Identification of new antimalarial compounds for target-centered drug repositioning approach

• Grant number: 19/27626-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): June 01, 2020
• Effective date (End): August 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Acordo de Cooperação: Fundação para a Ciência e a Tecnologia (FCT)
• Principal Investigator: Fabio Trindade Maranhão Costa
• Grantee: Tatyana Almeida Tavella
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 18/07007-4 - Identification of new antimalarial treatments through a target-centred "drug repositioning" approach, AP.R

Abstract

Malaria is an infectious disease caused by protozoa of the genus Plasmodium. The emergence of Plasmodium resistance to the most antimalarial drugs has highlighted the urgency of identifying and clarifying the mechanisms of new antimalarial drugs. However, the development of a new drug is a long and expensive. "Drug Repositioning" is the application of known and approved compounds that are redirected to new uses outside the scope of the original medical indication and represents the fastest way to get a drug because it is readily available for clinical trials. Recently, epirubicin was identified and this molecule showed optimal activity against the asexual stage of Plasmodium in both in vitro inhibition assays and in vivo efficacy assays. However, its toxicity precludes the use for malaria treatment. Therefore, we intend to use the epirubicin scaffold to identify new molecules with less toxicity and/or greater activity against malaria parasites. A preliminary search on the MolPort website identified ~ 50 commercially available compounds with similarity above 80% (Tanimoto coefficient) to epirubicin. Under the present proposal, these compounds will be evaluated for antimalarial activity for asexual blood stages and cytotoxicity. Secondly, we will also perform a "de novo" study to identify transmission-blocking compounds against proteins that are overexpressed at the sporozoite stage and proteins that are differentially expressed in gametocytes. Drugs thus identified will be evaluated in vivo for their ability to block the development of the parasite in the hepatic phase or its sporozoite development. (AU)

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)

PUHL, ANA C.; FRITCH, ETHAN J.; LANE, THOMAS R.; TSE, V, LONGPING; YOUNT, BOYD L.; SACRAMENTO, CAROLINA Q.; FINTELMAN-RODRIGUES, NATALIA; TAVELLA, TATYANA ALMEIDA; COSTA, FABIO TRINDADE MARANHAO; WESTON, STUART; et al. Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms. ACS OMEGA, v. 6, n. 11, p. 7454-7468, MAR 23 2021. (19/27626-3, 17/18611-7, 20/05369-6)

CASSIANO, G. C.; TAVELLA, T. A.; NASCIMENTO, M. N.; RODRIGUES, D. A.; CRAVO, P. V. L.; ANDRADE, CAROLINA HORTA; MARANHAO COSTA, FABIO TRINDADE; DONEV, R. Targeting malaria protein kinases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY, v. 124, p. 50-pg., 2021-01-01. (17/18611-7, 19/27626-3, 15/20774-6)

GAWRILJUK, VICTOR O.; ZIN, PHYO PHYO KYAW; PUHL, ANA C.; ZORN, KIMBERLEY M.; FOIL, DANIEL H.; LANE, THOMAS R.; HURST, BRETT; TAVELLA, TATYANA ALMEIDA; MARANHAO COSTA, FABIO TRINDADE; LAKSHMANANE, PREMKUMAR; et al. Machine Learning Models Identify Inhibitors of SARS-CoV-2. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 61, n. 9, p. 4224-4235, SEP 27 2021. (20/05369-6, 19/27626-3, 19/25407-2)

TAVELLA, T. A.; CASSIANO, G. C.; MARANHAO COSTA, FABIO TRINDADE; SUNNERHAGEN, P.; BILSLAND, E.; DONEV, R. Yeast-based high-throughput screens for discovery of kinase inhibitors for neglected diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY, v. 124, p. 35-pg., 2021-01-01. (19/27626-3, 15/20774-6, 12/16525-2, 15/03553-6)