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

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

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.

INTRANASAL medication; MERS coronavirus; CELL membranes; PEPTIDES; MEMBRANE fusion; VIRAL proteins; LABORATORY mice; INTERFERONS; CORONAVIRUS diseases; ANIMAL experimentation; ANTIVIRAL agents; BIOLOGICAL models; CELL lines; LUNGS; MICE; RESEARCH funding; VIRUSES; VIRAL load; PREVENTION

Journal of Infectious Diseases, 2015, Vol 212, Issue 12, p1894

0022-1899

Academic Journal

10.1093/infdis/jiv325