Novel coronavirus disease 2019 (COVID-19) has emerged as a global pandemic with far-reaching societal impact. Here we demonstrate that Pin1 is a key cellular molecule necessary for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagation. In this study, siRNA-mediated silencing of Pin1 expression markedly suppressed the proliferation of SARS-CoV-2 in VeroE6/TMPRSS2 cells. In addition, several recently generated Pin1 inhibitors showed strong inhibitory effects on SARS-CoV-2 proliferation, measured by both viral mRNA and protein synthesis, and alleviated the cytopathic effect (CPE) on VeroE6/TMPRSS2 cells. One compound, termed H-77, was found to block SARS-CoV-2 proliferation at an EC 50 below 5 μM regardless of whether it was added to the culture medium prior to or after SARS-CoV-2 infection. The inhibition of viral N protein mRNA synthesis by H-77 implies that the molecular mechanism underlying SARS-CoV-2 inhibition is likely to be associated with viral gene transcription or earlier steps. Another Pin1 inhibitor, all-trans retinoic acid (ATRA)—a commercially available drug used to treat acute promyelocytic leukemia (APL) and which both activates the retinoic acid receptor and inhibits the activity of Pin1—similarly reduced the proliferation of SARS-CoV-2. Taken together, the results indicate that Pin1 inhibitors could serve as potential therapeutic agents for COVID-19.
【저자키워드】 SARS-CoV-2, Infectious diseases, Drug development, Target identification, 【초록키워드】 COVID-19, coronavirus disease, Coronavirus disease 2019, coronavirus, SARS-COV-2 infection, Transcription, drug, novel coronavirus disease, molecular mechanism, severe acute respiratory syndrome Coronavirus, Novel coronavirus, global pandemic, Viral, Culture, cells, mRNA, siRNA, N protein, therapeutic agents, receptor, culture medium, novel, respiratory, inhibitor, retinoic acid, expression, leukemia, cellular, CPE, Cytopathic effect, protein synthesis, Acute promyelocytic leukemia, proliferation, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, potential therapeutic agents, medium, inhibitory effect, treat, ATRA, PIN1, Promyelocytic leukemia, addition, inhibit, reduced, added, potential therapeutic agent, suppressed, activate, APL, mRNA synthesis, 【제목키워드】 therapeutic target,