Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M^pro), its moderate activity in M^pro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.

多项药物筛选活动将 Calpeptin 确定为抗 SARS-CoV-2 的候选药物。最初报道以病毒主要蛋白酶 (M ^pro ) 为目标，其在 M ^pro抑制测定中的中等活性暗示了第二个目标。事实上，我们证明 Calpeptin 是一种极其有效的半胱氨酸组织蛋白酶抑制剂，这一发现还得到了 X 射线晶体学的支持。细胞感染测定证明了 Calpeptin 对 SARS-CoV-2 的功效。用磺化 Calpeptin 以 1 毫克/千克体重的剂量治疗感染 SARS-CoV-2 的金色叙利亚仓鼠，可减少气管中的病毒载量。尽管副作用风险较高，但与高度可变的病毒靶标相比，靶向宿主蛋白的内在优势是其突变稳定性。在这里，我们表明，通过钙肽抑制组织蛋白酶（宿主生物体的一种蛋白质家族）是治疗 SARS-CoV-2 和其他潜在病毒感染的一种有前景的方法。