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

Autor(es)

Borba, Joyce V. B. ; de Azevedo, Beatriz Rosa ; Ferreira, Larissa A. ; Rimoldi, Aline ; Alvarez, Luis C. Salazar ; Calit, Juliana ; Bargieri, Daniel Y. ; Costa, Fabio T. M. ; Andrade, Carolina Horta

• Tipo de documento: Artigo Científico
• Fonte: ACS OMEGA; v. 8, n. 37, p. 7-pg., 2023-09-05.

Resumo

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. (AU)

• Processo FAPESP: 18/24878-9 - Pesquisa de compostos bloqueadores da transmissão de Plasmodium usando novos modelos experimentais
• Beneficiário: Juliana Calit Paim
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/21854-4 - Priorização de quinases e descoberta de compostos com atividade antimalárica contra diferentes estágios de Plasmodium vivax utilizando ferramentas de quimiogenômica, bioinformática, quimioinformática e ensaios experimentais
• Beneficiário: Joyce Villa Verde Bastos Borba
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 21/06769-0 - Descoberta de alvos vacinais e compostos contra transmissão da Malária
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 17/18611-7 - Desenvolvimento de novas ferramentas para busca e validação de alvos moleculares para terapia contra Plasmodium vivax
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático