Bi-functional Polymer-Attached Inhibitors of Influenza Viruses

描述(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，两种不同的战略--疫苗和低分子药物--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，并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用于治疗和预防流感的抗病毒药物。其中两种药物金刚烷胺和金刚乙胺抑制病毒M2离子通道蛋白，另外两种药物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、副作用和高昂的成本外，大多数正在传播的病毒已经对这两种M2抑制剂产生了耐药性，如果广泛使用，对神经氨酸酶抑制剂的耐药性是不可避免的。迫切需要开发能够防止病毒耐药性或显著降低其发病率的新型流感疗法。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)，其基础是(I)同时干扰病毒上的两个不同靶点的联合治疗原理，以及(Ii)观察到竞争性抑制剂的聚合物形式比单体对应物更有效。在初步研究中，我们已经证明了双官能团聚合物附着的抑制剂比单体或单官能团聚合物附着的抑制剂更有效。在这一应用中，我们建议1)通过系统地优化接合水平以及聚合物骨架和连接子的类型和大小来提高聚合物附着抑制剂的抗病毒活性，2)系统地评估聚合物附着抑制剂在适当的人类靶细胞和动物模型中对包括高致病性禽流感病毒H5N1和H7N7在内的多种流感病毒分离株的效力，3)定量评估聚合物附着抑制剂降低病毒耐药性的能力，以及4)阐明聚合物附着抑制剂的抗病毒机制，以便进一步合理地提高其抗病毒活性。预计拟议的研究将(I)产生一种或多种用于未来临床开发的高效、优化的聚合物结合抑制剂(S)，以及(Ii)为克服微生物耐药性提供一种新的药物开发范式

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