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<p>Porcine reproductive and respiratory syndrome virus (PRRSV) remains a major economic threat to the global swine industry. The viral 3C-like serine main protease (non-structural protein 4, nsp4) is essential for replication and represents a promising drug target for antiviral intervention. Here, we report that shikonin, a natural naphthoquinone derived from <i>Lithospermum erythrorhizon</i>, covalently modifies C111 and C194 of PRRSV-2 nsp4 <i>in vitro</i>, leading to loss of its proteolytic activity (IC<sub>50</sub> = 4.9 μM). This site-specific covalent modification provides a biochemical basis for its inhibitory mechanism. Structural analysis of apo-nsp4 revealed a previously unobserved solvent-exposed conformation of C111, which defines a novel druggable pocket. In cellular assays, shikonin exhibited broad-spectrum antiviral activity against multiple PRRSV-2 strains, with EC<sub>50</sub> values ranging from 25.5 to 235.5 nM, achieving &gt;99% reduction in viral RNA at sub‑micromolar concentrations, and showed a high safety margin (CC<sub>50</sub> = 10.0 μM). Collectively, these findings elucidate the covalent inhibition mechanism of shikonin against PRRSV-2 nsp4 and support its potential as an agent or lead compound for developing anti-PRRSV therapeutics.</p>

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Shikonin covalently binding to cysteine to inhibits the cleavage activity of the 3C-like serine main protease (Nsp4) of PRRSV-2 and suppresses viral replication in Marc-145 cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Lin Wei,
  • Zhang Liu,
  • Huiting Zhang,
  • Guolin Wang,
  • Jun Weng,
  • Linzhen Hu,
  • Wei Wang,
  • Shuai Li,
  • Ke Ming,
  • Zigong Wei

摘要

Porcine reproductive and respiratory syndrome virus (PRRSV) remains a major economic threat to the global swine industry. The viral 3C-like serine main protease (non-structural protein 4, nsp4) is essential for replication and represents a promising drug target for antiviral intervention. Here, we report that shikonin, a natural naphthoquinone derived from Lithospermum erythrorhizon, covalently modifies C111 and C194 of PRRSV-2 nsp4 in vitro, leading to loss of its proteolytic activity (IC50 = 4.9 μM). This site-specific covalent modification provides a biochemical basis for its inhibitory mechanism. Structural analysis of apo-nsp4 revealed a previously unobserved solvent-exposed conformation of C111, which defines a novel druggable pocket. In cellular assays, shikonin exhibited broad-spectrum antiviral activity against multiple PRRSV-2 strains, with EC50 values ranging from 25.5 to 235.5 nM, achieving >99% reduction in viral RNA at sub‑micromolar concentrations, and showed a high safety margin (CC50 = 10.0 μM). Collectively, these findings elucidate the covalent inhibition mechanism of shikonin against PRRSV-2 nsp4 and support its potential as an agent or lead compound for developing anti-PRRSV therapeutics.