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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2

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Autor(es):
Bosch, Soraya S. [1, 2] ; Lunev, Sergey [2] ; Batista, Fernando A. [2] ; Linzke, Marleen [1] ; Kronenberger, Thales [3] ; Domling, Alexander S. S. [2] ; Groves, Matthew R. [2] ; Wrenger, Carsten [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, BR-05508000 Sao Paulo, SP - Brazil
[2] Univ Groningen, Dept Pharm, Struct Biol Unit, Drug Design XB20, NL-9700 AD Groningen - Netherlands
[3] Univ Hosp Tubingen, Dept Internal Med 8, D-72076 Tubingen - Germany
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: ACS INFECTIOUS DISEASES; v. 6, n. 5, p. 986-999, MAY 8 2020.
Citações Web of Science: 0
Resumo

Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant of Plasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials. (AU)

Processo FAPESP: 17/03966-4 - Alvejando a via de recuperação e biossíntese de ácido lipoico em MRSA
Beneficiário:Carsten Wrenger
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 15/26722-8 - Drug discovery contra doenças infecciosas humanos
Beneficiário:Carsten Wrenger
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/17577-9 - Análise da catálise da ATCase no metabolismo de Plasmodium falciparum
Beneficiário:Soraya Soledad Bosch
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 14/23330-9 - Análise morfológica da formação de apicoplasto em Plasmodium falciparum
Beneficiário:Marleen Linzke
Linha de fomento: Bolsas no Brasil - Doutorado