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Small Molecule Inhibitors Targeting Adenovirus

针对腺病毒的小分子抑制剂

基本信息

批准号：
10307542
负责人：
CHARLES E MCKENNA
金额：
$ 57.23万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307542
关键词：
Acute Address Adenovirus Infections Adenoviruses Adolescent Adult Alabama Antiviral Agents Biological Assay Biological Availability Caco-2 Cells California Cell Culture Techniques Cells Cellular Assay Cidofovir Clinic Cytomegalovirus Retinitis Data Disease Outbreaks Dose Drug Kinetics Ensure Equilibrium Evaluation FDA approved Fever Fibroblasts Gastrointestinal tract structure Goals Hamsters Health Hepatitis Human Immune Immunization Immunocompromised Host In Vitro Individual Infection Infection prevention Intravenous Joints Kidney Lead Liver Liver Microsomes Mesocricetus auratus Metabolism Military Personnel Modeling Nucleosides Oral Patients Permeability Pharmaceutical Chemistry Pharmacology Phosphate Buffer Physiological Plasma Pneumonia Population Prodrugs Property Public Health Research Research Personnel Research Project Grants Respiratory Disease Risk Safety Saints Series Serotyping Structure-Activity Relationship Temperature Testing Therapeutic Time Tissues Toxic effect Toxicology Training Treatment Efficacy Universities Urinary tract infection Vaccines Virulent Virus Diseases Work analog base chemical stability clinically relevant design efficacy evaluation efficacy study efficacy testing experimental study immunosuppressed in vivo indexing lead candidate metabolic abnormality assessment novel pediatric patients penis foreskin pharmacodynamic model pharmacokinetic characteristic pharmacokinetic model phosphonate pre-clinical preclinical efficacy preclinical safety prophylactic recruit research clinical testing small molecule inhibitor stability testing success vaccine access virology

项目摘要

PROJECT SUMMARY Adenovirus (Ad) infection is a significant health risk for immune-compromised pediatric patients, and can lead to serious complications such as pneumonia, urinary infections and hepatitis. Adenoviruses are endemic in military recruit populations engaging in basic training installations where they have been implicated in recurring outbreaks of febrile respiratory disease. A vaccine effective against Ad serotypes 4 and 7 has been licensed by the FDA, but the long-term availability of this vaccine is unclear, and immunization is not available for the prevention of infections by other Ad serotypes presenting a serious threat to health, including serotypes 6 and 14 which have caused fatal respiratory disease in both juvenile and adult patients. Cidofovir (CDV, HPMPC), an acyclic nucleoside phosphonate (ANP) derivative, is approved by the FDA for treatment of CMV retinitis. Although not approved by the FDA for treatment of Ad infection, it is used frequently in the clinic. CDV has relatively modest cellular anti-Ad potency due to its limited permeability and must be administered intravenously due to its low oral bioavailability. A further limitation of CDV is its renal toxicity due to concentration in kidney tissue. Recently, certain “tunable” prodrugs of CDV and HPMPA synthesized at the Univ. of Southern California (USC) have been demonstrated to be several orders of magnitude more potent against four Ad serotypes in vitro and orally effective against Ad6 in a Syrian hamster model. The proposed research will build on these highly promising preliminary data to elucidate the SAR and mechanism of these active prodrugs and structurally related derivatives. A series of prodrug analogs will be synthesized having variable structural features in the promoiety and evaluated for anti-Ad activity vs six virulent Ad serotypes. The analogs will also be compared for stability and PK characteristics, toxicity in a hamster model, and the most promising prodrugs will be further evaluated for efficacy against Ad6 in the Syrian hamster model. This research, which will be performed by an interdisciplinary team led by Prof. Charles McKenna (USC, analog design and synthesis), Prof. Mark Prichard (Univ. of Alabama-Birmingham, in vitro studies) and Prof. William Wold (Saint Louis University, in vivo studies), has the ultimate goal of identifying and developing a safe, highly effective oral prodrug of CDV for the treatment of acute respiratory disease and disseminating infection in immune-compromised individuals.

项目总结