Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate

Author(s):Show less -

Freire, Marjorie C. L. C. ; Basso, Luis G. M. ; Mendes, Luis F. S. ; Mesquita, Nathalya C. M. R. ; Mottin, Melina ; Fernandes, Rafaela S. ; Policastro, Lucca R. ; Godoy, Andre S. ; Santos, Igor A. ; Ruiz, Uriel E. A. ; Caruso, Icaro P. ; Sousa, Bruna K. P. ; Jardim, Ana C. G. ; Almeida, Fabio C. L. ; Gil, Laura H. V. G. ; Andrade, Carolina H. ; Oliva, Glaucius

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 12, n. 1, p. 15-pg., 2022-06-22.

Abstract

Chikungunya virus (CHIKV) is the causative agent of Chikungunya fever, an acute febrile and arthritogenic illness with no effective treatments available. The development of effective therapeutic strategies could be significantly accelerated with detailed knowledge of the molecular components behind CHIKV replication. However, drug discovery is hindered by our incomplete understanding of their main components. The RNA-dependent RNA-polymerase (nsP4-CHIKV) is considered the key enzyme of the CHIKV replication complex and a suitable target for antiviral therapy. Herein, the nsP4-CHIKV was extensively characterized through experimental and computational biophysical methods. In the search for new molecules against CHIKV, a compound designated LabMol-309 was identified as a strong ligand of the nsp4-CHIKV and mapped to bind to its active site. The antiviral activity of LabMol-309 was evaluated in cellular-based assays using a CHIKV replicon system and a reporter virus. In conclusion, this study highlights the biophysical features of nsP4-CHIKV and identifies a new compound as a promising antiviral agent against CHIKV infection. (AU)

• FAPESP's process: 18/17095-8 - Structural characterization of the Chikungunya Virus NSP4 RNA-dependent RNA polymerase and search for antiviral agents
• Grantee: Marjorie Caroline Liberato Cavalcanti Freire
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/05130-3 - Construction and characterization of a ZIKV sub-genomic replicon system for the discovery of antiviral agents.
• Grantee: Rafaela Sachetto Fernandes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/16812-0 - Multi-User Equipment approved in grant 2014/15546-1: SEC-MALS
• Grantee: Richard Charles Garratt
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 21/10465-7 - Exploring the dynamic assembly/disassembly of a Golgi matrix protein under stress-conditions
• Grantee: Luis Felipe Santos Mendes
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/24669-8 - Unraveling the molecular bases of the early protein secretory pathway in humans using biophysical techniques
• Grantee: Luis Felipe Santos Mendes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/01706-0 - Screening of compounds for the identification of drugs against the Chikungunya virus using a subgenomic replicon system
• Grantee: Lucca Rocha Policastro
• Support Opportunities: Scholarships in Brazil - Scientific Initiation