Advancement of poxvirus inhibitor

痘病毒抑制剂的研究进展

基本信息

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
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/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

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.

抽象的痘病毒是一大批人类病原体，包括天花，蒙基托克斯和牛波克斯。随着世界各地的痘病毒免疫力逐渐减弱，毒病毒的增加疾病，导致对预防蛇毒疾病的小分子疗法的需求日益增长。那里是几种用于治疗正托病毒感染病例的研究性药物最近被FDA批准用于有限使用，但已经注意到了对该化合物的病毒抗性。 WHO，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内在暴露以及天花作为生物疗法的潜在有目的释放。这个目标尚未实现。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对细胞的低/无毒性并抑制病毒mRNA的产生。我们当前的数据表明药物针对痘病毒RNA聚合酶（RNAP），这将是高度保守的理想目标在所有痘病毒中。通过该建议，我们将使用医学探索PDPM的有效抗病毒药物的潜力化学方法以鉴定具有高效力和有利的药代动力学特征的化合物。帮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标的方法及其阻断病毒复制的机制的方法。在鉴定出高效力，药物有利化合物之后，我们将测试它们的有效性在痘病毒疾病的动物模型中。这些实验将通过在 CDC。疾病预防控制中心将监督PDPMS针对天花的测试以及动物的效率测定痘病毒疾病的模型。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。痘病毒抑制剂 - 一种具有对现有FDA批准的抑制剂的抑制剂化合物和广泛的保护概况，满足了这些重要的多重化合物保护的需求人类病原体。