Proteomic Analysis Identifies the Glutathione Synthesizing Enzyme Gclc as an Andrographolide Target and a Protective Factor Against Sars-Cov-2 Infection

37 Pages Posted: 1 Jul 2024

See all articles by Jarinya Chaopreecha

Jarinya Chaopreecha

affiliation not provided to SSRN

Nut Phueakphud

affiliation not provided to SSRN

Ampa Suksatu

affiliation not provided to SSRN

Sucheewin Krobthong

Mahidol University

Suwimon Manopwisedjaroen

affiliation not provided to SSRN

Nattawadee Panyain

affiliation not provided to SSRN

Suradej Hongeng

Mahidol University - Division of Pediatric Hematology-Oncology

Arunee Thitithanyanont

affiliation not provided to SSRN

Patompon Wongtrakoongate

Mahidol University - Faculty of Science

Abstract

Even though advanced progresses have been made for COVID-19 vaccines, rapid and extensive mutations of the SARS-CoV-2 genomes have provided a selective advantage for the virus to escape the adaptive immunity leading to a critical challenge for current treatments and preventions of COVID-19. We report here the antiviral activity of andrographolide against SARS-CoV-2 wildtype and Omicron variants. Proteomic analysis was employed to identify cellular pathways and key proteins controlled by andrographolide in the human lung epithelial cells Calu-3 infected by SARS-CoV-2. Gene ontology analysis indicates that proteins involved in NRF2-regulated pathways are differentially expressed by andrographolide. Notably, andrographolide increases expression and nuclear localization of the transcription factor NRF2. In addition, transcriptional expression of GCLC and GCLM, which are NRF2 target genes, are induced by andrographolide. We further find that infection of SARS-CoV-2 results in a reduction of glutathione level in Calu-3; the effect that is rescued by andrographolide. Moreover, andrographolide also induces expression of the glutathione producing enzyme GCLC in SARS-CoV-2 infected lung epithelial cells. Importantly, an ectopic over-expression of GCLC or treatment of N-acetylcysteine in Calu-3 cells led to a decrease in SARS-CoV-2 infection. Collectively, our findings suggest the interplay between GCLC-mediated glutathione biogenesis induced by andrographolide and the anti-SARS-CoV-2 activity. The glutathione biogenesis and recycling pathways should be further exploited as a targeted therapy against SARS-CoV-2 infection.

Note:
Funding Information: This research project was supported by CIF Grant, Faculty of Science, Mahidol University. J.C. was supported by Science Achievement Scholarship of Thailand. A.T. was supported by Abhaiphubet Chaopraya Hospital Foundation. P.W. was supported by Fundamental Fund, Mahidol University (FF66; FF-067/2566); National Research Council of Thailand (NRCT; N35A650053); and Program Management Unit for Human Resources and Institutional Development, Research and Innovation (PMU-B; B05F640047); and Mahidol University (Reinventing University grant).

Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Keywords: andrographolide, GCLC, Glutathione, SARS-CoV-2

Suggested Citation

Chaopreecha, Jarinya and Phueakphud, Nut and Suksatu, Ampa and Krobthong, Sucheewin and Manopwisedjaroen, Suwimon and Panyain, Nattawadee and Hongeng, Suradej and Thitithanyanont, Arunee and Wongtrakoongate, Patompon, Proteomic Analysis Identifies the Glutathione Synthesizing Enzyme Gclc as an Andrographolide Target and a Protective Factor Against Sars-Cov-2 Infection. Available at SSRN: https://ssrn.com/abstract=4876852 or http://dx.doi.org/10.2139/ssrn.4876852

Jarinya Chaopreecha

affiliation not provided to SSRN ( email )

No Address Available

Nut Phueakphud

affiliation not provided to SSRN ( email )

No Address Available

Ampa Suksatu

affiliation not provided to SSRN ( email )

No Address Available

Sucheewin Krobthong

Mahidol University ( email )

Suwimon Manopwisedjaroen

affiliation not provided to SSRN ( email )

No Address Available

Nattawadee Panyain

affiliation not provided to SSRN ( email )

No Address Available

Suradej Hongeng

Mahidol University - Division of Pediatric Hematology-Oncology ( email )

Bangkok
Thailand

Arunee Thitithanyanont

affiliation not provided to SSRN ( email )

No Address Available

Patompon Wongtrakoongate (Contact Author)

Mahidol University - Faculty of Science ( email )

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