权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要