Bioavailable proteasome inhibitors as broad-spectrum antivirals

描述（由申请方提供）：泛素蛋白酶体途径（UPP）涉及多种病毒的生命周期。UPP调节多种蛋白质功能 和细胞过程，已知许多病毒操纵宿主细胞UPP以使复制、外出和免疫逃避成为可能。许多蛋白酶体抑制剂（PSM Inbs）在体外对病毒感染具有负面影响，但是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可以安全地开发为抗病毒治疗剂的考虑。2003年，FDA批准了第一个PSM Inb（硼替佐米）用于治疗多发性骨髓瘤，提供了原则证明，即可以开发具有可接受毒理学特征和良好药代动力学/生物利用度的PSM Inb。这导致了许多第二代PSM Inbs的开发，其具有改进的效力、选择性和生物利用度，其中一些已经在肿瘤应用的I-III期试验中。我们将充分利用制药行业在将这些PSM Inb引入临床试验方面已经进行的大量投资，以实现我们的主要目标：即根据经验评估这些生物可利用的PSM Inb并将其重新用作NIAID A-C类病原体引起的感染的潜在广谱抗病毒药。我们已经发表了硼替佐米抑制尼帕病毒复制的IC 50比患者血浆峰浓度低100倍。此外，我们还获得了体外初步数据，表明硼替佐米可以抑制多种A-C类病原体的复制：丝状病毒科（埃博拉）、副粘病毒科（尼帕）、布尼亚病毒科（裂谷热）、黄病毒科（俄罗斯春夏脑炎）和沙粒病毒科（朱宁）。为了实现我们的目标，我们建议在R21阶段（1）评价选定的蛋白酶体抑制剂对NIAID A至C类病毒病原体的抗病毒疗效，以及（2）阐明各种蛋白酶体抑制剂对不同病毒家族的差异疗效的机制。在第33阶段，我们将（3）在小动物模型中确定R21阶段表征的最有前途的蛋白酶体抑制剂的体内疗效，以及（4）使用相关的A至C类模型病毒确定耐药的相对屏障。我们的战略有三方面的优势：（a）在临床开发中集中于选定的PSM Inb利用了广泛的可用药代动力学数据，这将有助于指导动物功效研究，（B）靶向宿主细胞组分可能限制抗性和逃逸突变体的发展，和（c）至少两种动物模型的有效性数据提高了一些PSM Inb可被视为“标签外”的诱人可能性用于治疗没有其他治疗选择的急性和高致死性病毒性疾病。

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.