Nipah (NiV) has been recognized as both an important bioterror risk and a global health risk with broad, unpredictable pandemic potential. Infection from this paramyxovirus is devastating, rapidly causing lethal encephalitis and serious respiratory infections. Transmitted by air or food, its mechanism of infection is complex, and no drugs exist to prevent or treat it. Recently, we have successfully prevented and treated NiV infection in golden hamsters. Key to this success is the surprising finding from our biodistributio studies, that a single subcutaneous injection of the peptide generates sufficient antiviral concentrations for effectiveness in the lung, endothelium and, most importantly, in the brain, the organs targeted by NiV infection, without any toxic effect. We plan to use this information to develop highly effective fusion-inhibitory antivirals for henipaviruses;to determine the optimal dose regimens for CNS localization of cholesterol-conjugated peptides;to investigate the mechanisms of resistance to fusion inhibitors;and to test these hypotheses in animal models of NiV disease. We will apply the results of our fundamental research in chemistry, bioengineering and virology to the development of a new broad-spectrum antiviral strategy based on inhibiting virus entry systemically as well as in the central nervous system (CNS). By utilizing these innovative approaches and technologies, we will determine the feasibility of developing CNS-targeted fusion inhibitors for human use, and also set the stage for a platform technology applicable to other paramyxoviruses and for the treatment of other acute viral encephalitides.

Public Health Relevance

Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious CNS infection, including West Nile virus, Chikungunya virus, and other zoonotic viruses that cause lethal encephalitis in humans. Paramyxoviruses cause important human illnesses that contribute significantly to global disease and mortality. The zoonotic paramyxovirus that is the subject of this proposal, Nipah virus, is an urgent concern for public health due to its lethal encephalitis and transmissible nature. Current proposed antiviral drugs, which may be effective in reducing viral replication, cannot treat infection in the brain because they cannot freely diffuse across the blood-brain barrier (BBB). The development of antivirals which can penetrate the BBB is therefore a critical unmet medical need. We propose a strategy to deliver an antiviral drug across the BBB to block viral infection in the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI101333-01
Application #
8366672
Study Section
Special Emphasis Panel (ZAI1-LG-M (M1))
Program Officer
Tseng, Christopher K
Project Start
2012-06-11
Project End
2014-05-31
Budget Start
2012-06-11
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$193,625
Indirect Cost
$67,214
Name
Weill Medical College of Cornell University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Welsch, Jeremy C; Talekar, Aparna; Mathieu, Cyrille et al. (2013) Fatal measles virus infection prevented by brain-penetrant fusion inhibitors. J Virol 87:13785-94