Clomipramine suppresses ACE2-mediated SARS-CoV-2 entry

Kato, Yuri; Yamada, Shigeru; Nishiyama, Kazuhiro; Satsuka, Ayano; Re, Suyong; Tomokiyo, Daiki; Lee, Jae Man; Tanaka, Tomohiro; Nishimura, Akiyuki; Yonemitsu, Kenzo; Asakura, Hiroshi; Ibuki, Yuko; Imai, Yumiko; Kamiya, Noriho; Mizuguchi, Kenji; Kusakabe, Takahiro; Kanda, Yasunari; Nishida, Motohiro

Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells are initiated by binding with its receptor, angiotensin converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we found that clomipramine, a tricyclic antidepressant, potently inhibits SARS-CoV-2 infection and metabolic disorder in human iPS-derived cardiomyocytes. Among 13 approved drugs that we have previously identified as potential inhibitor of doxorubicin-induced cardiotoxicity, clomipramine showed the best potency to inhibit SARS-CoV-2 spike glycoprotein pseudovirus-stimulated ACE2 internalization. Indeed, SARS-CoV-2 infection to human iPS-derived cardiomyocytes (iPS-CMs) and TMPRSS2-expressing VeroE6 cells were dramatically suppressed even after treatment with clomipramine. Furthermore, the combined use of clomipramine and remdesivir was revealed to synergistically suppress SARS-CoV-2 infection. Our results will provide the potentiality of clomipramine for the breakthrough treatment of severe COVID-19.