scholarly journals The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection

Vaccine ◽  
2017 ◽  
Vol 35 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Lan Jiaming ◽  
Yao Yanfeng ◽  
Deng Yao ◽  
Hu Yawei ◽  
Bao Linlin ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Terminal Domain ◽  
Potential Vaccine ◽  
Spike Proteins

scholarly journals The 1H, 15N, and 13C resonance assignments of the N-terminal domain of the nucleocapsid protein from the Middle East respiratory syndrome coronavirus

2021 ◽  
Author(s):  
Talita Stelling de Araujo ◽  
Glauce Moreno Barbosa ◽  
Karoline Sanches ◽  
Jéssica M. Azevedo ◽  
Katia Maria dos Santos Cabral ◽  
...  
Keyword(s):  
Middle East ◽  
Nucleocapsid Protein ◽  
Resonance Assignments ◽  
Middle East Respiratory Syndrome ◽  
Terminal Domain

scholarly journals Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Courtney M. Daczkowski ◽  
Octavia Y. Goodwin ◽  
John V. Dzimianski ◽  
Jonathan J. Farhat ◽  
Scott D. Pegan
Keyword(s):  
Middle East ◽  
Gene Product ◽  
Isothermal Calorimetry ◽  
Middle East Respiratory Syndrome ◽  
Human Interferon ◽  
Type I ◽  
Peptide Cleavage ◽  
Terminal Domain ◽  
Immune Pathways ◽  
The Impact

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant ongoing threat to global human health. As part of its viral genome, MERS-CoV encodes a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize type I interferon (IFN-I) immune pathways. This activity is in addition to its viral polypeptide cleavage function. Although the overall impact of MERS-CoV PLpro function is observed to be essential, difficulty has been encountered in delineating the importance of its separate functions, particularly its deISGylase activity. As a result, the interface of MERS-CoV and human interferon-stimulated gene product 15 (hISG15) was probed with isothermal calorimetry, which suggests that the C-terminal domain of hISG15 is principally responsible for interactions. Subsequently, the structure of MERS-CoV PLpro was solved to 2.4 Å in complex with the C-terminal domain of hISG15. Utilizing this structural information, mutants were generated that lacked appreciable deISGylase activity but retained wild-type deubiquitinase and peptide cleavage activities. Hence, this provides a new platform for understanding viral deISGylase activity within MERS-CoV and other CoVs. IMPORTANCE Coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV), encode a papain-like protease (PLpro) that possesses the ability to antagonize interferon immune pathways through the removal of ubiquitin and interferon-stimulated gene product 15 (ISG15) from target proteins. The lack of CoV proteases with attenuated deISGylase activity has been a key obstacle in delineating the impact between deubiquitinase and deISGylase activities on viral host evasion and pathogenesis. Here, biophysical techniques revealed that MERS-CoV PLpro chiefly engages human ISG15 through its C-terminal domain. The first structure of MERS-CoV PLpro in complex with this domain exposed the interface between these two entities. Employing these structural insights, mutations were employed to selectively remove deISGylase activity with no appreciable impact on its other deubiquitinase and peptide cleavage biochemical properties. Excitingly, this study introduces a new tool to probe the pathogenesis of MERS-CoV and related viruses through the removal of viral deISGylase activity.

scholarly journals Molecular Evolution and Structural Mapping of N-Terminal Domain in Spike Gene of Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 502
Author(s):  
Asif Naeem ◽  
Maaweya E. Hamed ◽  
Majed F. Alghoribi ◽  
Waleed Aljabr ◽  
Hadel Alsaran ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Amino Acid ◽  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Heptad Repeat ◽  
Structural Mapping ◽  
Virus Shedding ◽  
Spike Gene ◽  
Viral Loads ◽  
Terminal Domain

