Targeting transcriptional regulation of SARS-CoV-2 entry factors  ACE2  and  TMPRSS2

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Significance

New therapeutic targets are urgently needed against SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Results in this study show that targeting the transcriptional regulation of host entry factors TMPRSS2 and ACE2 is a viable treatment strategy to prevent SARS-CoV-2 infection. In particular, inhibitors of androgen receptor (AR) or bromodomain and extraterminal domain (BET) proteins are effective against SARS-CoV-2 infection. AR inhibitors are already approved in the clinic for treatment of prostate cancer and are under investigation in COVID-19 patients; BET inhibitors are also in clinical development for other indications and could be rapidly repurposed for COVID-19.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Comprehensive Integration of Single-Cell Data

Tim Stuart, Andrew Butler, Paul Hoffman … (2019)

Single-cell transcriptomics has transformed our ability to characterize cell states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, a key analytical challenge is to integrate these datasets to better understand cellular identity and function. Here, we develop a strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq technologies, but also across different modalities. After demonstrating improvement over existing methods for integrating scRNA-seq data, we anchor scRNA-seq experiments with scATAC-seq to explore chromatin differences in closely related interneuron subsets and project protein expression measurements onto a bone marrow atlas to characterize lymphocyte populations. Lastly, we harmonize in situ gene expression and scRNA-seq datasets, allowing transcriptome-wide imputation of spatial gene expression patterns. Our work presents a strategy for the assembly of harmonized references and transfer of information across datasets.

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Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Renhong Yan, Yuanyuan Zhang, Yaning Li … (2020)

How SARS-CoV-2 binds to human cells Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan et al. present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. In the context of this complex, ACE2 is a dimer. A further structure shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures provide a basis for the development of therapeutics targeting this crucial interaction. Science, this issue p. 1444

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 07 January 2021

Publication date (Electronic): 28 December 2020

Publication date PMC-release: 28 December 2020

Volume: 118

Issue: 1

Electronic Location Identifier: e2021450118

Affiliations

[1] ^aMichigan Center for Translational Pathology, University of Michigan , Ann Arbor, MI 48109;

[2] ^bDepartment of Pathology, University of Michigan , Ann Arbor, MI 48109;

[3] ^cRogel Cancer Center, University of Michigan , Ann Arbor, MI 48109;

[4] ^dDepartment of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, MI 48109;

[5] ^eHoward Hughes Medical Institute , University of Michigan , Ann Arbor, MI 48109;

[6] ^fState Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences , Shanghai 200031, China;

[7] ^gDepartment of Internal Medicine, University of Michigan , Ann Arbor, MI 48109;

[8] ^hDepartment of Pharmacology, University of Michigan , Ann Arbor, MI 48109;

[9] ⁱCenter for Drug Repurposing, University of Michigan , Ann Arbor, MI 48109;

[10] ^jMichigan Institute for Clinical and Health Research, University of Michigan , Ann Arbor, MI 48109;

[11] ^kDepartment of Urology, University of Michigan , Ann Arbor, MI 48109

Author notes

³To whom correspondence may be addressed. Email: arul@ 123456umich.edu .

Contributed by Arul M. Chinnaiyan, November 18, 2020 (sent for review October 16, 2020; reviewed by William L. Dahut and Nicholas Nickols)

Author contributions: Y.Q., X.-M.W., R. Mannan, R. Mehra, J.Z.S., and A.M.C. designed research; Y.Q., X.-M.W., R. Mannan, S.P., Y.Z., J.W.W., L.X., D.R.R., Y.-M.W., J.C.-Y.T., X.C., S.A.S., I.J.A., P.B., S.K., S.P.N., S.Z.-W., L.M., F.S., R.W., Y.C., A.D.D., Z.M., C.D.P., and R. Mehra performed research; S.W. contributed new reagents/analytic tools; Y.Q., X.-M.W., R. Mannan, S.P., Y.Z., J.W.W., L.X., D.R.R., Y.-M.W., G.R., A.P., S.Z.-W., C.D.P., R. Mehra, J.Z.S., and A.M.C. analyzed data; and Y.Q., X.-M.W., R. Mannan, S.J.E., R. Mehra, J.Z.S., and A.M.C. wrote the paper.

Reviewers: W.L.D., National Cancer Institute; and N.N., University of California, Los Angeles.

¹Y.Q., X.-M.W., and R. Mannan contributed equally to this work.

²R. Mehra, J.Z.S., and A.M.C. contributed equally to this work.