Bioavailable proteasome inhibitors as broad-spectrum antivirals

生物可利用的蛋白酶体抑制剂作为广谱抗病毒药物

• 批准号: 9091400
• 负责人: Alexander Niclas Freiberg
• 金额: $ 41.59万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091400
• 关键词: Acute; Animal Model; Antiviral Agents; Arenaviridae; Attention; Benchmarking; Bioavailable; Biological Availability; Bortezomib; Bunyaviridae; Categories; Cell physiology; Cells; Cellular Structures; Chemicals; Clinical; Clinical Oncology; Coupled; DNA Viruses; Data; Dependency; Development; Drug Industry; Drug Kinetics; Ebola virus; Escape Mutant; FDA approved; FOLH1 gene; Family; Filoviridae; Flaviviridae; Generations; Genes; Goals; Health; Housekeeping; Immune; In Vitro; Infection; Investments; Junin virus; Label; Laboratory Study; Licensing; Modeling; Molecular; Multiple Myeloma; National Institute of Allergy and Infectious Disease; Nipah Virus; Paramyxoviridae; Pathway interactions; Patients; Phase; Plasma; Proteasome Inhibition; Proteasome Inhibitor; Publishing; RNA Viruses; RNA interference screen; Recording of previous events; Research; Resistance; Resistance development; Resources; Rift Valley Fever; Russian Spring-Summer Encephalitis; Specificity; Testing; Therapeutic; Therapeutic Index; Toxicology; Ubiquitin; Viral; Virus; Virus Diseases; Virus Replication; Work; animal efficacy; anti-viral efficacy; design; experience; genome-wide; improved; in vivo; inhibitor/antagonist; multicatalytic endopeptidase complex; pathogen; pressure; protein function; viral DNA; virus host interaction

DESCRIPTION (provided by applicant): The ubiquitin proteasome pathway (UPP) is implicated in the lifecycle of multiple viruses. The UPP regulates a wide array of protein function and cellular processes and many viruses are known to manipulate the host cell UPP to enable replication, egress and immune evasion. Many proteasome inhibitors (PSM Inbs) have a negative impact on viral infections in vitro, but the involvement of the UPP in multiple cellular functions, coupled with the lack of potency, specificity or in vivo stability of the first generatin PSM Inbs, discouraged the consideration that PSM Inbs could be developed safely as an antiviral therapeutic. In 2003, the FDA approval of the first PSM Inb, Bortezomib, for the treatment of multiple myeloma, provided proof-of-principle that PSM Inbs can be developed with acceptable toxicology profile and good pharmacokinetics/ bioavailability. This has led to the development of many second generation PSM Inbs with improved potency, selectivity, and bioavailability-several of which are already in Phase I-III trials for oncologic applications. We wll leverage the considerable pharmaceutical industry investment already made in bringing these PSM Inbs into clinical trails to accomplish our primary goal: which is to empirically evaluate and re-purpose these bioavailable PSM Inbs as potential broad-spectrum antivirals for infections caused by NIAID Category A-C pathogens. We have already published that Bortezomib inhibits Nipah virus replication with an IC50 100-fold less than the peak plasma concentrations found in patients. Furthermore, we have also obtained in vitro preliminary data showing that Bortezomib can inhibit the replication of multiple Category A-C pathogens: Filoviridae (Ebola), Paramyxoviridae (Nipah), Bunyaviridae (Rift Valley fever), Flaviviridae (Russian-Spring-Summer encephalitis), and Arenaviridae (Junin). To accomplish our goal, we propose during the R21 phase to (1) evaluate the anti-viral efficacy of selected proteasome inhibitors against a panel of NIAID Category A to C viral pathogens, and (2) elucidate the mechanisms underlying the differential efficacy of the various proteasome inhibitors against distinct viral families. In the 33 phase, we will (3) establish the in vivo efficacy, in small animal models, of the most promising proteasome inhibitors characterized in the R21 phase, and (4) determine the relative barriers to resistance using relevant Category A to C model viruses. The advantages of our strategy are three-fold: (a) focusing on the selected PSM Inbs in clinical development takes advantage of the extensive pharmacokinetic data available, which will help guide animal efficacy studies, (b) targeting a host cell component likely limits the development of resistant and escape mutants, and (c) efficacy data in at least two animal models raises the enticing possibility that some PSM Inbs can be considered for "off-label" use in the treatment of acute and highly lethal viral diseases with no other treatment options.

