Emodin inhibits current through SARS-associated coronavirus 3a protein

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Abstract

The open-reading-frame 3a of SARS coronavirus (SARS-CoV) had been demonstrated previously to form a cation-selective channel that may become expressed in the infected cell and is then involved in virus release. Drugs that inhibit the ion channel formed by the 3a protein can be expected to inhibit virus release, and would be a source for the development of novel therapeutic agents. Here we demonstrate that emodin can inhibit the 3a ion channel of coronavirus SARS-CoV and HCoV-OC43 as well as virus release from HCoV-OC43 with a K _1/2 value of about 20 μM. We suggest that viral ion channels, in general, may be a good target for the development of antiviral agents.

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Most cited references 18

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Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction

Tin-Yun Ho, Shih-Lu Wu, Jaw-Chyun Chen … (2006)

Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus (SARS-CoV). SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening 312 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we identified that three widely used Chinese medicinal herbs of the family Polygonaceae inhibited the interaction of SARS-CoV S protein and ACE2. The IC50 values for Radix et Rhizoma Rhei (the root tubers of Rheum officinale Baill.), Radix Polygoni multiflori (the root tubers of Polygonum multiflorum Thunb.), and Caulis Polygoni multiflori (the vines of P. multiflorum Thunb.) ranged from 1 to 10 μg/ml. Emodin, an anthraquinone compound derived from genus Rheum and Polygonum, significantly blocked the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS.

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Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses.

R Vlasak, W Luytjes, W Spaan … (1988)

Human coronavirus OC43 and bovine coronavirus elute from agglutinated chicken erythrocytes when incubated at 37 degrees C, suggesting the presence of a receptor-destroying enzyme. Moreover, bovine coronavirus exhibits an acetylesterase activity in vitro using bovine submaxillary mucin as substrate similar to the enzymatic activity found in influenza C viruses. Furthermore, pretreatment of erythrocytes with either influenza C virus or bovine coronavirus eliminates subsequent binding and agglutination by either coronaviruses or influenza C virus, whereas binding of influenza A virus remains intact. In addition, hemagglutination by coronaviruses can be inhibited by pretreatment of erythrocytes with Arthrobacter ureafaciens or Clostridium perfringens neuraminidase or by addition of sialic acid-containing gangliosides. These results suggest that, like influenza C viruses, human coronavirus OC43 and bovine coronavirus recognize O-acetylated sialic acid or a similar derivative as cell receptor.

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Structure of the Amantadine Binding Site of Influenza M2 Proton Channels In Lipid Bilayers

Sarah D. Cady, Klaus Schmidt-Rohr, Jun-Jun Wang … (2010)

The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine 1. Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1. A recent crystal structure of M2(22-46) showed electron densities attributed to a single amantadine in the N-terminal half of the pore 2, suggesting a physical occlusion mechanism for inhibition. However, a solution NMR structure of M2(18-60) showed four rimantadines bound to the C-terminal lipid-facing surface of the helices 3, suggesting an allosteric mechanism. Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers. The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses. Quantification of the protein – amantadine distances resulted in a 0.3 Å-resolution structure of the high-affinity binding site. The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer. The orientation and dynamics of the drug are distinct in the two sites, as shown by 2H NMR. These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses. The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.

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Author and article information

Contributors

Wolfgang Schwarz

Journal

Journal ID (nlm-ta): Antiviral Res

Journal ID (iso-abbrev): Antiviral Res

Title: Antiviral Research

Publisher: Elsevier B.V.

ISSN (Print): 0166-3542

ISSN (Electronic): 1872-9096

Publication date PMC-release: 26 February 2011

Publication date (Print): April 2011

Publication date (Electronic): 26 February 2011

Volume: 90

Issue: 1

Pages: 64-69

Affiliations

[a ]Shanghai Research Center for Acupuncture & Meridians, 199 Guoshoujing Rd., Shanghai 201203, China

[b ]Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai Institutes of Biological Sciences, 225 South Chongqing Road, Shanghai, 200025, China

[c ]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China

[d ]Max-Planck-Institute for Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt am Main, Germany

[e ]Institute for Biophysics, Goethe-University, Max-von-Laue-Str. 1, 60438 Frankfurt am Main, Germany

Author notes

[* ]Corresponding author. Institute for Biophysics/Goethe-University, Max-von-Laue-Str. 1, Frankfurt am Main 600438, Germany. Tel.: +49 0 171 469 0647; fax: +49 0 3212 888 3496. schwarz@ 123456biophys.eu

Article

Publisher ID: S0166-3542(11)00046-5

DOI: 10.1016/j.antiviral.2011.02.008

PMC ID: 7114100

PubMed ID: 21356245

SO-VID: 8efc20f7-0d5d-49f7-b014-a33c6ec87235

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 21 October 2010

Date revision received : 15 February 2011

Date accepted : 21 February 2011

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