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Novel beta-lactams as inhibitors of ebola virus infections

新型β-内酰胺作为埃博拉病毒感染的抑制剂

基本信息

批准号：
9046014
负责人：
Zachary David Aron
金额：
$ 30.44万
依托单位：
MICROBIOTIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-24 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9046014
关键词：
Address Affinity Africa African Americas Animal Model Antibody Therapy Antiviral Agents Biological Biological Assay Bioterrorism Categories Cell Culture Techniques Characteristics Chemicals Clinical Trials Development Disease Outbreaks Drug Kinetics Ebola virus Effectiveness Engineering Enzyme Inhibitor Drugs Enzyme Inhibitors Epidemic Europe Evaluation Event Exhibits Family Filovirus Fright Future Goals Health system In Vitro Infection Investigation Isomerism Lead Libraries Liver Microsomes Measures Medical Membrane Glycoproteins Military Personnel Modification Monitor Monoclonal Antibodies Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Probability Process Property Protein Isoforms Reporting Resources Risk Route Series Serum Services Site Spain Stereoisomer Structure Structure-Activity Relationship Survivors Testing Therapeutic TimeLine Toxic effect United Kingdom United States Vesicular stomatitis Indiana virus Viral Viral Hemorrhagic Fevers Virus Virus Diseases Virus Inhibitors Virus Replication Western Africa analog animal efficacy base beta-Lactams chemical property coping cytotoxicity design diphenyl efficacy testing enantiomer improved in vivo inhibitor/antagonist member mortality novel novel therapeutics pathogen phase 2 study polyclonal antibody pre-clinical prophylactic public health relevance scaffold small molecule small molecule therapeutics social success transmission process

项目摘要

DESCRIPTION (provided by applicant): Ebola virus (EBOV) is a member of the filovirus family that causes severe viral hemorrhagic fever (VHF). Although infrequent, epidemics of EBOV can cause high mortality rates of up to 90%; the subsequent medical and social upheaval can be widespread and severe, as seen in the recent outbreak in Western Africa which has already caused more than 10,000 fatalities in a region with insubstantial medical services. Although some success using monoclonal and polyclonal antibodies has been reported, these expensive treatments are not widely available to poorer regions of Africa without substantial assistance from America and Europe; additionally, it would be beneficial to have the ability to stockpile treatments in case of future outbreaks or bioterrorism. This option is not easily achieved with antibody therapies. A pressing need for small-molecule therapeutics is thus quite evident. The experimental drugs brincidofovir, favipiravir, and BCX 4430 have shown promise in vitro, but no clinical trials have proven their effectiveness in vivo. To address this critical unmet medical need, new small-molecule therapeutics/prophylactics are necessary to avert the risk of future epidemics. Using a pseudotype virus that mimics the viral entry process of EBOV, we have identified a novel set of small molecule EBOV entry inhibitors that has been validated in assays of infectious EBOV in vitro. Based on a beta-lactam central core, these compounds are readily modified, are drug-like, and represent an excellent starting point for medicinal chemistry optimization. By synthesizing new analogs of the hit compound, MBX 2806, we will generate structure-activity relationships to better understand the chemical features that lead to potent anti-EBOV activity and low cytotoxicity, and ultimately produce potent, selective inhibitors of infectious EBOV that display drug-like characteristics. The current proposal will use medicinal chemistry to optimize MBX 2806 using three aims: 1) We will synthesize novel analogs of MBX 2806 and assay the antiviral activity in a pseudotype assay of EBOV infection. 2) We will validate the results of the pseudotype assay using infectious EBOV under BSL4 conditions. 3) We will measure in vitro ADME predictors to improve the overall drug-likeness of the scaffold. Using an iterative process of compound design, synthesis, and biological assay, we will synthesize optimized compounds that are potent, selective, and have drug-like properties suitable for further development as therapeutics and/or prophylactics for EBOV infection.