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.

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尼帕病毒）。然而，这种化合物对未开发的病毒无效。体外和体内毒性测试在有效的抗病毒浓度下没有明显的毒性。该化合物称为LJ001，似乎通过一种新型的病毒抑制机制起作用：靶向和不可逆转的病毒脂质膜，同时使宿主细胞膜不受影响。 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迈克尔·霍尔布鲁克（Michael Holbrook）博士（加尔维斯顿UTMB的Co-Pi）的病毒学专业知识，以进一步开发我们的铅化合物对广泛的治疗效果，对各种A-C类病原体有效。因此，我们提出了以下特定目的：（1）进一步表征LJ001对其对包膜病毒的抑制作用的机制，（2）以在BSL4条件下使用具有代表性A-C病原体的实用A-C病原体在实时病毒挑战实验中优化LJ001及其在实时病毒挑战实验中的体内毒性和功效。 AIM 1利用UCLA（Jung博士和Lee博士）已经存在的基础设施和跨学科专业知识来识别和优化我们的铅化合物，这些化合物抑制病毒 - 细胞融合，AIM 2利用了迈克尔·霍尔布鲁克博士在动物模型中用于致病性RNA病毒的大量专业知识。 Holbrook博士还是Galveston UTMB的BSL4设施主任。我们的具体目的旨在对我们的铅化合物进行临床前优化，该化合物具有针对包膜病毒的广谱抗病毒活性，并采用了一种实验逻辑模型，该模型重新站立了，以提高其在动物挑战实验中的体内功效。相关性（请参阅说明）：生物融合研究的NIAID战略计划“认识到生物学威胁的扩大范围以及可用于应对每种个人威胁的有限资源”，因此鼓励开发广泛的方法和治疗方法，以满足这种威胁。我们的铅复合抑制了各种包裹的病毒，因此可以发展为广泛的抗病毒，以应对这些威胁。