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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：
7287080
负责人：
Jianzhu Chen
金额：
$ 69.73万
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/7287080
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 Range Rate 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 size 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）：甲型流感病毒在人群中引起流行病和大流行，造成巨大痛苦和经济损失。目前，有两种不同的策略——疫苗和低分子量药物——被用来控制流感的传播。疫苗接种提供的保护有限，并受到后勤挑战的阻碍：准确预测未来的流行毒株和在短时间内为大量人口生产足够数量的疫苗。美国已经批准了四种抗病毒药物用于治疗和预防流感。其中金刚烷胺和金刚乙胺抑制病毒M2离子通道蛋白，扎那米韦和奥司他韦抑制病毒神经氨酸酶活性。除了有限的治疗窗口、副作用和高昂的费用外，大多数循环病毒已经对这两种M2抑制剂具有耐药性，如果它们被广泛使用，对神经氨酸酶抑制剂的耐药性的发展是不可避免的。开发能够预防病毒耐药性或显著降低其发病率的新型流感疗法的需求是紧迫和迫切的。我们开发了双功能聚合物连接扎那米韦和唾液酸（一种病毒血凝素的竞争性抑制剂），基于(i)联合治疗的原则，同时干扰病毒上的两个不同靶点；（ii）观察到竞争性抑制剂的聚合形式比单体的对偶物更有效。在初步研究中，我们已经表明，双功能聚合物连接抑制剂比单体抑制剂或单功能聚合物连接抑制剂更有效。在本应用中，我们提出：1)通过系统优化缀合水平、聚合物主链和连接体的类型和大小来增强聚合物连接抑制剂的抗病毒活性；2)在适当的人类靶细胞和动物模型中系统评估聚合物连接抑制剂对广泛的流感病毒分离株的效力，包括高致病性禽流感病毒H5N1和H7N7；3)定量评价聚合物附着抑制剂降低病毒耐药性的能力；4)阐明聚合物附着抑制剂的抗病毒机制，进一步合理提高其抗病毒活性。预计拟议的研究将(i)为未来的临床开发产生一种或多种高效，优化的聚合物附着抑制剂(s), （ii）为克服微生物耐药性的药物开发提供新的范例