Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein

Virus Research
Volume 194, 19 December 2014, Pages 200-210

Shuai Xia, Qi Liu, Qian Wang, Zhiwu Sun, Shan Su, Lanying Du, Tianlei Ying, Lu Lu, Shibo Jiang

Abstract

The recent outbreak of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) infection has led to more than 800 laboratory-confirmed MERS cases with a high case fatality rate (∼35%), posing a serious threat to global public health and calling for the development of effective and safe therapeutic and prophylactic strategies to treat and prevent MERS-CoV infection. Here we discuss the most recent studies on the structure of the MERS-CoV spike protein and its role in virus binding and entry, and the development of MERS-CoV entry/fusion inhibitors targeting the S1 subunit, particularly the receptor-binding domain (RBD), and the S2 subunit, especially the HR1 region, of the MERS-CoV spike protein. We then look ahead to future applications of these viral entry/fusion inhibitors, either alone or in combination with specific and nonspecific MERS-CoV replication inhibitors, for the treatment and prevention of MERS-CoV infection.

Keywords

Middle East respiratory syndrome coronavirus, MERS-CoV, Receptor-binding domain, Fusion inhibitor, Entry inhibitor, Six-helix bundle

A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2

Antiviral Research
Volume 94, Issue 3, June 2012, Pages 288-296

Anna-WinonaStruck, Marco Axmanna, Susanne Pfefferle, ChristianDrosten, Bernd Meyera

Abstract

In vitro infection of Vero E6 cells by SARS coronavirus (SARS-CoV) is blocked by hexapeptide Tyr-Lys-Tyr-Arg-Tyr-Leu. The peptide also inhibits proliferation of coronavirus NL63. On human cells both viruses utilize angiotensin-converting enzyme 2 (ACE2) as entry receptor. Blocking the viral entry is specific as alpha virus Sindbis shows no reduction in infectivity. Peptide 438YKYRYL443 is part of the receptor-binding domain (RBD) of the spike protein of SARS-CoV. Peptide libraries were screened by surface plasmon resonance (SPR) to identify RBD binding epitopes. 438YKYRYL443 carries the dominant binding epitope and binds to ACE2 with KD = 46 μM. The binding mode was further characterized by saturation transfer difference (STD) NMR spectroscopy and molecular dynamic simulations. Based on this information the peptide can be used as lead structure to design potential entry inhibitors against SARS-CoV and related viruses.

Keywords

SARS coronavirus, Spike protein, ACE2, Entry inhibitor, Virus proliferation assay, SPR screening