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Targeting host deubiquitinases for broad spectrum anti-infective therapy

靶向宿主去泛素酶进行广谱抗感染治疗

基本信息

批准号：
8854184
负责人：
Mary O'Riordan
金额：
$ 46.65万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854184
关键词：
Affect Animal Model Anti-Infective Agents Antiviral Agents Bacteria Bacteriology Biochemistry Biological Assay Cantaloupes Categories Cells Chemicals Communicable Diseases Development Diagnosis Disease Outbreaks Drug Kinetics Drug resistance Early treatment Economics Encephalomyocarditis virus Enzymes Exhibits Future Gastroenteritis Goals Human In Vitro Infection Infection prevention Infectious Agent Injection of therapeutic agent Investigational New Drug Application La Crosse virus Lead Link Listeria Listeria monocytogenes Liver Microsomes Mediating Microbe Modeling Molecular Weight Morbidity - disease rate Mus Norovirus Organism Parasites Pharmaceutical Chemistry Pharmacology Phase Play Positioning Attribute Proteins Proteomics Public Health Research Role Salmonella enterica Series Sindbis Virus Solubility Structure-Activity Relationship Testing Therapeutic Toxic effect Toxoplasma gondii Ubiquitin Ubiquitination United States Vaccines Viral Gastroenteritis Virus War Water age group analog antimicrobial base cellular targeting cytotoxicity drug development drug resistant bacteria effective therapy foodborne foodborne illness foodborne infection foodborne pathogen in vivo inhibitor/antagonist methicillin resistant Staphylococcus aureus microbial mortality novel novel therapeutics pathogen polypeptide pre-clinical programs rapid diagnosis small molecule therapeutic development therapeutic target virology

项目摘要

There is an urgent need for new therapeutics that effectively target drug-resistant microbes and pathogens that currently have no treatment options. Noroviruses cause an estimated 23 million infections and over half of all food-borne gastroenteritis outbreaks in the US every year but no antivirals or vaccines exist to treat or prevent infections. Listeria monocytogenes is another food-borne pathogen with a high fatality rate of 20- 25%, responsible for the recent cantaloupe-associated outbreak. Rapid diagnosis of a specific pathogen during outbreaks is often challenging. Thus, there is a compelling rationale for the development of broad-spectrum therapeutics for early and effective treatment of infectious diseases. One approach towards that goal is to develop “anti- infective” compounds that target host-encoded proteins critical during infection of multiple microbes. We find that a small molecule, WP1130 (WP) and related compounds, exhibit anti-infective activity against multiple classes of pathogens, including several category B pathogens: bacteria (MRSA, Listeria monocytogenes, Salmonella enterica serovar Typhimurium), viruses (murine and human norovirus, encephalomyocarditis virus, Sindbis virus, La Crosse virus), and an apicomplexan parasite (Toxoplasma gondii). Our initial studies demonstrate that WP inhibits a subset of host deubiquitinases (DUBs) resulting in the accumulation of ubiquitinated proteins in cells, but does not directly affect pathogens outside the host. Ubiquitin is a eukaryotic low molecular weight polypeptide that acts as a post-translational regulatory switch when covalently linked to target proteins. Studies of WP analogs hold vital clues for the development of novel therapeutics that may effectively contain pathogens by interfering with key interactions between host and microbe. Ubiquitination and deubiquination of host targets play critical roles in many different microbial infections. We therefore hypothesize that WP treatment selectively inhibits key DUBs exploited by microbial pathogens, thereby limiting infection. We will use murine norovirus and L. monocytogenes as two unrelated pathogens with established small animal models of infection to define DUB targets that mediate the anti-infective effects of WP. Our goal is to advance the lead compound towards an investigational new drug (IND) application. We therefore propose the following specific aims: (1) Determine target DUBs of WP that mediate anti-infective activity, (2) Test a SAR series of WP in vitro to identify lead compounds, and (3) Test lead compounds for in vivo efficacy. This application aims to develop a broad-spectrum anti-infective therapeutic effective against many pathogens including multiple category B agents.

迫切需要有效针对耐药的新疗法