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Phytomedicine

Phytomedicine

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Dihydrotanshinone I targets the spike N-terminal domain to inhibit SARS-CoV-2 entry and spike-induced inflammation

Published:17 June 2025 DOI: 10.1016/j.phymed.2025.156989
Chan Yang , Kunyu Lu , Jinshen Wang , Hao Su , Luping Cheng , Chunmei Nong , Xiaoyan Pan , Haobin Li , Zheng Peng , Yinghua Chen , Yan Wu , Qinhai Ma , Guodong Hu , Shuwen Liu

Abstract

Background

Despite progress made in addressing the COVID-19 pandemic, numerous challenges persist, including breakthrough infections (BTI) and reinfections with SARS-CoV-2. There is an urgent need for broad-spectrum antiviral agents with multifaceted functionalities. Dihydrotanshinone I (DHT), a lipophilic monomer component of Salvia miltiorrhiza, exhibits diverse pharmacological activities, including antioxidant, anti-inflammatory, antibacterial and immunomodulatory effects. The efficacy and mechanisms underlying its "multi-target" advantages in treating COVID-19 warrant further investigation.

Purpose

To investigate the inhibitory activity and mechanisms of DHT against pan-SARS-CoV-2 invasion.

Methods

We examined the activity of DHT against SARS-CoV-2 Variants of Concern (VOCs) using the viral replicon system, pseudo virus-based entry assays, and a human ACE2 transgenic mouse model. The enzymatic activity and time-of-drug-addition assays were conducted to elucidate the viral life cycle targeted by DHT. Drug resistance induction assay, next-generation sequencing (NGS) analysis and molecular docking were employed to confirm DHT's target sites. Further ELISA, RT-qPCR, and western blot assays revealed the mechanism and anti-inflammatory activity of DHT.

Results

As a potent antiviral agent, DHT showed activity against SARS-CoV-2 VOCs with EC50 values ranging from 0.3–4.0 μM. DHT binds to two conserved sites on the spike N-terminal domain (NTD), inhibiting viral entry for both original and variant strains. Furthermore, DHT modulates the interaction between the spike and Toll-like receptor 4 (TLR4), stimulating nuclear factor-erythroid 2-related factor 2 (NRF2)-dependent immune response to attenuate cytokine production. Moreover, multiple administrations of DHT provide therapeutic benefits in mouse model of COVID-19.

Conclusions

The dual functionality of DHT is accomplished through binding to the spike NTD and inhibiting spike-activated inflammation, making it effective in preventing SARS-CoV-2 invasion. Our findings offer a conceptual framework for the rational design of prospective multitargeted inhibitors against SARS-CoV-2 spike NTD.

Substances (20)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Tanshinone IIA 568-72-9 C19H18O3 601 suppliers $8.00-$2431.80
Tanshinone IIA 568-72-9 C19H18O3 601 suppliers $8.00-$2431.80
Tanshinone IIA 568-72-9 C19H18O3 601 suppliers $8.00-$2431.80
Tanshinone IIA 568-72-9 C19H18O3 601 suppliers $8.00-$2431.80
Cryptotanshinone 35825-57-1 C19H20O3 448 suppliers $5.00-$1840.00
Cryptotanshinone 35825-57-1 C19H20O3 448 suppliers $5.00-$1840.00
Cryptotanshinone 35825-57-1 C19H20O3 448 suppliers $5.00-$1840.00
Cryptotanshinone 35825-57-1 C19H20O3 448 suppliers $5.00-$1840.00
Tanshinone I 568-73-0 C18H12O3 397 suppliers $10.00-$1720.00
Tanshinone I 568-73-0 C18H12O3 397 suppliers $10.00-$1720.00
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