Discovery and Nanosized Preparations of (S,R)-Tylophorine Malate as Novel anti-SARS-CoV-2 Agents

[Image: see text] The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has stimulated the search for effective drugs for its prevention and treatment. Natural products are an important source for new drug discovery. Here, we report that, NK007(S,R), a tylophorine malate, displays high antiviral activity against SARS-CoV-2 with an EC(50) 0.03 μM in vitro, which is substantially lower than that of remdesivir (EC(50): 0.8 μM in vitro), the only authorized drug to date. The histopathological research revealed that NK007(S,R) (5 mg/kg/dose) displayed a protection effect in lung injury induced by SARS-CoV-2, which is better than remdesivir (25 mg/kg/dose). We also prepared two nanosized preparations of NK007(S,R), which also showed good efficacy (EC(50): NP-NK007, 0.007 μM in vitro; LP-NK007, 0.014 μM in vitro). Our findings suggest that tylophora alkaloids, isolated from the traditional Chinese medicine Cynanchum komarovii AL, offer a new skeleton for the development of anticoronavirus drug candidate.