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

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 á-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.

Original languageEnglish (US)
Pages (from-to)1894-1903
Number of pages10
JournalJournal of Infectious Diseases
Volume212
Issue number12
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Coronavirus Infections
Infection
Protein S
Membrane Fusion Proteins
Dipeptidyl Peptidase 4
Peptides
Mutation
Cell Fusion
Protein Subunits
Viral Proteins
Middle East Respiratory Syndrome Coronavirus
Adenoviridae
Interferons
Delivery of Health Care
Lung
Membranes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Protective effect of intranasal regimens containing peptidic middle east respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. / Channappanavar, Rudragouda; Lu, Lu; Xia, Shuai; Du, Lanying; Meyerholz, David K.; Perlman, Stanley; Jiang, Shibo.

In: Journal of Infectious Diseases, Vol. 212, No. 12, 01.01.2015, p. 1894-1903.

Research output: Contribution to journalArticle

Channappanavar, Rudragouda ; Lu, Lu ; Xia, Shuai ; Du, Lanying ; Meyerholz, David K. ; Perlman, Stanley ; Jiang, Shibo. / Protective effect of intranasal regimens containing peptidic middle east respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. In: Journal of Infectious Diseases. 2015 ; Vol. 212, No. 12. pp. 1894-1903.
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