title: Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection.
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.
authors.affiliation: Departments of Microbiology, University of Iowa, Iowa City.
authors.forename: Rudragouda
authors.initials: R
authors.lastname: Channappanavar
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Xia
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York.
authors.forename: Lanying
authors.initials: L
authors.lastname: Du
authors.affiliation: Pathology, University of Iowa, Iowa City.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Departments of Microbiology, University of Iowa, Iowa City Pediatrics, University of Iowa, Iowa City.
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
authors.affiliation: 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.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D002460:Cell Line; D018352:Coronavirus Infections / Q000517:prevention & control*; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000821:virology; D008810:Mice, Inbred C57BL; D065207:Middle East Respiratory Syndrome Coronavirus / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000008:administration & dosage*; D019562:Viral Load; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D010455:Peptides
keywords: MERS-CoV; fusion inhibitor; interferon; peptide