/19733-9 - Estudo dos efeitos de uma metaloproteinase de veneno ofídico em pré-adipócitos: ativação de resposta inflamatória e diferenciação celular, BP.MS; 17/06736-0 - Identificação/elucidação e validação de novos alvos/vias envolvidos na osteoartrite, BP.PD; 17/07009-4 - Vias de sinalização envolvidas na resposta inflamatória em modelos de cultura 3D de osteoartrite, BP.PD; 16/11965-5 - Alvos terapêuticos epigenômicos: perfil de miRNA em um modelo in vitro de osteoartrite tratado com rLosac (PD-1), BP.PD; 16/12128-0 - Mecanismos moleculares da dor na artrite: identificação de novos alvos para o desenvolvimento de fármacos, BP.PD; 16/10886-4 - Ações de toxinas isoladas de diferentes venenos animais sobre a glicação de matriz extracelular no modelo de osteoartrite in vitro, BP.PD; 16/13588-4 - Revisitar bibliotecas de cDNA, BP.PD - menos bolsas vinculadas
• Assunto(s): Biodiversidade Degeneração neural Sobrevivência celular Inflamação
• Publicação FAPESP: https://media.fapesp.br/bv/uploads/pdfs/fapesp_uk_o8j4cK8_178_178.pdf

Resumo

Successful drug development requires a disease target that plays a vital role in the causation and/or progression of the disease phenotype and that can be modulated with a drug molecule. In other words, therapeutically relevant targets are both “disease-modifying” and “druggable”. It has been estimated that around 10% of the entire human genome is involved in disease onset or progression, resulting in approximately 3000 potential targets suitable for therapeutic intervention. Thus, the rapid and reliable identification of the most promising targets for drug discovery efforts would be the major challenge for the pharmaceutical industry. Moreover, the knowledge of the mechanisms that govern the inflammatory process and cell survival, generated by basic research, is essential for the identification and validation of potential and more specific molecular target. Natural products are a rich source of biologically active compounds. Many of today’s medicines are either obtained directly from a natural source or were developed from a lead compound originally obtained from a natural source. Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects, slugs, and microorganisms are extremely potent because the often have very specific interactions with a macromolecular target in the body. As a result, they have proved to be important not only as lead compounds in the development of novel drugs, but also as tools in studying receptors, ion channels, and enzymes. In our research group, interesting bioactive molecules from animal venoms and secretions, such as proteins (wild or recombinant form) and derived-peptides, targeting the homeostatic system and inflammatory events, have been exploited and are in different phases of development. We have been focusing our efforts on understanding their mechanism of action through the exploitation of specific signaling pathways in order to identify and validate novel molecular targets. Among the proteins’ families taken into account are lipocalins, hemolins, serine protease inhibitors, phospholipases and chaperones. In this regard, the main idea is to consider the expertise of the Butantan Institute researchers already have in computer-aided molecular design/bioinformatics/OMICS (transcriptome, proteome) field, molecular and cellular biology and immunology approaches (in vitro assays), and in vivo models and image techniques in order to create a Center of Excellence for Research in Target Discovery. (AU)

Publicações científicas

(10)

(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)

BUFALO, MICHELLE C.; ALMEIDA, MAIRA E.; FRANCA, ISABELLA ARAUJO; ZAMBELLI, VANESSA O.; SANT'ANNA, MORENA BRAZIL MARTINS; KIMURA, LOUISE F.; GIARDINI, ALINE CAROLINA; CURY, YARA; SAMPAIO, SANDRA COCCUZZO. Advanced glycation endproducts produced by in vitro glycation of type I collagen modulate the functional and secretory behavior of dorsal root ganglion cells cultivated in two-dimensional system. Experimental Cell Research, v. 382, n. 2-3 SEP 15 2019. Citações Web of Science: 0.

TEIXEIRA, CATARINA; FERNANDES, CRISTINA MARIA; LEIGUEZ, ELBIO; CHUDZINSKI-TAVASSI, ANA MARISA. Inflammation Induced by Platelet-Activating Viperid Snake Venoms: Perspectives on Thromboinflammation. FRONTIERS IN IMMUNOLOGY, v. 10, SEP 4 2019. Citações Web of Science: 0.

