AUTHOR=Yang Cheng-Wei , Lee Yue-Zhi , Hsu Hsing-Yu , Jan Jia-Tsrong , Lin Yi-Ling , Chang Sui-Yuan , Peng Tzu-Ting , Yang Ruey-Bing , Liang Jian-Jong , Liao Chun-Che , Chao Tai-Ling , Pang Yu-Hau , Kao Han-Chieh , Huang Wen-Zheng , Lin Jiunn-Horng , Chang Chun-Ping , Niu Guang-Hao , Wu Szu-Huei , Sytwu Huey-Kang , Chen Chiung-Tong , Lee Shiow-Ju TITLE=Inhibition of SARS-CoV-2 by Highly Potent Broad-Spectrum Anti-Coronaviral Tylophorine-Based Derivatives JOURNAL=Frontiers in Pharmacology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.606097 DOI=10.3389/fphar.2020.606097 ISSN=1663-9812 ABSTRACT=

Tylophorine-based compounds and natural cardiotonic steroids (cardenolides and bufadienolides) are two classes of transmissible gastroenteritis coronavirus inhibitors, targeting viral RNA and host cell factors, respectively. We tested both types of compounds against two types of coronaviruses, to compare and contrast their antiviral properties, and with view to their further therapeutic development. Examples of both types of compounds potently inhibited the replication of both feline infectious peritonitis virus and human coronavirus OC43 with EC50 values of up to 8 and 16 nM, respectively. Strikingly, the tylophorine-based compounds tested inhibited viral yields of HCoV-OC43 to a much greater extent (7–8 log magnitudes of p.f.u./ml) than the cardiotonic steroids (about 2–3 log magnitudes of p.f.u./ml), as determined by end point assays. Based on these results, three tylophorine-based compounds were further examined for their anti-viral activities on two other human coronaviruses, HCoV-229E and SARS-CoV-2. These three tylophorine-based compounds inhibited HCoV-229E with EC50 values of up to 6.5 nM, inhibited viral yields of HCoV-229E by 6–7 log magnitudes of p.f.u./ml, and were also found to inhibit SARS-CoV-2 with EC50 values of up to 2.5–14 nM. In conclusion, tylophorine-based compounds are potent, broad-spectrum inhibitors of coronaviruses including SARS-CoV-2, and could be used for the treatment of COVID-19.