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Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-fi...

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Autores principales: Sun, Yaping, Zhang, Huaidong, Shi, Jian, Zhang, Zhe, Gong, Rui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618021/
https://www.ncbi.nlm.nih.gov/pubmed/28906430
http://dx.doi.org/10.3390/v9090255
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author Sun, Yaping
Zhang, Huaidong
Shi, Jian
Zhang, Zhe
Gong, Rui
author_facet Sun, Yaping
Zhang, Huaidong
Shi, Jian
Zhang, Zhe
Gong, Rui
author_sort Sun, Yaping
collection PubMed
description The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (K(D)) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC(50)) of about 1 μM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable α-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent.
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spelling pubmed-56180212017-09-29 Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus Sun, Yaping Zhang, Huaidong Shi, Jian Zhang, Zhe Gong, Rui Viruses Article The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (K(D)) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC(50)) of about 1 μM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable α-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent. MDPI 2017-09-14 /pmc/articles/PMC5618021/ /pubmed/28906430 http://dx.doi.org/10.3390/v9090255 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sun, Yaping
Zhang, Huaidong
Shi, Jian
Zhang, Zhe
Gong, Rui
Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title_full Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title_fullStr Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title_full_unstemmed Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title_short Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus
title_sort identification of a novel inhibitor against middle east respiratory syndrome coronavirus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618021/
https://www.ncbi.nlm.nih.gov/pubmed/28906430
http://dx.doi.org/10.3390/v9090255
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