Structural characterization of the Chikungunya Virus NSP4 RNA-dependent RNA polymerase and search for antiviral agents

• Grant number: 18/17095-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2019
• End date: June 30, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Glaucius Oliva
• Grantee: Marjorie Caroline Liberato Cavalcanti Freire
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

The Chikungunya fever is an Arboviral disease caused by the Chikungunya Virus (CHIKV), which is transmitted to humans by the bite of infected female mosquitoes, usually from the Aedes aegypti species. The symptoms are related to the patient's gender and age, and include rash, vomiting, joint and musculoskeletal pain, edema and fever, as well as neurological problems in adults, such as Guillain-Barré syndrome. The pregnancy miscarriage, although rare, has also been reported. Currently, there are no effective treatments or methods to eradicate the virus. Thus, the prevention and control of the transmitter mosquito populations are the only way to combat CHIKV. The absence of effective treatment against the disease, associated with the debilitating period caused by acute pain, creates the need to intensify studies that may lead to new candidates for CHIKV drugs or vaccines. The CHIKV is a positive-strand RNA virus from the Alphavirus genus, whose genetic material encodes two polyproteins, one structural and one non-structural. The polyproteins cleavage releases nine mature proteins. Three of these proteins form the viral envelope (E1, E2 and E3), one the capsid (protein C), and another four are involved in the viral replication process. The envelope proteins E1, E2 and E3, as well as the proteins nsP2 domain C9-peptidase, nsP3 Macrodomain and protein C already have their three-dimensional structures solved. This project proposes the structural and functional characterization of the protein nsP4, whose structure remains unpublished. The nsP4 will be explored by Structure-Based Drug Design and the Fragment Based Drug Design (FBDD) strategies towards the discovery of new candidates to antiviral drugs. This project is tied to the FAPESP's project CIBFar/CEPID, and it also aims to establish a base in the group for CHIKV studies, which already has experience with other Arboviruses. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FERNANDES, RAFAELA S.; FREIRE, MARJORIE C. L. C.; BUENO, V, RENATA; GODOY, ANDRE S.; GIL, LAURA H. V. G.; OLIVA, GLAUCIUS. Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses. Viruses-Basel, v. 12, n. 6, JUN 2020. (16/19712-9, 18/05130-3, 13/07600-3, 18/17095-8)

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.; et al. Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate. SCIENTIFIC REPORTS, v. 12, n. 1, p. 15-pg., 2022-06-22. (18/17095-8, 18/05130-3, 15/16812-0, 21/10465-7, 13/07600-3, 17/24669-8, 21/01706-0)

FREIRE, MARJORIE C. L. C.; NOSKE, GABRIELA D.; BITENCOURT, NATALIA V.; SANCHES, PAULO R. S.; SANTOS-FILHO, NORIVAL A.; GAWRILJUK, VICTOR O.; DE SOUZA, EDUARDO P.; NOGUEIRA, VICTOR H. R.; DE GODOY, MARIANA O.; NAKAMURA, ALINE M.; et al. Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors. Molecules, v. 26, n. 16, AUG 2021. (18/17095-8, 20/04602-9, 13/07600-3, 20/05761-3, 20/12519-4, 18/25600-4, 16/19712-9, 16/13884-2, 18/13588-0)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FREIRE, Marjorie Caroline Liberato Cavalcanti. Search for drug candidates against epidemic and pandemic viruses, targeting the RNA-dependent RNA polymerase (nsP4) of the Chikungunya virus and the papain-like protease (PL-Pro) of the SARS-CoV-2 virus. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) São Carlos.