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Published on: December 23, 2020
Prolyl isomerase Pin1 plays an essential role in SARS-CoV-2 proliferation, indicating its possibility as a novel
Takeshi Yamamotoya1, Yusuke Nakatsu1, Machi Kanna1
1Department of Medical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Abstract:
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 EC50 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.
Insights
Pin1 is essential for SARS-CoV-2 replication. Inhibiting Pin1 with compounds like H-77 and ATRA significantly reduced viral proliferation and cytopathic effects, suggesting Pin1 inhibitors as potential COVID-19 therapeutics.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates novel therapeutic strategies.
- Cellular factors involved in viral propagation are potential drug targets.
Purpose of the Study:
- To investigate the role of the peptidyl-prolyl isomerase Pin1 in SARS-CoV-2 replication.
- To evaluate the efficacy of Pin1 inhibitors as potential antiviral agents against SARS-CoV-2.
Main Methods:
- siRNA-mediated silencing of Pin1 expression in VeroE6/TMPRSS2 cells.
- Treatment with Pin1 inhibitors (H-77 and ATRA) to assess SARS-CoV-2 proliferation.
- Measurement of viral mRNA and protein synthesis, and cytopathic effect (CPE).
Main Results:
- Silencing Pin1 significantly suppressed SARS-CoV-2 proliferation.
- Pin1 inhibitors H-77 and ATRA demonstrated strong inhibitory effects on viral replication.
- H-77 inhibited viral N protein mRNA synthesis, suggesting interference with transcription or earlier steps.
- ATRA, a drug for acute promyelocytic leukemia, also reduced SARS-CoV-2 proliferation.
Conclusions:
- Pin1 is a critical host factor for SARS-CoV-2 propagation.
- Pin1 inhibitors show promise as a new class of antiviral therapeutics for COVID-19.
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