While conducting high throughput screening for small molecule inhibitors of Nipah virus infection (a priority pathogen), we found a compound that exhibited potent antiviral activity against all enveloped viruses tested to date including, but not limited to, many viruses listed as Category A, B and C pathogens (e.g. Ebola, Marburg, Rift Valley Fever, Junin, La Crosse, and Nipah viruses). Yet, this compound was ineffective against nonenveloped viruses. In vitro and in vivo toxicity tests showed no overt toxicity at effective antiviral concentrations. The compound, termed LJ001, appears to act via a novel mechanism for viral inhibition: targeting and irreversibly inactivating viral lipid membranes while leaving host cell membranes unaffected. In response to RFA-AI-08-001 (Co-operative Research Partnership for Biodefense), we have proposed a highly collaborative, inter-disciplinary, and trans-center research effort that will synergize the synthetic organic chemistry expertise of Dr. Michael Jung (co-Pi), the virus-cell membrane fusion expertise of the Dr. Benhur Lee (PI), and the biodefense and BSL4 virological expertise of Dr. Michael Holbrook (co-Pi at UTMB, Galveston), to further the development of our lead compound into a broad spectrum therapeutic effective against a wide variety of Category A-C pathogens. Thus, we propose the following Specific Aims: (1) To further characterize the mechanisms by which LJ001 effectuates its inhibition on enveloped viruses, and (2) To optimize the in vivo toxicity and efficacy of LJ001 and its derivatives in live virus challenge experiments using representative Category A-C pathogens under BSL4 conditions.
Aim 1 exploits the infrastructure and inter-disciplinary expertise already present at UCLA (Dr. Jung and Dr. Lee) to identify and optimize our lead compound which inhibits virus-cell fusion, and Aim 2 makes use of the considerable expertise of Dr. Michael Holbrook in animal models for highly pathogenic RNA viruses. Dr. Holbrook is also Director of the BSL4 facilities at UTMB, Galveston.
Our Specific Aims are geared towards the pre-clinical optimization of our lead compound that has broad spectrum antiviral activity against enveloped viruses, and uses an experimental logic model that re-iteratively hones in on improving its in vivo efficacy in animal challenge experiments.
The NIAID Strategic Plan for Biodefense Research "recognizes the expanding range of biological threats and the limited resources available to address each individual threat" and thus encourages the development of broad-spectrum approaches and therapeutics to meet this threat. Our lead compound inhibits a wide variety of enveloped viruses, and thus could be developed into a broad spectrum antiviral to meet these threats.
|Vigant, Frederic; Hollmann, Axel; Lee, Jihye et al. (2014) The rigid amphipathic fusion inhibitor dUY11 acts through photosensitization of viruses. J Virol 88:1849-53|
|Vigant, Frederic; Lee, Jihye; Hollmann, Axel et al. (2013) A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion. PLoS Pathog 9:e1003297|
|Tanner, Lukas Bahati; Lee, Benhur (2013) The greasy response to virus infections. Cell Host Microbe 13:375-7|
|Vigant, Frederic; Lee, Benhur (2011) Hendra and nipah infection: pathology, models and potential therapies. Infect Disord Drug Targets 11:315-36|
|Lee, Benhur; Ataman, Zeynep Akyol (2011) Modes of paramyxovirus fusion: a Henipavirus perspective. Trends Microbiol 19:389-99|
|Lee, Benhur (2011) Containing the contagion: treating the virus that inspired the film. Sci Transl Med 3:105fs6|
|Aguilar, Hector C; Lee, Benhur (2011) Emerging paramyxoviruses: molecular mechanisms and antiviral strategies. Expert Rev Mol Med 13:e6|
|Wolf, Mike C; Freiberg, Alexander N; Zhang, Tinghu et al. (2010) A broad-spectrum antiviral targeting entry of enveloped viruses. Proc Natl Acad Sci U S A 107:3157-62|
|Freiberg, Alexander N; Worthy, Melissa N; Lee, Benhur et al. (2010) Combined chloroquine and ribavirin treatment does not prevent death in a hamster model of Nipah and Hendra virus infection. J Gen Virol 91:765-72|
|Wang, Yao E; Park, Arnold; Lake, Michael et al. (2010) Ubiquitin-regulated nuclear-cytoplasmic trafficking of the Nipah virus matrix protein is important for viral budding. PLoS Pathog 6:e1001186|
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