Designed miniproteins potently inhibit and protect against MERS-CoV

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• Middle-East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus with a high human case-fatality rate.
• There are currently no approved vaccines or therapeutics for MERS-CoV in humans or its camel reservoir.

Purpose of the Study:

• To computationally design high-affinity miniproteins targeting the MERS-CoV spike (S) glycoprotein.
• To evaluate the broad neutralization capacity and mechanism of action of these miniproteins.
• To assess the in vivo efficacy of a lead miniprotein as a potential MERS-CoV countermeasure.

Main Methods:

• Computational design of monomeric and homo-oligomeric miniproteins.
• In vitro neutralization assays against a panel of MERS-CoV S variants.
• Analysis of miniprotein binding to the MERS-CoV receptor-binding domain (RBD) and competition with DPP4 receptor binding.
• In vivo prophylactic efficacy study using intranasal administration in a MERS-CoV mouse model.

Main Results:

• Designed miniproteins demonstrated high affinity binding to the MERS-CoV S glycoprotein.
• Miniproteins broadly neutralized diverse MERS-CoV variants by targeting a conserved RBD site.
• The miniproteins blocked viral attachment and membrane fusion by competing with DPP4 receptor binding.
• Intranasal administration of a lead miniprotein conferred prophylactic protection in a MERS-CoV mouse challenge model.

Conclusions:

• Computationally designed miniproteins represent a promising therapeutic strategy against MERS-CoV.
• These miniproteins offer broad neutralization and act via a novel mechanism targeting viral entry.
• Further clinical development of these miniproteins is warranted as a next-generation countermeasure against MERS-CoV.