Advancement of poxvirus inhibitor

痘病毒抑制剂的研究进展

基本信息

批准号：
10576934
负责人：
John H Connor
金额：
$ 65.64万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10576934
关键词：
Adenoviruses Animal Model Antiviral Agents Behavior Biochemical Biological Assay Biology Cameroon Category A pathogen Cells Central African Republic Characteristics Chemicals Circulation 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 Licensure Mail Order Messenger RNA Modality Modification Molecular Target Monkeypox Morbidity - disease rate Nigeria Orf virus Orthopoxvirus Pharmaceutical Chemistry Pharmaceutical Preparations Polymerase Population Poxviridae Poxviridae Infections Production Property Protease Inhibitor RNA Polymerase I RNA Viruses Regimen Reporting Resistance Risk Safety Sierra Leone Singapore 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 candidate selection combat comparative druggable target efficacy evaluation 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 pharmacologic pre-clinical assessment reconstitution scaffold small molecule small molecule therapeutics therapeutic development viral resistance

项目摘要

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.

抽象的痘病毒在包括天花的病原体的大量人类病原体牛波克斯作为世界各地的痘病毒免疫疾病，导致对预防痘病毒疾病的小型小分子疗法的需求日益增长。是几种用于治疗正托病毒病例的研究性药物已有一种最近被FDA批准了有限的使用，但对该化合物的耐药性没有。疾病预防控制中心和其他机构对至少两个小分子疗法的渴望很大由于流行暴露以及潜在的有目的的天花作为生物疗法。我们已经确定了一个非核苷小分子（“ PDPM”），该家族显示出广泛的反氧化病毒频谱活性和低/不对细胞的作用，并抑制病毒mRNA的产生。药物靶向Poxvirus RNA聚合酶（RNAP），该聚合物将靶靶靶标保持稳定在所有痘毒中。通过该建议，我们将使用药用探测PDPM的潜力成为有效的抗病毒药化学方法可以鉴定具有高效力和有利的药代动力学特征的化合物。并补充这些分子的治疗发展，我们将使用遗传，生化和化学确定构成目标及其阻断病毒复制机制的方法。在鉴定出高势，药理学有利化合物之后，我们将测试其功效在痘病毒疾病的动物模型中。 CDC。痘病毒疾病的模型。完成这些努力后，他们将使（朝着人类的第一届）进行高级测试。 Poxvirus抑制剂 - 具有行动机制的AN抑制剂，批准了Exsting FDA 组合和广泛的保护概况，满足了多方面的保护需求人类病原体。