Bi-functional Polymer-Attached Inhibitors of Influenza Viruses

双功能聚合物附着的流感病毒抑制剂

• 批准号: 8105130
• 负责人: Jianzhu Chen
• 金额: $ 75.51万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105130
• 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

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，造成巨大的痛苦和经济损失。目前，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。疫苗接种提供的保护有限，并受到后勤挑战的阻碍：准确预测未来的流行菌株，并在短时间内为大量人群生产足够数量的疫苗。美国已批准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、副作用和高成本之外，大多数循环病毒已经对两种M2抑制剂具有耐药性，并且如果广泛使用，则对神经氨酸酶抑制剂的耐药性的发展是不可避免的。迫切需要开发新的流感疗法，可以防止病毒耐药性或显着降低其发病率是迫切和引人注目的。我们开发了双功能聚合物连接的扎那米韦和唾液酸（病毒血凝素的竞争性抑制剂），其基础是（i）同时干扰病毒上两个不同靶标的联合治疗原理和（ii）观察到竞争性抑制剂的聚合物形式比单体形式更有效。在初步研究中，我们已经表明，双功能聚合物连接的抑制剂比单体抑制剂或单功能聚合物连接的抑制剂更有效。在本申请中，我们提出1）通过系统地优化缀合水平以及聚合物骨架和接头的类型和大小来增强聚合物连接的抑制剂的抗病毒活性，2）系统地评估聚合物连接的抑制剂在适当的人靶细胞和动物模型中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H5 N1和H7 N7，3）定量评估聚合物连接的抑制剂降低病毒抗性的能力，和4）阐明聚合物连接的抑制剂的抗病毒机制，以进一步合理地提高其抗病毒活性。预计拟议的研究将（i）产生一种或多种高效、优化的聚合物附着抑制剂用于未来的临床开发，以及（ii）提供用于克服微生物耐药性的药物开发的新范例

项目成果

Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus.

• DOI: 10.1002/jps.22338
• 发表时间: 2011-03
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Weight, Alisha K.;Haldar, Jayanta;de Cienfuegos, Luis Alvarez;Gubareva, Larisa V.;Tumpey, Terrence M.;Chen, Jianzhu;Klibanov, Alexander M.
• 通讯作者: Klibanov, Alexander M.

Conjugating drug candidates to polymeric chains does not necessarily enhance anti-influenza activity.

将候选药物与聚合物链缀合并不一定会增强抗流感活性。

• DOI: 10.1002/jps.23253
• 发表时间: 2012
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Larson,AlyssaM;Wang,Hongmei;Cao,Yang;Jiang,Taijiao;Chen,Jianzhu;Klibanov,AlexanderM
• 通讯作者: Klibanov,AlexanderM

Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants.

与靶向 M2 离子通道的流感药物聚合链缀合可部分恢复对耐药突变体的抑制。

• DOI: 10.1002/jps.23644
• 发表时间: 2013
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Larson,AlyssaM;Chen,Jianzhu;Klibanov,AlexanderM
• 通讯作者: Klibanov,AlexanderM

Hydrophobic polycationic coatings disinfect poliovirus and rotavirus solutions.

• DOI: 10.1002/bit.22967
• 发表时间: 2011-03
• 期刊: BIOTECHNOLOGY AND BIOENGINEERING
• 影响因子: 3.8
• 作者: Larson, Alyssa M.;Hsu, Bryan B.;Rautaray, Debabrata;Haldar, Jayanta;Chen, Jianzhu;Klibanov, Alexander M.
• 通讯作者: Klibanov, Alexander M.

Bifunctional polymeric inhibitors of human influenza A viruses.

• DOI: 10.1007/s11095-009-0013-1
• 发表时间: 2010-02
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Haldar, Jayanta;de Cienfuegos, Luis Alvarez;Tumpey, Terrence M.;Gubareva, Larisa V.;Chen, Jianzhu;Klibanov, Alexander M.
• 通讯作者: Klibanov, Alexander M.