Broad spectrum therapeutics that target the viral membrane

描述（由申请人提供）：在对尼帕病毒感染（优先病原体）的小分子抑制剂进行高通量筛选时，我们发现了一种化合物，该化合物对迄今为止测试的所有包膜病毒表现出有效的抗病毒活性，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、Junin病毒、La Crosse病毒和尼帕病毒）。然而，该化合物对非包膜病毒无效。体外和体内毒性试验显示，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起作用：靶向并不可逆地灭活病毒脂质膜，同时不影响宿主细胞膜。为了响应RFA-AI-08-001（生物防御合作研究伙伴关系），我们提出了一项高度协作、跨学科和跨中心的研究工作，将协同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（Galveston UTMB的合作PI）的生物防御和BSL4病毒学专业知识。进一步发展我们的先导化合物，使其成为一种广谱治疗药物，对多种a - c类病原体有效。因此，我们提出以下具体目标：(1)进一步表征LJ001对包膜病毒的抑制机制；(2)优化LJ001及其衍生物在BSL4条件下使用代表性A-C类病原体进行活体病毒攻击实验的体内毒性和有效性。Aim 1利用UCLA现有的基础设施和跨学科专业知识（Dr. Jung和Dr. Lee）来确定和优化我们抑制病毒细胞融合的先导化合物，Aim 2利用Michael Holbrook博士在高致病性RNA病毒动物模型中的大量专业知识。他也是加尔维斯顿UTMB的BSL4设施主任。我们的具体目标是针对我们的先导化合物的临床前优化，具有广谱抗病毒活性的包膜病毒，并使用一个实验逻辑模型，反复地在动物挑战实验中提高其体内功效。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，可用于应对每种威胁的资源有限”，因此鼓励开发广谱方法和治疗方法来应对这一威胁。我们的先导化合物抑制多种包膜病毒，因此可以开发成一种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.