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Bioprospecting and rational design for the discovery of next generation proteasome inhibitors

Abstract

The proteasome complex is a validated target against cancer and two drugs, carfilzomib e bortezomib, are currently available in the market. However, there still some problems, such as resistance, toxicity and distribution, found in these inhibitors. Therefore, the discovery and development of next generation proteasome inhibitors are necessary. In this project we aim to discover new chemical scaffolds and proteasome inhibition mechanisms, focusing on finding new chemical substances that can overcome resistance, and improve toxicity, found in the currently available inhibitors. For this, we will conduct experimental assays using native and resistant forms of the proteasome, for the analysis of planned substances and natural product libraries. In this project, we propose the synthesis of four planned molecules, which were inspired in reported crystal structures of the proteasome in complex with natural products. These molecules were planned for testing new molecular hypothesis to overcome the problems of resistance and toxicity. The interaction of the newly synthesized chemical substances with the native and resistant proteasome will be characterized in details using biochemical (potency and inhibition mechanism) and structural (protein crystallography) analysis. In parallel, we will screen, in HTS, natural product libraries, aiming at the future identification of new potential chemical scaffolds and reactive groups (warheads) that would inspire a second round of rational design of inhibitors of the native and resistant forms of the proteasome. Overall, these studies aim to move forward in the direction of the identification of new mechanisms of proteasome inhibition and new molecular possibilities for next generation inhibitors of this interesting therapeutical target against cancer. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
WAECHTER, FERNANDA; DA SILVA, GLORIA N. S.; WILLIG, JULIA B.; DE OLIVEIRA, CRISTIANE B.; VIEIRA, BRUNA D.; TRIVELLA, DANIELA B. B.; ZIMMER, ALINE R.; BUFFON, ANDREIA; PILGER, DIOGO A.; GNOATTO, SIMONE C. B.. Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 17, n. 13, p. 1777-1785, . (14/10753-9)
DE FELICIO, RAFAEL; BALLONE, PATRICIA; BAZZANO, CRISTINA FREITAS; ALVES, LUIZ F. G.; SIGRIST, RENATA; INFANTE, GINA POLO; NIERO, HENRIQUE; RODRIGUES-COSTA, FERNANDA; FERNANDES, ARTHUR ZANETTI NUNES; TONON, LUCIANE A. C.; et al. Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions. METABOLITES, v. 11, n. 2, . (14/10753-9, 17/12436-9, 15/19906-5)
STALOCH, BRENDON EGON KORMANN; NIERO, HENRIQUE; DE FREITAS, ROBERT CARDOSO; BALLONE, PATRICIA; RODRIGUES-COSTA, FERNANDA; TRIVELLA, DANIELA BARRETTO BARBOSA; DESSEN, ANDREA; DA SILVA, MARCUS ADONAI CASTRO; LIMA, ANDRE OLIVEIRA DE SOUZA. Draft genome sequence of Psychrobacter nivimaris LAMA 639 and its biotechnological potential. DATA IN BRIEF, v. 41, p. 11-pg., . (14/10753-9, 17/12436-9, 15/19906-5)
GRIGOLETTO, DIANA F.; TRIVELLA, DANIELA B. B.; TEMPONE, ANDRE G.; RODRIGUES, ANDRE; CORREIA, ANA MARIA L.; LIRA, SIMONE P.. Antifungal compounds with anticancer potential from Trichoderma sp. P8BDA1F1, an endophytic fungus from Begonia venosa. Brazilian Journal of Microbiology, v. 51, n. 3, . (14/10753-9, 14/15760-3, 13/50228-8, 14/12021-5)

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