Intranasally administered peptidic viral fusion inhibitor protected hDPP4 transgenic mice from MERS-CoV infection

ABSTRACT:

Background

Middle East respiratory syndrome coronavirus (MERS-CoV), a new coronavirus that emerged in 2012, causes severe and fatal acute respiratory illness in man. Its high mortality (roughly 38%) has raised public fear worldwide, calling for the development of effective and safe therapeutics to combat MERS-CoV infection. On the basis of our previous work in development of peptide fusion inhibitors against HIV and SARS-CoV, and the crystal structure of the six-helix-bundle core of the MERS-CoV spike protein, we identified a peptide derived from the MERS-CoV S protein S2 subunit HR2 domain (HR2P) with a potent inhibitory activity against S-protein-mediated cell–cell fusion. Here, we tested an HR2P analogue with improved pharmaceutical properties, HR2P-M2, for its inhibitory activity against MERS-CoV infection in vitro and in vivo (appendix).

Methods

We assessed the anti-MERS-CoV activities of HR2P-M2 in vitro with pseudotyped MERS-CoVs in cell culture and in vivo with live MERS-CoVs in hDPP4-transgenic mice. The activities of HR2P-M2 to form six-helix bundles with HR1 peptides and to block fusion core formation between HR1 and HR2 peptides were studied using methods such as circular dichroism, N-PAGE, and FN-PAGE.

Findings

HR2P-M2 was highly effective in blockade of cell–cell fusion mediated by MERS-CoV S proteins and inhibition of infection by MERS pseudoviruses expressing MERS-CoV S protein with or without mutation in the HR1 region, with IC50 (the concentration causing 50% inhibition) less than 0·7 ?M. HR2P-M2 bound to the HR1 peptide to form stable six-helix bundles and blocked fusion core formation between the HR1 and HR2 peptides. Intranasal administration of HR2P-M2 before viral challenge fully protected hDPP4-transgenic mice (n=5) from MERS-CoV infection, whereas all the untreated mice (n=5) died 8 days after viral challenge.

Interpretation

Our findings suggest that the HR2P-M2 peptide merits further development as an effective and safe anti-MERS-CoV drug, alone or in combination with other antiviral drugs, to treat MERS-CoV-infected patients and to prevent the disease in high-risk populations, including health-care workers and family members of patients.

Funding

This work was supported by grants from the National Science Fund of China (81173098 and 81361120378 to SJ, 81373456 to LL), the National 973 Program of China (2012CB519001 to SJ), and the US National Biocontainment Laboratories Operations Support (5UC7AI094660-05 to C-TKT). The funders had no role in interpretation of the findings and writing of this abstract.

SUBMITTER: Jiang S 

PROVIDER: S-EPMC7159274 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature