Identification of new antimalarial treatments through a target-centred "drug repositioning" approach

• Grant number: 18/07007-4
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2018 - September 30, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Convênio/Acordo: Fundação para a Ciência e a Tecnologia (FCT)
• Principal Investigator: Elizabeth Bilsland
• Grantee: Elizabeth Bilsland
• Principal researcher abroad: Pedro Vitor Lemos Cravo
• Institution abroad: Universidade Nova de Lisboa, Portugal
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Carolina Horta Andrade
• Associated scholarship(s): 19/27626-3 - Identification of new antimalarial compounds for target-centered drug repositioning approach, BP.PD

Abstract

The evolution of drug resistant malaria parasites coupled with the scarcity of new drugs, urge for discovery of new antimalarials. However, developing a brand new drug is a lengthy and costly process, due to bottlenecks in both the discovery and the therapeutic development (clinical trials) phases. Drug repositioning, which is the application of known and approved drugs and compounds to treat new indications, provides the quickest possible transition from bench to bedside, since the repositioned drug has already passed toxicity and other tests, and thus can ready for clinical trials quickly. We are using this paradigm to identify new treatments against malaria. We first produce a list of prospective malaria therapeutic targets (proteins) based on defined criteria, through a data mining strategy using genome databases (TDR Targets, PlasmoDB). Subsequently, primary protein sequences selected as candidate targets are used to interrogate different platforms that provide synoptic data about drugs and their targets, namely, Drug-Bank, STITCH and Therapeutic Targets Database (TTD). This allows identifying homologous targets from other organisms, against which approved drugs already exist. The targets thus identified are subject to further bioinformatics filtering, including "pairwise" alignment, conservation of functional regions, chemical space analysis, principal component analysis (PCA) and Quantitative Structure Analyses Relationships (QSAR). As a result, a list of drugs with high probability of efficacy against these targets is generated. The "real" efficacy of these compounds is then evaluated in in vitro experimental assays and drugs that display good activity in vitro undergo preclinical trials in vivo, using rodent malaria models. Within the scope of the present proposal, we intend to follow up on our previous drug repositioning work, through which we have generated a list of candidate drugs against blood stages of the two major malaria parasites of humans, P. falciparum and P. vivax. These compounds will be evaluated as to their cytotoxicity and tested for their in vitro and ex vivo efficacy. The most potent and safe drugs will be taken through to in vivo efficacy studies, also known as pre-clinical trials. Secondly, we will perform a de novo study aiming at identifying transmission-blocking drugs against both parasites. This study will initially follow bioinformatics workflow previously described, aiming at identifying compounds that may be active against proteins that are up regulated in sporozoite stages and proteins that are differentially expressed in gametocytes. Candidate drugs identified through this process will be evaluated ex vivo and in vivo for their ability to block either liver-stage or sporogonic development. Finally, drugs that prove to be safe and efficacious against blood or transmission stages will be compiled into a list candidate compounds for repositioning, that will be readily available for clinical trials in humans (AU)

Scientific publications

(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)

FERREIRA, LETICIA T.; VENANCIO, VINICIUS P.; KAWANO, TAILA; ABRAO, LAILAH C. C.; TAVELLA, TATYANA A.; ALMEIDA, LUDIMILA D.; PIRES, GABRIEL S.; BILSLAND, ELIZABETH; SUNNERHAGEN, PER; AZEVEDO, LUCIANA; et al. Chemical Genomic Profiling Unveils the in Vitro and in Vivo Antiplasmodial Mechanism of Acai (Euterpe oleracea Mart.) Polyphenols. ACS OMEGA, v. 4, n. 13, p. 15628-15635, SEP 24 2019. (15/03553-6, 17/01986-8, 17/18611-7, 17/50400-6, 18/07007-4)

LIMA, MARILIA N. N.; BORBA, JOYCE V. B.; CASSIANO, GUSTAVO C.; MOTTIN, MELINA; MENDONCA, SABRINA S.; SILVA, ARTHUR C.; TOMAZ, KAIRA C. P.; CALIT, JULIANA; BARGIERI, DANIEL Y.; COSTA, FABIO T. M.; et al. Artificial Intelligence Applied to the Rapid Identification of New Antimalarial Candidates with Dual-Stage Activity. CHEMMEDCHEM, v. 16, n. 7, p. 1093-1103, APR 8 2021. (15/20774-6, 13/13119-6, 17/18611-7, 18/24878-9, 18/07007-4, 19/21854-4)

LIMA, MARILIA N. N.; CASSIANO, GUSTAVO C.; TOMAZ, KAIRA C. P.; SILVA, ARTHUR C.; SOUSA, BRUNA K. P.; FERREIRA, LETICIA T.; TAVELLA, TATYANA A.; CALIT, JULIANA; BARGIERI, DANIEL Y.; NEVES, BRUNO J.; et al. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. FRONTIERS IN CHEMISTRY, v. 7, NOV 21 2019. (18/05926-2, 13/13119-6, 18/07007-4, 17/02353-9, 17/18611-7, 12/16525-2, 18/24878-9, 15/20774-6)