Title:Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life
Cycle
Volume: 20
Issue: 1
Author(s): Mohammadjavad Sotoudeheian, Seyed-Mohamad-Sadegh Mirahmadi, Mohammad Pirhayati, Navid Farahmandian, Reza Azarbad and Hamidreza Pazoki Toroudi*
Affiliation:
- Physiology Research
Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
Keywords:
Gelseminic, coumarin, anti-inflammatory, antioxidant, autophagy, ACE2.
Abstract: Natural products have historically driven pharmaceutical discovery, but their reliance has
diminished with synthetic drugs. Approximately 35% of medicines originate from natural products.
Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral,
and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore,
it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus
2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation.
Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent
Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells via FOXO3, inhibits
apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine
monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances
the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary
diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation,
inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The
coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5
COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated
by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus
replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases.
Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated
oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit
the entry and life cycle of XBB.1.5 COVID-19 in host cells.