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a lethal zoonotic pathogen circulating in the Arabian Peninsula since 2012. There is no vaccine for MERS and anti-viral treatment is generally not applicable. We investigated the evolution of the MERS-CoV spike gene sequences and changes in viral loads over time from patients in Saudi Arabia from 2015–2017. All the MERS-CoV strains belonged to lineage 5, and showed high sequence homology (99.9%) to 2017 strains. Recombination analysis showed a potential recombination event in study strains from patients in Saudi Arabia. The spike gene showed eight amino acid substitutions, especially between the A1 and B5 lineage, and contained positively selected codon 1020. We also determined that the viral loads were significantly (p < 0.001) higher in fatal cases, and virus shedding was prolonged in some fatal cases beyond 21 days. The viral concentration peaked during the first week of illness, and the lower respiratory specimens had higher levels of MERS-CoV RNA. The presence of the diversifying selection and the topologies with the structural mapping of residues under purifying selection suggested that codon 1020 might have a role in the evolution of spike gene during the divergence of different lineages. This study will improve our understanding of the evolution of MERS-CoV, and also highlights the need for enhanced surveillance in humans and dromedaries. The presence of amino acid changes at the N-terminal domain and structural mapping of residues under positive selection at heptad repeat 1 provides better insight into the adaptive evolution of the spike gene and might have a potential role in virus-host tropism and pathogenesis.

scholarly journals Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Chu-Ming Luo ◽  
Ning Wang ◽  
Xing-Lou Yang ◽  
Hai-Zhou Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Middle East ◽  
South China ◽  
Middle East Respiratory Syndrome ◽  
Epidemiological Surveillance ◽  
Content Type ◽  
Dipeptidyl Peptidase 4 ◽  
Protein Protein Interaction ◽  
Evolutionary Origins ◽  
Bat Coronavirus ◽  
Spike Proteins

ABSTRACTMiddle East respiratory syndrome coronavirus (MERS-CoV) has represented a human health threat since 2012. Although several MERS-related CoVs that belong to the same species as MERS-CoV have been identified from bats, they do not use the MERS-CoV receptor, dipeptidyl peptidase 4 (DPP4). Here, we screened 1,059 bat samples from at least 30 bat species collected in different regions in south China and identified 89 strains of lineage C betacoronaviruses, includingTylonycteris pachypus coronavirus HKU4,Pipistrellus pipistrelluscoronavirus HKU5, and MERS-related CoVs. We sequenced the full-length genomes of two positive samples collected from the great evening bat,Ia io, from Guangdong Province. The two genomes were highly similar and exhibited genomic structures identical to those of other lineage C betacoronaviruses. While they exhibited genome-wide nucleotide identities of only 75.3 to 81.2% with other MERS-related CoVs, their gene-coding regions were highly similar to their counterparts, except in the case of the spike proteins. Further protein-protein interaction assays demonstrated that the spike proteins of these MERS-related CoVs bind to the receptor DPP4. Recombination analysis suggested that the newly discovered MERS-related CoVs have acquired their spike genes from a DPP4-recognizing bat coronavirus HKU4. Our study provides further evidence that bats represent the evolutionary origins of MERS-CoV.IMPORTANCEPrevious studies suggested that MERS-CoV originated in bats. However, its evolutionary path from bats to humans remains unclear. In this study, we discovered 89 novel lineage C betacoronaviruses in eight bat species. We provide evidence of a MERS-related CoV derived from the great evening bat that uses the same host receptor as human MERS-CoV. This virus also provides evidence for a natural recombination event between the bat MERS-related CoV and another bat coronavirus, HKU4. Our study expands the host ranges of MERS-related CoV and represents an important step toward establishing bats as the natural reservoir of MERS-CoV. These findings may lead to improved epidemiological surveillance of MERS-CoV and the prevention and control of the spread of MERS-CoV to humans.

