Fatty Acid Synthase Inhibitors As Broad Spectrum Anti-Flaviviral Therapeutics

脂肪酸合酶抑制剂作为广谱抗黄病毒治疗药物

• 批准号: 8487364
• 负责人: Glenn C Randall
• 金额: $ 21.64万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487364
• 关键词: Adverse event; Animal Model; Animals; Antiviral Agents; Arboviruses; Binding; Bioavailable; Biological Assay; Bioterrorism; Categories; Cell Culture Techniques; Cellular Membrane; Central Nervous System Diseases; Clinical Trials; Collaborations; Complex; Cytomegalovirus; Dengue Virus; Diamond; Disease model; Drug Evaluation; Drug Kinetics; Enzymes; Evaluation; Family; Fatty-acid synthase; Flavivirus; Flavivirus Infections; HIV; Hepatitis C virus; Ice; In Vitro; Infection; Influenza; Lead; Liver; Lung; Modeling; Mus; Mutate; Mutation; Pathway interactions; Pharmaceutical Chemistry; Pharmacodynamics; Property; Protein Binding; RNA Viruses; Recruitment Activity; Research; Resistance; Resistance profile; Safety; Site; Structure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicity Tests; Viral; Virus; Virus Diseases; Virus Replication; West Nile virus; Yellow fever virus; analog; cell type; clinically relevant; dengue virus NS3; efficacy testing; experience; fatty acid biosynthesis; in vivo; inhibitor/antagonist; mouse model; mutant; novel; resistance mechanism; small molecule; viral resistance; virus host interaction

DESCRIPTION (provided by applicant): Dengue virus (DENV) is the most clinically important arbovirus and a Category A bioterrorism agent. As with other positive stranded RNA viruses, DENV rearranges cellular membranes to establish unique cytosolic structures that are the sites of replication complex formation. We found that DENV co-opts cellular fatty acid biosynthesis to establish its sites of replication. The viral NS3 protein binds to fatty acid synthase (FASN), recruits it to sites of viral replication, and stimulates its activity. The NS3 domain required for FASN binding has been defined. Mutation of the FASN interaction domains established that the NS3-FASN interaction is absolutely essential for replication. Importantly, FASN inhibitors block the replication of DENV and other flaviviruses including West Nile virus and yellow fever virus. Additionally the FASN pathway has been implicated in the replication of many other viruses, including HIV, HCV, influenza, and HCMV. This suggests that FASN inhibitors may be a broad spectrum antiviral therapeutic if tolerated. We have identified a FASN inhibitor lead compound, IPI- 9119, that fits this criteria. It inhibits FASN in cell culture and in the liver and lungs of ice. The compound is orally bioavailable and irreversibly inhibits the thioesterase domain of FASN. Toxicity studies in vitro and in mice demonstrate that the inhibitor is well tolerated with minimal toxicity issues. This project is a collaboration between three groups. The Randall lab has characterized the DENV- FASN interaction and has assessed antiviral activity of FASN inhibitors in vitro. The Diamond lab are leaders in flavivirus research and are highly experienced with DENV and West Nile Virus animal models and inhibitor testing. The Infinity group developed the FASN inhibitor class and characterized its efficacy and (lack of) toxicity in vivo. They have expertise in medicinal chemistry, animal toxicity testing, and analysis of IND-enabling studies. We propose to test the efficacy of this compound against DENV and WNV infection in vitro and in mouse models and then build toward an IND filing. We will validate the efficacy of FASN inhibitors against DENV infection in vitro and in vivo. Anti-DENV activity will be characterized in cell culture and mouse models, while mechanisms of resistance are evaluated. Further drug evaluation assessing pharmacokinetics, pharmacodynamics, and various toxicity assays will be performed to advance these compounds toward IND filing. This project will move a likely broad-spectrum antiviral that targets a well-characterized virus-host interaction in dengue virus replication inhibitor into IND filing for clinical trials. Importantly, although the inhibitor targets an important cellular enzyme, it is non-toxic in mice.

描述（由申请人提供）：登革病毒（DENV）是临床上最重要的虫媒病毒，也是A类生物恐怖剂。与其他正链RNA病毒一样，DENV重排细胞膜以建立作为复制复合物形成位点的独特胞质结构。我们发现，登革病毒选择细胞脂肪酸的生物合成，以建立其复制的网站。病毒NS 3蛋白与脂肪酸合成酶（FATCH）结合，将其招募到病毒复制位点，并刺激其活性。所需的NS 3域 已定义绑定。Festival相互作用结构域的突变确定了NS 3-Festival相互作用对于复制是绝对必要的。 重要的是，FEV 1抑制剂阻断DENV和其他黄病毒（包括西尼罗河病毒和黄热病病毒）的复制。此外，FXR途径还涉及许多其他病毒的复制，包括HIV、HCV、流感和HCMV。这表明，如果耐受的话，Festival抑制剂可能是广谱抗病毒治疗剂。我们已经确定了一种符合这一标准的Festival抑制剂先导化合物IPI- 9119。它抑制细胞培养物中的Festival，以及冰的肝脏和肺中的Festival。所述化合物是口服生物可利用的，并且不可逆地抑制Festival的硫酯酶结构域。体外和小鼠毒性研究表明，该抑制剂耐受性良好， 毒性问题。 这个项目是三个团队的合作。Randall实验室已经表征了DENV-Festival相互作用，并评估了Festival抑制剂的体外抗病毒活性。Diamond实验室是黄病毒研究的领导者，在DENV和西尼罗河病毒动物模型和抑制剂测试方面经验丰富。Infinity小组开发了Festival抑制剂类，并表征了其体内疗效和（无）毒性。他们在药物化学，动物毒性测试和IND研究分析方面具有专业知识。 我们建议在体外和小鼠模型中测试这种化合物对DENV和WNV感染的有效性，然后建立IND申请。我们将在体外和体内验证Festival抑制剂对DENV感染的功效。抗DENV活性将在细胞培养和小鼠模型中表征，同时评估抗性机制。将进行进一步的药物评价，评估药代动力学，药效学和各种毒性试验，以推动这些化合物向IND申请。该项目将把一种可能的广谱抗病毒药物转移到IND申请中进行临床试验，该药物靶向登革病毒复制抑制剂中一种特征良好的病毒-宿主相互作用。重要的是，尽管这种抑制剂靶向一种重要的细胞酶，但它在小鼠中无毒。