Abstract
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 (KD) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC50) 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.
Highlights
The newly emerging pathogen Middle East respiratory syndrome coronavirus (MERS-CoV)was first recognized in Saudi Arabia in June 2012 [1]
As of June 2017, the World Health Organization (WHO) has been notified of 2037 laboratory-confirmed cases of infection with MERS-CoV and at least 710 deaths related to MERS-CoV, showing a much higher fatality rate [7] compared to SARS-CoV
The lysate was clarified by centrifugation and the supernatant was passed over a nickel-nitrilotriacetic acid (Ni-NTA) Resin (Qiagen, Hilden, Germany) column pre-equilibrated with phosphate buffer saline (PBS) containing 500 mM NaCl
Summary
The newly emerging pathogen Middle East respiratory syndrome coronavirus (MERS-CoV). Was first recognized in Saudi Arabia in June 2012 [1]. MERS-CoV causes severe respiratory disease in the lower respiratory tract and is often accompanied by renal failure, showing similar clinical, epidemiological, and virological features to severe acute respiratory syndrome coronavirus (SARS-CoV). Since September 2012, 27 countries have reported cases of MERS-CoV globally while most cases were found in Saudi Arabia [8,9]. Various therapeutics including peptide inhibitors, neutralizing antibodies, and vaccines are under development for the treatment and prevention of MERS-CoV [10,11,12,13,14,15]. Development of efficient countermeasures to curb the spread of MERS-CoV is of great importance
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