Potential Simultaneous Inhibitors of Angiotensin-Converting Enzyme 2 and Transmembrane Protease, Serine 2

Ching-Yuan Wu,Hung Te Liu,Yu-Shih Lin,Yu-Ching Cheng,Li-Hsin Shu,Yao-Hsu Yang

doi:10.3389/fphar.2020.584158

Abstract

Outbreak of coronavirus disease 2019 occurred in Wuhan and has rapidly spread to almost all parts of world. GB-1, the herbal formula from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, is used for the prophylaxis of SARS-CoV-2 in Taiwan. In this study, we investigated that the effect of GB-1 and the index compounds of GB-1 on the ACE2 and TMPRSS2 expression through in vitro and in vivo study. In our result, GB-1 can inhibit ACE2 and TMPRSS2 protein expression in HepG2 cells, 293T cells, and Caco-2 cells without cytotoxicity. For the mouse model, GB-1 treatment could decrease ACE2 and TMPRSS2 expression levels of the lung and kidney tissue without adverse effects, including nephrotoxicity and hepatotoxicity. In the compositions of GB-1, 0.5–1 mg/ml of Glycyrrhiza uralensis Fisch. ex DC. extract could not inhibit ACE2 mRNA and protein expression in HepG2 cells. In addition, theaflavin-3-gallate could inhibit protein expression of ACE2 and TMPRSS2 without significant cytotoxicity. Our results suggest that GB-1 and theaflavin-3-gallate could act as potential candidates for prophylaxis or treatment of SARS-CoV-2 infection through inhibiting protein expression of ACE2 and TMPRSS2 for the further study.

Highlights

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced coronavirus disease 2019 (COVID-19) was recorded in December 2019
Because the SARS-CoV-2 spike protein can bind directly to Angiotensin-converting enzyme 2 (ACE2) and is primed by TMPRSS2 (Hoffmann et al, 2020b; Walls et al, 2020; Yan et al, 2020), we examined the effect of GB-1 on ACE2 and TMPRSS2 expression in host cells
We examined the effect of GB-1 on signal transducer and activator of transcription 3 (STAT3) expression in host cells

Summary

Introduction

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced coronavirus disease 2019 (COVID-19) was recorded in December 2019. Angiotensin-converting enzyme 2 (ACE2) is a membrane-associated enzyme for catalyzing the cleavage of angiotensin I to angiotensin (1–9) (Donoghue et al, 2000). Its peptidase domain can directly bind to the receptor-binding domain of the spike protein on the surface of the SARS-CoV-2 viral envelope, promoting viral entry into host cells (Hoffmann et al, 2020b; Walls et al, 2020; Yan et al, 2020). Potential Prophylaxis of COVID-19 receptor, transmembrane protease, serine 2 (TMPRSS2), and furin of host cells can cleave and activate the SARS-CoV-2 spike protein (Hoffmann et al, 2020a; Hoffmann et al, 2020b)

Methods

Results

Conclusion