Bi-functional Polymer-Attached Inhibitors of Influenza Viruses

双功能聚合物附着的流感病毒抑制剂

基本信息

批准号：
7658898
负责人：
Jianzhu Chen
金额：
$ 74.8万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2007-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7658898
关键词：
Adverse effects Amantadine Animal Model Antiviral Agents Appearance Avidity Binding Biocompatible Biological Assay Birds Cells Clinical Combined Modality Therapy Development Drug resistance Drug usage Enzymes Epidemic Future Genotype H7N7 Hour Human Human Cell Line Incidence Infection Influenza Influenza A Virus, H5N1 Subtype Influenza A virus Influenza Therapeutic Ion Channel Protein Laboratories Length Logistics Measures Methods Microbe Microbial Drug Resistance Molecular Weight Mono-S Neuraminidase Neuraminidase inhibitor Oseltamivir Pharmaceutical Preparations Phenotype Polymers Population Process Production Prophylactic treatment Proteins Research Research Personnel Resistance Resistance development Rimantadine Severities Sialic Acids Structure-Activity Relationship Symptoms Testing Therapeutic Time United States Vaccination Vaccines Variant Vertebral column Viral Viral Hemagglutinins Virion Virus Virus Diseases Virus Inhibitors Water anti-influenza drug base cost design and construction drug development improved influenzavirus inhibitor/antagonist insight novel novel strategies pandemic disease prevent programs resistant strain viral resistance virucide zanamivir

项目摘要

DESCRIPTION (provided by applicant): Influenza A viruses cause epidemics and pandemics in human populations, inflicting enormous suffering and economical loss. Currently, two distinct strategies - vaccines and low molecular weight drugs - are utilized to control the spread of influenza. Vaccination offers limited protection and is hampered by logistic challenges: accurate prediction of future circulating strains and production of sufficient quantities of vaccine for large populations in a short time. Four antiviral drugs have been approved in the United States for the treatment and prophylaxis of influenza. Two of them, amantadine and rimantadine, inhibit the viral M2 ion channel protein, and other two, zanamivir and oseltamivir, inhibit the viral neuraminidase activity. Besides the limited therapeutic window, side effects and high costs, most circulating viruses are already resistant to the two M2 inhibitors and development of resistance to the neuraminidase inhibitors is inevitable if they are widely used. The need to develop novel influenza therapeutics that can prevent viral resistance or significantly reduce its incidence is urgent and compelling. We have developed bi-functional polymer-attached zanamivir and sialic acid (a competitive inhibitor of viral hemagglutinin) based on (i) the principle of combination therapy of simultaneously interfering with two distinct targets on the virus and (ii) the observation that polymeric forms of a competitive inhibitor are much more potent than the monomeric counterpart. In preliminary studies, we have shown that the bi-functional polymer-attached inhibitor is much more potent than monomeric inhibitors or mono-functional polymer-attached inhibitors. In this application, we propose to 1) enhance the antiviral activity of the polymer-attached inhibitors by systematically optimize the level of conjugation and the type and size of the polymer backbone and the linker, 2) systematically evaluate the potency of the polymer-attached inhibitors in appropriate human target cells and animal models to a broad range of influenza virus isolates, including the highly pathogenic avian viruses H5N1 and H7N7, 3) to quantitatively assess the ability of the polymer-attached inhibitors to reduce viral resistance, and 4) to elucidate the antiviral mechanisms of the polymer-attached inhibitors so as to further rationally improve their antiviral activities. It is anticipated that the proposed research will (i) yield one or more highly potent, optimized polymer-attached inhibitor(s) for future clinical development and (ii) provide a new paradigm of drug development for overcoming microbial drug resistance

描述（由申请人提供）：流感病毒在人群中引起流行病和流行病，造成巨大的痛苦和经济损失。目前，使用两种不同的策略 - 疫苗和低分子量药物 - 用于控制流感的传播。疫苗接种提供有限的保护，并受到后勤挑战的阻碍：准确预测未来的循环菌株，并在短时间内为大种群生产足够数量的疫苗。在美国批准了四种抗病毒药，用于治疗和预防流感。其中两个是阿甘丹丁和里米坦丁，抑制病毒M2离子通道蛋白，而其他两个Zanamivir和Oseltamivir抑制了病毒神经氨基酶的活性。除了有限的治疗窗口，副作用和高成本外，大多数循环病毒已经对两种M2抑制剂具有抵抗力，并且如果广泛使用了对神经氨酸酶抑制剂的抗性。需要开发可防止病毒抗性或显着降低其发病率的新型流感治疗剂的需求是紧迫而引人注目的。我们已经基于（i）基于（i）同时干扰病毒和（ii）比较有竞争力的抑制剂对抗抑制剂的观察值，基于（i）同时干扰对病毒的两个明显靶点的组合疗法的原理，基于（i）同时干扰了两个独特的靶标的两个独特的靶标的是，我们已经开发了与竞争性抑制剂更具抑制剂对反相反的抗衡药。在初步研究中，我们已经表明，与单体抑制剂或单官能聚合物连接的抑制剂相比，双功能聚合物抑制剂更有效。在此应用中，我们建议1）通过系统地优化聚合物的结合水平以及聚合物主链和链接器的类型和大小，从而增强聚合物附着抑制剂的抗病毒活性。 H5N1和H7N7，3）用于定量评估聚合物附着的抑制剂降低病毒抗性的能力，以及4）阐明聚合物附属抑制剂的抗病毒机制的能力，以便进一步改善其抗体活性。预计拟议的研究将（i）产生一种或多种高度有效的，优化的聚合物连接抑制剂，用于将来的临床发育，（ii）为克服微生物耐药性提供了新的药物开发范式