STRUCTURE OF POLIOVIRUS/ANTIVIRAL DRUG COMPLEXES

许多抗病毒药物已被证明能与肠道病毒结合(例如： 小儿麻痹症和柯萨奇病毒)和鼻病毒，并抑制其 通过阻止细胞所需的构象变化而具有感染性 附件和入口处。这些药物具有相当大的医疗和经济价值。 预防鼻病毒所致感冒的意义 占美国感冒的80%)和早期 干预脊髓灰质炎和柯萨奇病毒引起的疾病。我们 提出了一系列化合物的结晶学研究 带有脊髓灰质炎病毒的抗病毒药物。这些研究的目标将是 双重作用：1)为合理设计新型抗病毒药物提供依据 随着肠道和犀牛活跃度的提高或特异性的改变- 病毒，以及2)探索控制构象的因素 与细胞附着和细胞进入相关的重排。这个 结晶学研究将包括制成的抗病毒药物的复合体 由Janssen PharmPharmtica和Sterling-Winthrop与Sabin菌株 3型和1型脊髓灰质炎病毒的马奥尼株。结晶学 研究还将包括耐药变异体的结构( 将由加州大学的罗兰·鲁克特挑选并测序 威斯康星州)。这些络合物的结构将与 类似药物与鼻病毒14和鼻病毒复合体的结构 1A(目前由Rossmann等人研究。在普渡大学)。这个 从结构中获得的信息将被用于设计和 合成活性和特性改变的化合物(在 与Janssen制药公司和RISC的K.C.Nicolau合作)。

A number of antiviral drugs have been shown to bind to enteroviruses (e.g. polio- and coxsackieviruses) and rhinoviruses and to inhibit their infectivity by preventing conformational changes required for cell attachment and entry. These drugs are of considerable medical and economic significance for prophylaxis of rhinovirus induced common cold (which account for 80% of the colds in the United States) and for early intervention in poliomyelitis and coxsackievirus induced diseases. We propose a series of crystallographic studies of complexes of several antiviral drugs with poliovirus. The goals of these studies will be twofold: 1) to provide a basis for the rational design of new antivirals with improved activity or altered specificities among the entero and rhino- viruses, and 2) to probe the factors controlling the conformational rearrangements associated with cell attachment and cell entry. The crystallographic studies will include complexes of antiviral agents made by Janssen Pharmaceutica and by Sterling-Winthrop with the Sabin strain of type 3 and the Mahoney strain of type 1 poliovirus. The crystallographic studies will also include the structures of drug resistant variants (which will be selected and sequenced by Roland Rueckert at the University of Wisconsin). The structures of the complexes will be compared with the structures of complexes of similar agents with rhinovirus 14 and rhinovirus 1a (currently being studied by Rossmann et al. at Purdue University). The information gained from the structures will be used to design and synthesize compounds with altered activities and specificities (in collaboration with Janssen Pharmaceutica and with K.C. Nicolau at RISC).