Novel Transmission-Blocking Antimalarials Identified by High-Throughput Screening of Plasmodium berghei Ookluc

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Calit, Juliana ; Araujo, Jessica E. ; Deng, Bingbing ; Miura, Kazutoyo ; Gaitan, Xiomara A. ; Araujo, Maisa da Silva ; Medeiros, Jansen F. ; Long, Carole A. ; Simeonov, Anton ; Eastman, Richard T. ; Bargieri, Daniel Y.

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 67, n. 4, p. 11-pg., 2023-03-01.

Resumo

Safe and effective malaria transmission-blocking chemotherapeutics would allow a community-level approach to malaria control and eradication efforts by targeting the mosquito sexual stage of the parasite life cycle. However, only a single drug, primaquine, is currently approved for use in reducing transmission, and drug toxicity limits its widespread implementation. Safe and effective malaria transmission-blocking chemotherapeutics would allow a community-level approach to malaria control and eradication efforts by targeting the mosquito sexual stage of the parasite life cycle. However, only a single drug, primaquine, is currently approved for use in reducing transmission, and drug toxicity limits its widespread implementation. To address this limitation in antimalarial chemotherapeutics, we used a recently developed transgenic Plasmodium berghei line, Ookluc, to perform a series of high-throughput in vitro screens for compounds that inhibit parasite fertilization, the initial step of parasite development within the mosquito. Screens of antimalarial compounds, approved drug collections, and drug-like molecule libraries identified 185 compounds that inhibit parasite maturation to the zygote form. Seven compounds were further characterized to block gametocyte activation or to be cytotoxic to formed zygotes. These were further validated in mosquito membrane-feeding assays using Plasmodium falciparum and P. vivax. This work demonstrates that high-throughput screens using the Ookluc line can identify compounds that are active against the two most relevant human Plasmodium species and provides a list of compounds that can be explored for the development of new antimalarials to block transmission. (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: 13/13119-6 - Biologia celular e genética molecular de hemoparasitas
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• 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: 19/21507-2 - Caracterização da proteína pequena secretada rica em cisteína (CSs) como candidato a vacina contra Plasmodium
• Beneficiário: Xiomara Alexandra Gaitán
• Modalidade de apoio: Bolsas no Brasil - Doutorado