Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells

Autor(es):Mostrar menos -

dos Santos, Daiane Fernanda ^{[1, 2]} ; Bairros de Pilger, Denise Regina ^{[3, 4]} ; Vandermeulen, Charlotte ^[5] ; Khouri, Ricardo ^[6] ; Mantoani, Susimaire Pedersoli ^[7] ; Goncalves Nunes, Paulo Sergio ^[7] ; de Andrade, Peterson ^[7] ; Carvalho, Ivone ^[7] ; Casseb, Jorge ^[8] ; Twizere, Jean-Claude ^[5] ; Willems, Luc ^[9] ; Freitas-Junior, Lucio ^[4] ; Kashima, Simone ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Reg Blood Ctr Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[3] Univ Fed Sao Paulo, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Biomed Sci Inst, Dept Microbiol, Sao Paulo, SP - Brazil

^[5] Univ Liege, Prot Signaling & Interact GIGA, Liege - Belgium

^[6] Oswaldo Cruz Fdn FIOCRUZ, Goncalo Moniz Res Ctr CPqGM, Salvador, BA - Brazil

^[7] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[8] Univ Sao Paulo, Inst Trop Med Sao Paulo, Sao Paulo, SP - Brazil

^[9] Univ Liege, Mol & Cellular Epigenet GIGA, Liege - Belgium

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 28, n. 22 NOV 15 2020.
• Citações Web of Science: 0

Resumo

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10-20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible -tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity >= 70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible -tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL. (AU)

• Processo FAPESP: 15/11566-0 - Triagem em larga escala para a identificação de novos compostos no tratamento da infecção pelo HTLV-1 e doenças associadas
• Beneficiário: Daiane Fernanda dos Santos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/17301-1 - Estabelecimento de uma linhagem celular repórter estável infectada pelo HTLV-1 para ensaios de triagem de compostos antivirais
• Beneficiário: Daiane Fernanda dos Santos
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado