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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.)

Targeting the Plasmodium falciparum plasmepsin V by ligand-based virtual screening

Texto completo
Autor(es):
Meissner, Kamila Anna [1] ; Kronenberger, Thales [2, 1] ; Maltarollo, Vinicius Goncalves [3] ; Goulart Trossini, Gustavo Henrique [4] ; Wrenger, Carsten [1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Unit Drug Discovery, Dept Parasitol, Sao Paulo, SP - Brazil
[2] Univ Hosp Tubingen, Dept Internal Med 8, Tubingen - Germany
[3] Univ Fed Minas Gerais, Fac Pharm, Dept Pharmaceut Prod, Belo Horizonte, MG - Brazil
[4] Univ Sao Paulo, Fac Pharmaceut Sci, Sao Paulo, SP - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 93, n. 3, p. 300-312, MAR 2019.
Citações Web of Science: 2
Resumo

Malaria is a devastating disease depending only on chemotherapy as treatment. However, medication is losing efficacy, and therefore, there is an urgent need for the discovery of novel pharmaceutics. Recently, plasmepsin V, an aspartic protease anchored in the endoplasmaic reticulum, was demonstrated as responsible for the trafficking of parasite-derived proteins to the erythrocytic surface and further validated as a drug target. In this sense, ligand-based virtual screening has been applied to design inhibitors that target plasmepsin V of P. falciparum (PMV). After screening 5.5 million compounds, four novel plasmepsin inhibitors have been identified which were subsequently analyzed for the potency at the cellular level. Since PMV is membrane-anchored, the verification in vivo by using transgenic PMV overexpressing P. falciparum cells has been performed in order to evaluate drug efficacy. Two lead compounds, revealing IC50 values were 44.2 and 19.1 mu m, have been identified targeting plasmepsin V in vivo and do not significantly affect the cell viability of human cells up to 300 mu m. We herein report the use of the consensus of individual virtual screening as a new technique to design new ligands, and we propose two new lead compounds as novel protease inhibitors to target malaria. (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: 16/24790-9 - Validação da importância de PfEXP1/GST2 para defesa contra xenobióticos em modelos de deficiência de glicose-6-fosfato desidrogenase infectados com Plasmodium Falciparum
Beneficiário:Kamila Anna Meissner
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/03644-9 - Sítios de interação alternativos em receptores nucleares e sua viabilidade como alvos terapêuticos usando triagem computacional e experimental
Beneficiário:Thales Kronenberger
Linha de fomento: Bolsas no Brasil - Doutorado