Massive Infektion und alveolare Schädigung der humanen Lunge durch das Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Pneumologie ◽  
2015 ◽  
Vol 69 (04) ◽  
Author(s):  
A Becher ◽  
J von Recum ◽  
K Schierhorn ◽  
T Wolff ◽  
M Tönnies ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome

Aerogen übertragene Infektionskrankheiten bei Kindern auf Reisen

2018 ◽  
Vol 18 (06) ◽  
pp. 422-426
Author(s):  
C. Rau ◽  
J. Lindert ◽  
S. Kotsias-Konopelska ◽  
R. Kobbe
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Bakterielle Infektionen ◽  
Saisonale Influenza

ZusammenfassungErkrankungen der Atemwege gehören zu den häufigsten Gesundheitsproblemen von Kindern und treten regelhaft auch während und nach Reisen auf. Virale Atemwegsinfektionen können die Reisefähigkeit von Kindern – und damit auch ihren Angehörigen – ungünstig beeinflussen, beispielsweise durch Fieber, bronchiale Obstruktion und Schwierigkeiten beim Druckausgleich während des Fliegens durch Schwellungen und Sekretionen der Schleimhäute und der eustachi‘schen Röhre. Zu den reisemedizinisch relevanten aerogen übertragenen Krankheiten zählen neben banalen, viralen Erkältungen auch potenziell schwer verlaufende Viruserkrankungen, allen voran die saisonale Influenza und die Masern, sowie bakterielle Infektionen durch Meningokokken und die Tuberkulose. Gegen einige dieser Erkrankungen stehen effektive Impfstoffe zur Verfügung. Auch seltene, schwer verlaufende Atemwegsinfektionen, die unter bestimmten epidemiologischen Umständen außerhalb Europas erworben werden können, sollen im Folgenden exemplarisch an den Erkrankungen Middle East respiratory syndrome (MERS) und der Histoplasmose dargestellt werden.

Lead Molecule Prediction and Characterization for Designing MERS-CoV 3C-like Protease Inhibitors: An In silico Approach

2018 ◽  
Vol 15 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Md. Mostafijur Rahman ◽  
Md. Bayejid Hosen ◽  
M. Zakir Hossain Howlader ◽  
Yearul Kabir
Keyword(s):  
Binding Energy ◽  
Middle East ◽  
Virtual Screening ◽  
In Silico ◽  
Screening Method ◽  
Middle East Respiratory Syndrome ◽  
Cytochrome P450 Enzymes ◽  
Drug Molecules ◽  
Essential Enzyme ◽  
Reduced Toxicity

Background: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease, and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. </P><P> Methods: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method. Further, the compounds were validated through absorption, distribution, metabolism and excretion filtering. Results: Based on binding energy, ADME properties, and toxicology analysis, we finally selected 3 compounds from structure-based virtual screening (ZINC ID: 75121653, 41131653, and 67266079) having binding energy -7.12, -7.1 and -7.08 Kcal/mol, respectively and 5 compounds from ligandbased virtual screening (ZINC ID: 05576502, 47654332, 04829153, 86434515 and 25626324) having binding energy -49.8, -54.9, -65.6, -61.1 and -66.7 Kcal/mol respectively. All these compounds have good ADME profile and reduced toxicity. Among eight compounds, one is soluble in water and remaining 7 compounds are highly soluble in water. All compounds have bioavailability 0.55 on the scale of 0 to 1. Among the 5 compounds from structure-based virtual screening, 2 compounds showed leadlikeness. All the compounds showed no inhibition of cytochrome P450 enzymes, no blood-brain barrier permeability and no toxic structure in medicinal chemistry profile. All the compounds are not a substrate of P-glycoprotein. Our predicted compounds may be capable of inhibiting 3C-like protease but need some further validation in wet lab.

scholarly journals Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus

2021 ◽  
Author(s):  
Sumathi Sivapalasingam ◽  
George A Saviolakis ◽  
Kirsten Kulcsar ◽  
Aya Nakamura ◽  
Thomas Conrad ◽  
...  
Keyword(s):  
Middle East ◽  
Adverse Events ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Preclinical Study ◽  
Middle East Respiratory Syndrome ◽  
Lung Pathology ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Dipeptidyl Peptidase 4

Abstract Background REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. Methods Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. Results Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. Conclusions REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

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