Is the ADP ribose site of the Chikungunya virus NSP3 Macro domain a target for antiviral approaches?

Autor: Ana Carolina Gomes Jardim, Jacqueline Farinha Shimizu, Daniel Oliveira Silva Martins, Andres Merits, Mark Harris, Martin J. McPhillie, Grace C. Roberts, Carsten Zothner
Přispěvatelé: Universidade Estadual Paulista (Unesp), Universidade Federal de Uberlândia (UFU), Univ Leeds, Univ Tartu
Rok vydání: 2019
Předmět:
Zdroj: Web of Science
Repositório Institucional da UNESP
Universidade Estadual Paulista (UNESP)
instacron:UNESP
ISSN: 1873-6254
0001-706X
Popis: Made available in DSpace on 2020-12-10T17:35:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Royal Society - Newton Advanced Fellowship Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Wellcome Trust Chikungunya virus (CHIKV) is a mosquito-transmitted virus of special concern as it causes Chikungunya fever, characterized by an acute febrile illness, rash, and arthralgia that can progress to chronic and debilitating arthritic symptoms. The effects of climate change on the geographic distribution of the mosquito vector has the potential to expose more of the globe to this virus. No antiviral agents or vaccines are currently available against CHIKV infection and the development of novel therapies that may lead to a future treatment is therefore necessary. In this context, the ADP-ribose binding site of the CHIKV nsP3 macro domain has been reported as a potential target for the development of antivirals. Mutations in the ADP-ribose binding site demonstrated decreased viral replication in cell culture and reduced virulence. In this study, 48,750 small molecules were screened in silico for their ability to bind to the ADP-ribose binding site of the CHIKV nsP3 macro domain. From this in silico analysis, 12 molecules were selected for in vitro analysis using a CHIKV subgenomic replicon in Huh-7 cells. Cell viability and CHIKV replication were evaluated and molecules C5 and C13 demonstrated 53 and 66% inhibition of CHIKV replication, respectively. By using a CHIKV-Dual luciferase replicon contain two reporter genes, we also demonstrated that the treatment with either compounds are probably interfering in the early replication rather than after RNA replication has occurred. Sao Paulo State Univ, IBILCE, Sao Jose Do Rio Preto, SP, Brazil Univ Fed Uberlandia, Inst Biomed Sci, Lab Virol, ICBIM, Uberlandia, MG, Brazil Univ Leeds, Fac Engn & Phys Sci, Sch Chem, Leeds LS2 9JT, W Yorkshire, England Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England Univ Tartu, Inst Technol, Nooruse 1, EE-50411 Tartu, Estonia Sao Paulo State Univ, IBILCE, Sao Jose Do Rio Preto, SP, Brazil Royal Society - Newton Advanced Fellowship: NA 150195 CNPq: 445021/2014-4 FAPEMIG: APQ-00587-14 FAPEMIG: SICONV 793988/2013 CAPES: 001 Wellcome Trust: 096670
Databáze: OpenAIRE
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