Small Molecule Inhibitors Targeting Adenovirus

针对腺病毒的小分子抑制剂

基本信息

批准号：
10540736
负责人：
CHARLES E MCKENNA
金额：
$ 56.86万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540736
关键词：
Acute 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 Joints Kidney Licensing 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 Recurrence Research Research Personnel Research Project Grants Respiratory Disease Risk Safety Series Serotyping Structure-Activity Relationship Temperature Testing Therapeutic Time Tissues Toxic effect Toxicology Training Treatment Efficacy Universities Urinary tract infection Vaccines Viral Viral Physiology Virulent Virus Diseases Work analog chemical stability clinically relevant design efficacy evaluation efficacy study efficacy testing experimental study immunosuppressed in vivo indexing intravenous administration lead candidate metabolic abnormality assessment novel pediatric patients penis foreskin pharmacodynamic model pharmacokinetic characteristic pharmacokinetics and pharmacodynamics 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.

项目概要腺病毒 (Ad) 感染对免疫功能低下的儿科患者来说是一个重大的健康风险，并可能导致肺炎、尿路感染和腺病毒等严重并发症在军队中很常见。招募参与基础训练设施的人员，因为他们经常参与这些训练针对 Ad 血清型 4 和 7 的疫苗已获得许可。 FDA 批准了该疫苗，但该疫苗的长期可用性尚不清楚，而且免疫接种不适用于以下人群预防对健康构成严重威胁的其他 Ad 血清型感染，包括血清型 6 和 14 已在青少年和成人患者中引起致命的呼吸道疾病。无环核苷磷酸 (ANP) 衍生物已被 FDA 批准用于治疗 CMV 视网膜炎。尽管 FDA 未批准用于治疗 Ad 感染，但 CDV 已在临床上经常使用。由于其渗透性有限，细胞抗 Ad 效力相对较低，必须静脉注射由于其口服生物利用度低，CDV 的另一个限制是其在肾脏中浓度所致的肾毒性。最近，南加州大学合成了 CDV 和 HPMPA 的某些“可调节”前药。 (USC) 已被证明在体外对四种 Ad 血清型的效力要强几个数量级以及在叙利亚仓鼠模型中口服有效对抗 Ad6。拟议的研究将建立在这些高度的基础上。有前景的初步数据可阐明这些活性前药及其结构相关的 SAR 和机制将合成一系列在前体中具有可变结构特征的前药类似物。并评估其与六种有毒力Ad血清型的抗Ad活性，还将比较类似物的稳定性。药代动力学特征、仓鼠模型中的毒性以及最有前途的前药将得到进一步评估这项研究将由叙利亚仓鼠模型进行，以了解针对 Ad6 的功效。由 Charles McKenna 教授（南加州大学，模拟设计与综合）、Mark Prichard 教授领导的跨学科团队（阿拉巴马-伯明翰大学，体外研究）和 William Wold 教授（圣路易斯大学，体内研究），最终目标是识别和开发一种安全、高效的 CDV 口服前药用于治疗急性呼吸道疾病和在免疫功能低下的个体中传播感染。