Broad spectrum therapeutics that target the viral membrane

针对病毒膜的广谱疗法

• 批准号: 7645244
• 负责人: Benhur Lee
• 金额: $ 73.82万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645244
• 关键词: Address; Animal Model; Animals; Antiviral Agents; Binding; Biological; Biological Assay; Categories; Cell fusion; Cell membrane; Data; Development; Drug Kinetics; Drug resistance; Ebola virus; Exhibits; In Vitro; Individual; Instruction; Junin virus; Lead; Left; Life; Lipid Bilayers; Logic; Membrane; Membrane Fusion; Membrane Lipids; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nipah Virus; Organic Chemistry; Principal Investigator; Property; RNA Viruses; Research; Research Infrastructure; Resources; Rift Valley Fever; Rift Valley fever virus; Strategic Planning; Structure-Activity Relationship; System; Taxon; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicity Tests; Toxicology; Viral; Virus; Virus Diseases; Virus Replication; analog; biodefense; biosafety level 4 facility; experience; high throughput screening; improved; in vivo; inhibitor/antagonist; interdisciplinary approach; meetings; novel; pathogen; pre-clinical; product development; research study; response; small molecule; therapeutic target

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.

描述（由申请方提供）：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强效抗病毒活性，包括但不限于列为A类、B类和C类病原体的许多病毒（例如埃博拉病毒、马尔堡病毒、裂谷热病毒、朱宁病毒、拉克罗斯病毒和尼帕病毒）。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LJ 001的化合物似乎通过一种新的病毒抑制机制发挥作用：靶向和不可逆地灭活病毒脂质膜，同时使宿主细胞膜不受影响。响应RFA-AI-08-001（生物防御合作研究伙伴关系），我们提出了一个高度合作，跨学科和跨中心的研究工作，将协同迈克尔荣格博士（合作PI）的合成有机化学专业知识，本胡尔李博士（PI）的病毒细胞膜融合专业知识，以及Michael Holbrook博士（UTMB，加尔维斯顿的合作PI）的生物防御和BSL 4病毒学专业知识，以进一步将我们的先导化合物开发为有效对抗各种A-C类病原体的广谱治疗剂。因此，我们提出了以下具体目的：（1）进一步表征LJ 001对包膜病毒的抑制机制，以及（2）在BSL 4条件下使用代表性A-C类病原体进行的活病毒攻击实验中，优化LJ 001及其衍生物的体内毒性和功效。目标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）来鉴定和优化我们抑制病毒-细胞融合的先导化合物，目标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。Holbrook博士也是加尔维斯顿UTMB的BSL 4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，该化合物对包膜病毒具有广谱抗病毒活性，并使用实验逻辑模型，该模型在动物挑战实验中反复改进其体内功效。相关性（参见说明）：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，而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。