Broad spectrum therapeutics that target the viral membrane

描述(申请人提供)：在对Nipah病毒感染的小分子抑制剂(优先病原体)进行高通量筛选时，我们发现了一种化合物，它对迄今测试的所有包膜病毒都具有很强的抗病毒活性，包括但不限于许多被列为A、B和C类病原体的病毒(例如埃博拉病毒、马尔堡病毒、裂谷热病毒、Junin病毒、La Crosse病毒和Nipah病毒)。然而，这种化合物对无包膜病毒无效。体外和体内毒性试验表明，在有效的抗病毒浓度下没有明显的毒性。这种名为LJ001的化合物似乎通过一种新的病毒抑制机制发挥作用：靶向并不可逆转地使病毒脂膜失活，而宿主细胞膜不受影响。为响应RFA-AI-08-001(生物防务合作研究伙伴关系)，我们提议开展高度协作、跨学科和跨中心的研究，以整合Michael Jung博士(合作PI)的合成有机化学专业知识、Benhur Lee博士(PI)的病毒-细胞膜融合专业知识以及Michael Holbrook博士(UTMB，Galveston大学生物防御合作研究伙伴关系)的生物防御和BSL4病毒学专业知识，以进一步将我们的先导化合物发展成为对多种A-C类病原体有效的广谱治疗药物。因此，我们提出了以下具体目标：(1)进一步表征LJ001对包膜病毒的抑制作用机制；(2)在BSL4条件下，利用具有代表性的A-C类病原体进行活体病毒攻击实验，优化LJ001及其衍生物的体内毒性和有效性。Aim 1利用加州大学洛杉矶分校现有的基础设施和跨学科专业知识(Jung博士和Lee博士)来识别和优化我们抑制病毒与细胞融合的先导化合物，而Aim 2利用Michael Holbrook博士在高致病性RNA病毒动物模型方面的丰富专业知识。霍尔布鲁克博士也是加尔维斯顿UTMB BSL4设施的主任。我们的具体目标是针对我们的先导化合物进行临床前优化，这种化合物具有广谱的抗病毒活性，并使用一个实验逻辑模型，在动物挑战实验中反复磨练提高其体内疗效。相关性(见说明)：NIAID生物防御研究战略计划“认识到生物威胁的范围不断扩大，并认识到可用于应对每一种威胁的资源有限”，因此鼓励开发广谱方法和疗法来应对这一威胁。我们的先导化合物可以抑制多种包膜病毒，因此可以开发成广谱抗病毒药物来应对这些威胁。

DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions): 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.