Transcriptomics-Guided In Silico Drug Repurposing: Identifying New Candidates with Dual-Stage Antiplasmodial Activity.

Autor:	Borba JVB; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmacia, Universidade Federal de Goias, 74605-170 Goiânia, Goiás, Brazil.; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, University of Campinas, 13083-970 Campinas, São Paulo, Brazil., de Azevedo BR; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmacia, Universidade Federal de Goias, 74605-170 Goiânia, Goiás, Brazil., Ferreira LA; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, University of Campinas, 13083-970 Campinas, São Paulo, Brazil., Rimoldi A; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, University of Campinas, 13083-970 Campinas, São Paulo, Brazil., Salazar Alvarez LC; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, University of Campinas, 13083-970 Campinas, São Paulo, Brazil., Calit J; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, São Paulo, Brazil., Bargieri DY; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, São Paulo, Brazil., Costa FTM; Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, University of Campinas, 13083-970 Campinas, São Paulo, Brazil., Andrade CH; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmacia, Universidade Federal de Goias, 74605-170 Goiânia, Goiás, Brazil.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2023 Sep 05; Vol. 8 (37), pp. 34084-34090. Date of Electronic Publication: 2023 Sep 05 (Print Publication: 2023).
DOI:	10.1021/acsomega.3c05138
Abstrakt:	In tropical and subtropical areas, malaria stands as a profound public health challenge, causing an estimated 247 million cases worldwide annually. Given the absence of a viable vaccine, the timely and effective treatment of malaria remains a critical priority. However, the growing resistance of parasites to currently utilized drugs underscores the critical need for the identification of new antimalarial therapies. Here, we aimed to identify potential new drug candidates against Plasmodium falciparum , the main causative agent of malaria, by analyzing the transcriptomes of different life stages of the parasite and identifying highly expressed genes. We searched for genes that were expressed in all stages of the parasite's life cycle, including the asexual blood stage, gametocyte stage, liver stage, and sexual stages in the insect vector, using transcriptomics data from publicly available databases. From this analysis, we found 674 overlapping genes, including 409 essential ones. By searching through drug target databases, we discovered 70 potential drug targets and 75 associated bioactive compounds. We sought to expand this analysis to similar compounds to known drugs. So, we found a list of 1557 similar compounds, which we predicted as actives and inactives using previously developed machine learning models against five life stages of Plasmodium spp. From this analysis, two compounds were selected, and the reactions were experimentally evaluated. The compounds HSP-990 and silvestrol aglycone showed potent inhibitory activity at nanomolar concentrations against the P. falciparum 3D7 strain asexual blood stage. Moreover, silvestrol aglycone exhibited low cytotoxicity in mammalian cells, transmission-blocking potential, and inhibitory activity comparable to those of established antimalarials. These findings warrant further investigation of silvestrol aglycone as a potential dual-acting antimalarial and transmission-blocking candidate for malaria control. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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