Advancement of poxvirus inhibitor

痘病毒抑制剂的研究进展

• 批准号: 10381584
• 负责人: John H Connor
• 金额: $ 59.34万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-12 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381584
• 关键词: Adenoviruses; Animal Model; Antiviral Agents; Behavior; Biochemical; Biological Assay; Biology; Bioterrorism; Blood Circulation; Cameroon; Category A pathogen; Cells; Centers for Disease Control and Prevention (U.S.); Central African Republic; Characteristics; Chemicals; Collaborations; Complement; Cowpox; DNA; DNA-Directed RNA Polymerase; Data; Democratic Republic of the Congo; Development; Disease; Disease Outbreaks; Dose; Drug Kinetics; Drug Targeting; Enzymes; Family; General Population; Genetic; Goals; Hepatitis C virus; Herpesviridae; Immunity; In Vitro; Infection; Infectious Agent; Investigational Drugs; Israel; Lead; Licensure; Mail Order; Messenger RNA; Modality; Modification; Molecular Target; Monkeypox; Monobactams; Morbidity - disease rate; Orf virus; Orthopoxvirus; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Polymerase; Population; Poxviridae; Poxviridae Infections; Production; Property; Protease Inhibitor; RNA Polymerase I; RNA Viruses; Regimen; Reporting; Resistance; Risk; Safety; Smallpox; Testing; Therapeutic; Toxic effect; Travel; United States Food and Drug Administration; Vaccines; Vaccinia; Variola major virus; Viral; Viral Physiology; Virus; Virus Replication; Work; World Health; analog; antimicrobial; beta-Lactams; combat; comparative; druggable target; efficacy testing; experimental study; first-in-human; human pathogen; improved; in vivo; in vivo Model; in vivo evaluation; inhibitor; interest; mortality; novel; pathogen; pathogenic bacteria; pathogenic fungus; pre-clinical assessment; reconstitution; scaffold; small molecule; small molecule therapeutics; therapeutic development; viral resistance

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.

抽象的 痘病毒是一大类人类病原体，包括天花、猴痘和痘痘的病原体 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不断增长。那里 有几种用于治疗正痘病毒感染病例的研究药物，其中一种已被 最近 FDA 批准其有限使用，但已注意到病毒对该化合物产生耐药性。 WHO， 疾病预防控制中心和其他机构表示强烈希望至少有两种小分子疗法能够广泛应用 针对痘病毒，因为人们普遍认为，地方性接触和感染导致痘病毒疾病的风险很高 潜在有目的地释放天花作为生物恐怖剂。这一目标尚未实现。 我们已经鉴定出一系列具有广谱抗痘病毒作用的非核苷小分子（“PDPM”） 活性和对细胞低/无毒性，并抑制病毒 mRNA 的产生。我们目前的数据表明 该药物针对的是痘病毒 RNA 聚合酶 (RNAP)，这将是高度保守的理想靶点 跨越所有痘病毒。 通过这项提案，我们将探讨 PDPM 成为有效抗病毒药物的潜力，利用药物 化学方法来识别具有高效力和有利药代动力学特征的化合物。援助 并补充这些分子的治疗发展，我们将使用遗传、生化和化学 确定化合物靶点及其阻断病毒复制机制的方法。 在鉴定出高效、药理学上有利的化合物后，我们将测试其功效 在痘病毒疾病的动物模型中。这些实验将通过以下机构的持续合作进行： 疾病预防控制中心。 CDC 将监督 PDPM 对抗天花的测试以及动物身上的功效测定 痘病毒疾病模型。 当这些努力完成后，他们将能够对一类新的药物进行高级（首次人体）测试。 痘病毒抑制剂——一种与 FDA 批准的现有抑制剂具有补充作用机制的抑制剂 化合物和广泛的保护特性，满足对这些重要化合物的多化合物保护的需求 人类病原体。