Identification and Evaluation of a Highly Effective Fusion Inhibitor for Human Metapneumovirus

Abstract

Human metapneumovirus (hMPV) can cause acute upper and lower respiratory tract infections that are particularly severe in young children, elderly subjects, and immunocompromised patients. To date, no treatments or vaccines are available for hMPV infections. Our objective was to assess the inhibitory potential of several peptides derived from the heptad repeat A and B (HRA and HRB) domains of the hMPV fusion protein. Nine candidate peptides were expressed in Escherichia coli or obtained synthetically and tested in vitro and in an animal model. Excellent in vitro inhibition of an hMPV strain of the A1 subgroup was obtained with five peptides, with 50% inhibitory concentrations ranging from 1.4 nM to 3.3 M. One peptide, HRA2, displayed very potent activity against all four hMPV subgroups. It was also moderately active against human respiratory syncytial virus (strain A2) but displayed no activity against human parainfluenza virus type 3. BALB/c mice that received the HRA2 peptide and a lethal hMPV intranasal challenge simultaneously were completely protected from clinical symptoms and mortality. On day 5 postinfection, HRA2-treated mice had undetectable lung viral loads which were significantly less than those of untreated mice (3 ؋ 10 4 50% tissue culture infective doses/lung). Pulmonary inflammation, levels of proinflammatory cytokines/chemokines (RANTES, gamma interferon, and monocyte chemoattractant protein 1) and airway obstruction were also significantly decreased in HRA2-treated mice. The results of this study demonstrate that potent antivirals can be derived from the hMPV fusion protein HR domains. Moreover, hMPV, compared to other paramyxoviruses and to the human immunodeficiency virus, seems to be more susceptible to HRA-than HRB-derived peptides.

Age-Associated Aggravation of Clinical Disease after Primary Metapneumovirus Infection of BALB/c Mice

“…At the same time, the pulmonary levels of IFN-␥ and MCP-1 were significantly greater in the young mice than in the aged mice. These results are in accordance with those of Deffranes et al (12), who reported a lesser degree of airway obstruction concomitant with lower levels of IFN-␥, MCP-1, and RANTES in mice treated with a peptide derived from the hMPV fusion protein (12). Two studies on RSV infection with high inoculum titers described a significant increase in AO associated with a high IFN-␥ concentration and cellular infiltration of the lungs (28,54).…”

Human Metapneumovirus and Human Bocavirus in Children

“…Potential treatment strategies include ribavirin, immunoglobulin administration (46), and fusion inhibitors (47). Virus-specific MAb are currently available for the prevention of RSV in high-risk infants and such preventive therapy may be available for hMPV in the future.…”

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…[26][27][28][29] The ineffectiveness of the natural infection to induce long-term immunity has hampered vaccine generation and currently there is no licensed vaccine available to prevent the bronchiolitis and pneumonia caused either by hRSV or hMPV. [30][31][32][33][34] However, several candidate vaccines are in different stages of development for preventing the diseases caused by these viral agents. Candidate vaccines for hRSV and hMPV employ different approaches, including a chimeric virus (hMPV), 35 live attenuated virus (hRSV), 36 and purified proteins (hRSV), 37 among others.…”