Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

预防严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的感染和传播是 2019 年冠状病毒病 (COVID-19) 大流行中的重中之重。在这里，我们描述了参与 SARS-CoV-2 感染的多种蛋白质的 S-亚硝基化，包括病毒进入的受体血管紧张素转换酶 2 (ACE2)。该反应可防止 ACE2 与 SARS-CoV-2 刺突蛋白结合，从而抑制病毒进入、感染性和细胞毒性。氨基金刚烷化合物还抑制由包膜 (E) 蛋白形成的冠状病毒离子通道。因此，我们开发了双机制氨基金刚烷硝酸酯化合物，该化合物可抑制病毒进入，从而通过在 E 蛋白通道阻断后通过 S-亚硝基化 ACE2 靶向递送药物来抑制感染的传播。这些无毒化合物在叙利亚仓鼠 COVID-19 模型中具有体外和体内活性，因此提供了一种新的治疗途径。