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

• Grant number: 14/10753-9
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2014
• End date: February 28, 2017
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Daniela Barretto Barbosa Trivella
• Grantee: Daniela Barretto Barbosa Trivella
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Ana Carolina Migliorini Figueira ; Artur Torres Cordeiro ; Marjorie Christine Paule Bruder ; Roberto Gomes de Souza Berlinck ; Ronaldo Aloise Pilli

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)

Scientific publications

(6)

(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, 2017. (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, FEB 2021. (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., 2022-04-01. (14/10753-9, 17/12436-9, 15/19906-5)

MENEGHELLO, RAPHAEL; RUSTIGUEL, JOANE K.; DE ARAUJO, EVANDRO ARES; DE FELICIO, RAFAEL; FERNANDES, ARTHUR ZANETTI N.; FERREIRA, EVERTON L. F.; GUBIANI, JULIANA R.; TAKEDA, AGNES A. S.; ARAUJO, AMANDA; DE LIMA SILVA, CAIO C.; et al. High-throughput protein crystallography to empower natural product-based drug discovery. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 81, p. 14-pg., 2025-05-01. (19/13497-7, 15/01017-0, 14/10753-9, 21/01309-1, 23/01133-6, 19/17721-9)

BAZZANO, CRISTINA F.; DE FELICIO, RAFAEL; ALVES, LUIZ FERNANDO GIOLO; COSTA, JONAS HENRIQUE; ORTEGA, RAQUEL; VIEIRA, BRUNA DOMINGUES; MORAIS-URANO, RAQUEL PERES; FURTADO, LUCIANA COSTA; FERREIRA, EVERTON L. F.; GUBIANI, JULIANA R.; et al. NP³ MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics. Analytical Chemistry, v. 96, n. 19, p. 10-pg., 2024-05-03. (15/01017-0, 19/17721-9, 13/50228-8, 14/10753-9, 15/17177-6, 17/18235-5, 20/08987-2)

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, APR 2020. (14/10753-9, 14/15760-3, 13/50228-8, 14/12021-5)