Nucleocapsid-Specific Small Molecule Inhibitors of the Bunyaviridae

点击翻译按钮获取中文摘要

The Bunyaviridae family of viruses include a set of Category A and C virus species. For the Bunyaviridae these include the members of the hantavirus genus, as well as Rift Valley fever virus and Crimean-Congo hemorrhagic fever virus. Current therapies against most of these viruses either do not exist or are only marginally efficient. Thus, it would be highly beneficial to identify and develop additional drugs directed at specific viral targets required for replication. The goal of this revised proposal is to refine and use an assay system for the identification of molecules that disrupt the function of the principle nucleocapsid protein of theses viruses, and to carry out screening for such candidate drugs. The nucleocapsid protein (N) functions both in the process of RNA encapsidation during virus assembly and during genome replication in conjunction with the viral polymerase. Since these are essential steps in virus replication, disruption of one or both processes would effectively block virus propagation. Our basic work indicates that for the Bunyaviridae, the principle in vitro RNA substrate for N is the RNA panhandle formed by the hydrogen bonding of the genome termini. In vivo discrimination and encapsidation of minus strand viral RNAs likely requires high affinity interaction of N with the panhandle. Our approach will be to use this specific interaction as the basis of a rapid and convenient assay to identify molecules that block N function. This is likely to lead to the identification of a constellation of novel candidate molecules that interfere the correct interaction of N with vRNA. Candidate molecules will be examined for their effect on cell viability and virus replication.