描述(申请人提供)：泛素蛋白酶体途径(UPP)与多种病毒的生命周期有关。UPP调节广泛的蛋白质功能 已知的是，细胞过程和许多病毒操纵宿主细胞UPP，以实现复制、出口和免疫逃避。许多蛋白酶体抑制剂(PSM INBS)在体外对病毒感染有负面影响，但UPP参与多种细胞功能，加上第一代PSM INBS缺乏效力、特异性或体内稳定性，阻碍了PSM INBS作为抗病毒治疗药物的安全开发的考虑。2003年，FDA批准了第一个PSM INB，Bortezomib，用于治疗多发性骨髓瘤，提供了原则证明，PSM INBS可以开发出具有可接受的毒理学特征和良好的药代动力学/生物利用度。这导致了许多第二代PSM INBS的开发，具有更好的效力、选择性和生物利用度-其中几种已经处于肿瘤学应用的I-III阶段试验。我们将利用制药行业已经进行的大量投资，将这些PSM INBS投入临床试验，以实现我们的主要目标：对这些生物可用PSM INBS进行经验性评估，并将其重新用于治疗由NIAID A-C类病原体引起的感染的潜在广谱抗病毒药物。我们已经发表了Bortezomib抑制Nipah病毒复制的IC50是患者血浆峰值浓度的100倍。此外，我们还在体外获得了初步数据，显示Bortezomib可以抑制多种A-C类病原体的复制：丝状病毒科(埃博拉)、副粘病毒科(Nipah)、布尼亚病毒科(裂谷热)、黄病毒科(俄罗斯春夏脑炎)和阿伦病毒科(Junin)。为了实现我们的目标，我们建议在R21阶段(1)评估选定的蛋白酶体抑制剂对一组NIAID A到C类病毒病原体的抗病毒效果，以及(2)阐明不同蛋白酶体抑制剂对不同病毒家族不同疗效的机制。在33阶段，我们将(3)在小动物模型中建立以R21阶段为特征的最有希望的蛋白酶体抑制剂的体内有效性，以及(4)使用相关的A到C类模型病毒来确定抗药性的相对屏障。我们的策略有三方面的优势：(A)在临床开发中重点关注选定的PSM INBS利用现有的广泛药代动力学数据，这将有助于指导动物疗效研究，(B)针对宿主细胞成分可能限制耐药和逃逸突变株的开发，以及(C)至少两个动物模型的疗效数据增加了诱人的可能性，即一些PSM INBS可考虑在没有其他治疗选择的情况下，在“标签外”用于治疗急性和高度致命的病毒疾病。

项目成果

Tilorone-Dihydrochloride Protects against Rift Valley Fever Virus Infection and Disease in the Mouse Model.

Tilorone-dhydrocride在小鼠模型中可预防裂谷热病毒感染和疾病。

• DOI: 10.3390/microorganisms10010092
• 发表时间: 2021-12-31
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Johnson KN;Kalveram B;Smith JK;Zhang L;Juelich T;Atkins C;Ikegami T;Freiberg AN
• 通讯作者: Freiberg AN

In Vivo Imaging of Nipah Virus Infection in Small Animal Rodent Models.

小动物啮齿动物模型中尼帕病毒感染的体内成像。

• DOI: 10.1007/978-1-0716-3283-3_11
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Johnson,Kendra;Juelich,Terry;Smith,Jennifer;Lee,Benhur;Freiberg,AlexanderN
• 通讯作者: Freiberg,AlexanderN