Novel Chemotypes Against Influenza A Virus

抗甲型流感病毒的新化学型

基本信息

批准号：
7366980
负责人：
Maurizio Pellecchia
金额：
$ 2.5万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7366980
关键词：
Adverse effects Affinity Amantadine Amantadine resistance Antiviral Agents Antiviral resistance Asia Biochemical Biological Assay Chemical Structure Chemicals Class Communities Complement Data Deposition Depth Development Doctor of Philosophy Drug Delivery Systems Funding Genomics Goals Hot Spot Human Infection Influenza Influenza A Virus, H3N2 Subtype Influenza A virus Knowledge Lead Ligand Binding Ligands Link Membrane Proteins Metalloproteases Methods Mission Molecular Bank Mutation N-Methyl-D-Aspartate Receptors North America Nucleic Acids Pharmaceutical Preparations Preparation Principal Investigator Protein Kinase Proteins Protons RNA Range Role Screening procedure Tacrolimus Binding Protein 1A Techniques Translations United States National Institutes of Health Validation Variant Viral Viral Drug Resistance Virus Work anti-influenza base caspase-2 chemical genetics design drug development follow-up high throughput screening influenzavirus inhibitor/antagonist interest macromolecule mutant novel nuclear transfer pandemic influenza pressure programs promoter protein protein interaction research study response scaffold small molecule success tool viral RNA

项目摘要

DESCRIPTION (provided by applicant): Strains of influenza A (H3N2) virus have specific mutations in the M2 proton channel that result in resistance to the antiviral drug amantadine, one of the very few drugs currently available against the virus. Recent years have witnessed a dramatic increase in resistance to amantadine in communities in Asia and North America due to the spread of the H3N2 strain despite the absence of sustained selective drug pressure. Another important problem that limits the use of amantadine is its interference with the human NMDA receptor, causing potentially severe side effects. For these reasons, we propose to use NMR- and fragment-based screening approaches to derive novel agents against H3N2 influenza A infections by directly targeting the mutant M2 variants. In addition, we propose to target an essential RNA viral promoter by using similar NMR- based approaches. The chemical structures, SAR data and range of biochemical activities of the resulting compounds will provide a framework onto which to develop potentially novel anti-influenza therapies.

描述（由申请人提供）：流感A（H3N2）病毒的菌株在M2质子通道中具有特异性突变，导致对抗病毒药amantadine的抗性，抗病毒药物是目前针对该病毒的少数药物之一。近年来，尽管没有持续的选择性药物压力，但由于H3N2菌株的传播，亚洲和北美社区对阿曼塔丁的抵抗力急剧增加。限制使用阿甘丹丁的另一个重要问题是它干扰了人类NMDA受体，从而导致潜在的严重副作用。由于这些原因，我们建议使用基于NMR和碎片的筛选方法来通过直接靶向突变体M2变体来推导针对H3N2流感A感染的新型药物。此外，我们建议通过使用类似的基于NMR的方法来靶向必需的RNA病毒启动子。所得化合物的化学结构，SAR数据和生化活性范围将提供一个框架，以开发潜在的新型抗激素疗法。