Therapeutics for Ebola virus

丝状病毒，如埃博拉病毒(EBOV)，是引起严重出血热综合征的疾控中心A类病原体。不幸的是，几乎没有治疗方案可用于治疗这些病毒感染。 APath有一个正在进行的筛查计划，该计划利用基于EBOV微型基因组表达系统的基于细胞的、不受感染的检测。这项提案的目标是推进我们在这项专利筛选试验中确定的EBOV抑制剂的开发。我们已经在USAMRIID进行的病毒检测中证实了几种化合物的抗埃博拉病毒活性，对其他化合物的测试正在进行中。对于这项BioShield计划，我们建议将这些潜在的抗EBOV先导化合物通过临床前吸收、分配、代谢、消除(ADME)、毒理学(Tox)和药代动力学(PK)研究，为最终向FDA申请研究性新药(IND)做准备。这些研究将分两个阶段进行。最初，将进行初步评估，以预测抗病毒化合物在完全监管方案下进行的研究中最终将如何表现。这些初步分析将包括细胞毒性、溶解性、代谢稳定性、细胞 通透性，血浆蛋白结合，和细胞色素P450抑制。在这些初步分析中表现出最有希望的特征的化合物将被推进到完整的ADME-Tox和PK研究计划中，该计划将根据良好实验室操作规范(GLP)进行，以获得支持IND应用的数据。预计这些研究将导致生产抗病毒药物，用于未来的临床试验，以确定对抗EBOV感染的安全性和有效性。

Filoviruses, such as Ebola virus (EBOV), are CDC category A agents that cause severe hemorrhagic fever syndromes. Unfortunately, few therapeutic options are available to treat infections with these viruses. Apath has an ongoing screening program that utilizes a cell-based, infection-independent assay based on an EBOV minigenome-expression system. The goal of this proposal is to advance the development of EBOV inhibitors that we have identified in this proprietary screening assay. We have confirmed anti-Ebola virus activity for several compounds in viral assays performed at USAMRIID and testing of others is ongoing. For this Bioshield initiative we propose to bring these potential anti-EBOV lead compounds through a preclinical program of absorption, distribution, metabolism, elimination (ADME), toxicology (Tox), and pharmacokinetic (PK) studies in preparation for an eventual investigational new drug (IND) application to the FDA. These studies will be performed in two stages. Initially a preliminary evaluation will be performed to predict how the antiviral compounds will eventually behave in studies performed with full regulatory protocols. These preliminary analyses will include cytotoxicity, solubility, metabolic stability, cell permeability, plasma protein binding, and CYP inhibition. The compounds that demonstrate the most promising profiles in these preliminary analyses will be advanced to a full program of ADME-Tox and PK studies performed under good laboratory practices (GLP) regulations to obtain data to support an IND application. It is expected that these studies will result in the production of antiviral drugs for future clinical trials to determine safety and efficacy against EBOV infection.