Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection

Rudragouda Channappanavar; Lu Lu; Shuai Xia; Lanying Du; David K Meyerholz; Stanley Perlman; Shibo Jiang

doi:10.1093/infdis/jiv325

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Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection

Journal article

Open access

Peer reviewed

Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection

Rudragouda Channappanavar, Lu Lu, Shuai Xia, Lanying Du, David K Meyerholz, Stanley Perlman and Shibo Jiang

The Journal of infectious diseases, Vol.212(12), pp.1894-1903

12/15/2015

DOI: 10.1093/infdis/jiv325

PMCID: PMC4655857

PMID: 26164863

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Abstract

To gain entry into the target cell, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) uses its spike (S) protein S2 subunit to fuse with the plasma or endosomal membrane. Previous work identified a peptide derived from the heptad repeat (HR) 2 domain in S2 subunit, HR2P, which potently blocked MERS-CoV S protein-mediated membrane fusion. Here, we tested an HR2P analogue with improved pharmaceutical property, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo. HR2P-M2 was highly effective in inhibiting MERS-CoV S protein-mediated cell-cell fusion and infection by pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region. It interacted with the HR1 peptide to form stable α-helical complex and blocked six-helix bundle formation between the HR1 and HR2 domains in the viral S protein. Intranasally administered HR2P-M2 effectively protected adenovirus serotype-5-human dipeptidyl peptidase 4-transduced mice from infection by MERS-CoV strains with or without mutations in the HR1 region of S protein, with >1000-fold reduction of viral titers in lung, and the protection was enhanced by combining HR2P-M2 with interferon β. These results indicate that this combination regimen merits further development to prevent MERS in high-risk populations, including healthcare workers and patient family members, and to treat MERS-CoV-infected patients.

Coronavirus Infections - prevention & control

Cell Line

Humans

Mice, Inbred C57BL

Middle East Respiratory Syndrome Coronavirus - drug effects

Virus Internalization - drug effects

Administration, Intranasal

Antiviral Agents - administration & dosage

Peptides - administration & dosage

Viral Load

Lung - virology

Animals

Middle East Respiratory Syndrome Coronavirus - physiology

Disease Models, Animal

Details

Title: Subtitle: Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection
Creators: Rudragouda Channappanavar - Departments of Microbiology, University of Iowa, Iowa City
Lu Lu - Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China
Shuai Xia - Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China
Lanying Du - Lindsley F. Kimball Research Institute, New York Blood Center, New York
David K Meyerholz - Pathology, University of Iowa, Iowa City
Stanley Perlman - Departments of Microbiology, University of Iowa, Iowa City Pediatrics, University of Iowa, Iowa City
Shibo Jiang - Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China Lindsley F. Kimball Research Institute, New York Blood Center, New York
Resource Type: Journal article
Publication Details: The Journal of infectious diseases, Vol.212(12), pp.1894-1903
DOI: 10.1093/infdis/jiv325
PMID: 26164863
PMCID: PMC4655857
NLM abbreviation: J Infect Dis
ISSN: 1537-6613
eISSN: 1537-6613
Publisher: United States
Grant note: R01AI091322 / NIAID NIH HHS R01 AI091322 / NIAID NIH HHS P01AI60699 / NIAID NIH HHS P01 AI060699 / NIAID NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 12/15/2015
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777348302771

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