ALVAREZ-FLORES, MILYAM P.; HEBERT, AUDREY; GOUELLE, CATHY; GELLER, SARAH; CHUDZINSKI-TAVASSI, ANA M.; PELLERIN, LUC. Neuroprotective effect of rLosac on supplement-deprived mouse cultured cortical neurons involves maintenance of monocarboxylate transporter MCT2 protein levels. Journal of Neurochemistry, v. 148, n. 1, p. 80-96, JAN 2019. Citações Web of Science: 1.

VILLAS-BOAS, ISADORA MARIA; BONFA, GIULIANO; TAMBOURGI, DENISE V. Venomous caterpillars: From inoculation apparatus to venom composition and envenomation. Toxicon, v. 153, p. 39-52, OCT 2018. Citações Web of Science: 1.

MAMBELLI-LISBOA, NICOLE CAROLINE; SCIANI, JULIANA MOZER; BRANDAO PRIETO DA SILVA, ALVARO ROSSAN; KERKIS, IRINA. Co-Localization of Crotamine with Internal Membranes and Accentuated Accumulation in Tumor Cells. Molecules, v. 23, n. 4 APR 2018. Citações Web of Science: 1.

IQBAL, ASIF; GOLDFEDER, MAURICIO BARBUGIANI; MARQUES-PORTO, RAFAEL; ASIF, HUMA; DE SOUZA, JEAN GABRIEL; FARIA, FERNANDA; CHUDZINSKI-TAVASSI, ANA MARISA. Revisiting antithrombotic therapeutics; sculptin, a novel specific, competitive, reversible, scissile and tight binding inhibitor of thrombin. SCIENTIFIC REPORTS, v. 7, MAY 3 2017. Citações Web of Science: 2.

KERKIS, IRINA; DE BRANDO PRIETO DA SILVA, ALVARO ROSSAN; POMPEIA, CELINE; TYTGAT, JAN; DE SA JUNIOR, PAULO L. Toxin bioportides: exploring toxin biological activity and multifunctionality. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 74, n. 4, p. 647-661, FEB 2017. Citações Web of Science: 4.

BRANCO, VANIA G.; IQBAL, ASIF; ALVAREZ-FLORES, MIRYAM P.; SCIANI, JULIANA M.; DE ANDRADE, SONIA A.; IWAI, LEO K.; SERRANO, SOLANGE M. T.; CHUDZINSKI-TAVASSI, ANA M. Amblyomin-X having a Kunitz-type homologous domain, is a noncompetitive inhibitor of FXa and induces anticoagulation in vitro and in vivo. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1864, n. 10, p. 1428-1435, OCT 2016. Citações Web of Science: 6.

DE SOUZA, JEAN GABRIEL; MORAIS, KATIA L. P.; ANGLES-CANO, EDUARDO; BOUFLEUR, PAMELA; DE MELLO, EVANDRO SOBROZA; MARIA, DURVANEI AUGUSTO; TAEMI ORIGASSA, CLARICE SILVIA; ZAMPOLLI, HAMILTON DE CAMPOS; SARAIVA CAMARA, NIELS OLSEN; BERRA, CAROLINA MARIA; BOSCH, ROSEMARY VIOLA; CHUDZINSKI-TAVASSI, ANA MARISA. Promising pharmacological profile of a Kunitz-type inhibitor in murine renal cell carcinoma model. ONCOTARGET, v. 7, n. 38, p. 62255-62266, SEP 20 2016. Citações Web of Science: 6.

BOSCH, ROSEMARY VIOLA; ALVAREZ-FLORES, MIRYAM PAOLA; MARIA, DURVANEI AUGUSTO; CHUDZINSKI-TAVASSI, ANA MARISA. Hemolin triggers cell survival on fibroblasts in response to serum deprivation by inhibition of apoptosis. BIOMEDICINE & PHARMACOTHERAPY, v. 82, p. 537-546, AUG 2016. Citações Web of Science: 5.