SARS-CoV-2 Nsp9 protein in oxidative stress: nutraceuticals as a therapeutic approach

• Grant number: 20/09527-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2021
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Luiz Guilherme Salvino da Silva
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 23/04255-5 - Characterization of the relationship between SARS-CoV-2 NSP9 and host interactors, BE.EP.DR

Abstract

A new outbreak of lung disease caused by a new Coronavirus appeared in Wuhan (capital of the province of Hubei in China) in December 2019 and has spread to different parts of the world, which has prompted the World Health Organization to confirm the outbreak as a pandemic on March 11, 2020. The new coronavirus SARS-CoV-2 genome is composed of a single-stranded positive-sense RNA (+ ssRNA) of approximately 30 kb that encodes four main structural genes and two polyproteins that when cleaved generate 16 non-structural proteins. The SARS-CoV non-structural protein 9 (Nsp9SARS) is considered of great importance for replication and, recently, homologues of the Nsp9 protein have been identified in numerous coronaviruses, including SARS-Cov-2, dimerizing in solution via a motif conserved ±-helical 'GxxxG'. Evidence indicates that Nsp9 proteins are dimerized by disulfide bonds and react to the redox balance of the host cell, possibly leading at Nsp9 to detect oxidative stress caused by the viral infection and to obtain greater affinity with RNA through dimerization. Recently, as a strategy to co-treat the critical symptoms of viral infections, many studies have focused on nutraceuticals, mainly natural antioxidants. Flavones, a group of flavonoids, have already been shown to be effective against RNA and DNA viruses. Apigenin in particular is effective against many viruses, including herpes simplex viruses type 1 and 2 and hepatitis C virus. In addition to nutraceuticals, pharmacological antioxidants such as N-acetyl-cysteine (NAC) have also shown positive effects in several different types of viruses, which demonstrates the importance of the redox balance in the host cell during viral infection in general. With this in mind, the present project aims to analyze the role of SARS-CoV-2 Nsp9 protein and its interactome in oxidative stress, analyzing Nsp9 dimerization and its relationship with the redox balance. Furthermore, we intend to investigate the interaction that this dimerization has on the stabilizing proteins of the redox flow of host cells, analyzing the role of Nrf2 in this context and proposing nutraceutical antioxidants (such as apigenin and NAC) as possible relievers of this type of stress. (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)

MANCINI, MARIANA C. S.; MORELLI, ANA P.; SEVERINO, MATHEUS B.; PAVAN, ISADORA C. B.; ZAMBALDE, ERIKA P.; GOIS, MARIANA M.; DA SILVA, LUIZ G. S.; QUINTERO-RUIZ, NATHALIA; ROMEIRO, CAIO F.; DOS SANTOS JR, DANIEL F. G.; et al. Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin. Journal of Cellular Biochemistry, v. 123, n. 12, p. 14-pg., 2022-10-03. (20/09310-6, 20/09133-7, 16/06457-0, 20/13660-2, 20/09527-5, 15/00311-1, 20/08684-0, 18/14818-9, 19/00607-9, 19/25582-9, 19/25731-4)

MORELLI, ANA PAULA; TORTELLI JR, THARCISIO CITRANGULO; SILVA MANCINI, MARIANA CAMARGO; BETIM PAVAN, ISADORA CAROLINA; SALVINO SILVA, LUIZ GUILHERME; SEVERINO, MATHEUS BRANDEMARTE; GRANATO, DANIELA CAMPOS; PESTANA, NATHALIE FORTES; SABOIA PONTE, LUIS GUSTAVO; PERUCA, GUILHERME FRANCISCO; et al. TAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinom. Neoplasia, v. 23, n. 10, p. 1048-1058, OCT 2021. (19/25582-9, 15/22814-5, 15/00311-1, 18/14818-9, 19/00607-9, 20/09527-5)