Advancement of poxvirus inhibitor

摘要 痘病毒是一大类人类病原体，包括天花、猴痘和 牛痘。随着世界各地痘病毒免疫力的减弱，痘病毒的数量也随之增加。 疾病，导致对预防痘病毒疾病的小分子疗法的需求日益增长。那里 有几种已用于治疗正痘病毒感染的研究药物，其中一种已被 最近被FDA批准用于有限用途，但已经注意到对这种化合物的病毒耐药性。世界卫生组织， 疾控中心和其他机构表示，他们强烈希望至少有两种小分子疗法 针对痘病毒，因为地方性接触和 可能有目的地释放天花作为生物恐怖因子。这一目标尚未实现。 我们已经鉴定出一类显示广谱抗痘病毒的非核苷类小分子。 活性和对细胞的低/无毒性，并抑制病毒信使核糖核酸的产生。我们目前的数据表明， 药物针对的是痘病毒RNA聚合酶(Rnap)，这将是一个高度保守的理想靶点。 所有的痘病毒。 通过这项提议，我们将探索PDPM成为有效的抗病毒药物的潜力，使用药物 化学方法，以确定具有高效力和有利的药代动力学曲线的化合物。去帮助 并补充这些分子的治疗开发，我们将使用遗传、生化和化学 确定该化合物的靶标和它阻止病毒复制的机制的方法。 在鉴定出高效、药理上有利的化合物后，我们将测试它们的有效性。 在痘病毒病的动物模型中。这些实验将通过正在进行的合作在 疾控中心。疾病预防控制中心将监督PDPM对天花的测试和在动物身上的疗效测定 痘病毒疾病的模型。 当这些努力完成后，他们将能够进行高级(接近于人类的第一次)测试 痘病毒抑制剂-一种作用机制与FDA批准的现有药物互补的抑制剂 复合和广泛的保护配置文件，满足多复合保护的需求 人类病原体。

Abstract Poxviruses are a large group of human pathogens that include the causative agent of smallpox, Monkeypox, and Cowpox. As poxvirus immunity around the world wanes there has been a concomitant increase in poxviral disease, leading to a growing need for small molecule therapeutics that protect against poxviral disease. There are several investigational drugs that have been used to treat cases of orthopoxvirus infection and one has been recently approved by the FDA for limited use, but viral resistance to this compound has been noted. The WHO, CDC and other agencies have stated a strong desire for at least two small molecule therapeutics that broadly target poxviruses due to the high perceived risk of poxviral disease both from endemic exposure as well as the potential purposeful release of smallpox as a bioterror agent. This goal has not yet been met. We have identified a family of non-nucleoside small molecules (“PDPMs”) that show broad spectrum antipoxviral activity and low/no toxicity to cells and suppress viral mRNA production. Our current data suggests is that the drug is targeting the poxvirus RNA polymerase (RNAP), which would be an ideal target that is highly conserved across all poxviruses. Through this proposal we will probe the potential of PDPMs to become effective antivirals, using medicinal chemistry approaches to identify compounds with high potency and favorable pharmacokinetic profiles. To aid and complement the therapeutic development of these molecules, we will use genetic, biochemical and chemical approaches to determine the target of the compound and the mechanism by which it blocks viral replication. Following the identification of high potency, pharmacologically favorable compounds, we will test their efficacy in animal models of poxvirus disease. These experiments will be carried out through an ongoing collaboration at the CDC. The CDC will oversee testing of PDPMs against smallpox and in efficacy determination in animal models of poxviral disease. When these efforts are completed they will enable advanced (towards first-in-human) testing of a new class of poxvirus inhibitor – an inhibitor that has a mechanism of action complementary to the existing FDA approved compound and a broad protection profile, fulfilling the need for multi-compound protection from these significant human pathogens.