A CETR-based partnership accelerator for rapid drug development targeting SARS-CoV-2 and pan-CoVs

摘要 史无前例的新冠肺炎全球健康危机是由于缺乏有效的疫苗和没有特效药而加剧的 抗病毒药物。因此，主要的研究努力集中在确定有效的治疗方法上。最多的 有效的短期解决方案是重新调整已批准的药物或临床阶段候选药物的用途和重新定位， 因为这种方法缩短了去诊所的时间。此外，由于没有针对任何人畜共患病的药物 与人类呼吸道感染有关的冠状病毒，泛冠状病毒药物方案至关重要 未来的疫情。为了最好地解决这一紧迫性，已经建立了一个药物开发加速器，作为 我们的NIH翻译研究卓越中心(CETR)与默克公司和 全球抗病毒药物发现和开发的领先者。CETR计划，这是 专注于针对高威胁细菌感染的新型和重新定位的药物，提供了全面的 药物发现的平台。默克公司带来了全套批准的抗病毒药物和先进的候选药物 用于重新用途和重新定位，重点是新的核苷和蛋白水解酶抑制剂。首先，小规模 发现代表FDA批准药物和临床阶段候选药物的分子化合物 抗其他病毒的作用将在病毒细胞病变和中和试验中进行评估，以评估对SARS的抑制- CoV-2。将评估候选铅的EC50/90/CC50值、ADME药代动力学和安全性 确定它们在治疗中立即使用的潜力。如果数据支持强有力的治疗窗口，那么 重新调整用途的化合物(S)将提交FDA EUA下的IND。利用SARS-CoV-2建立啮齿动物模型 感染将用于评估支持临床剂量范围和安全边际的体内PK/PD参数。 其次，泛冠状病毒药物开发候选者将从药物重新定位或从 默克公司针对现有抗病毒类别发现的针对其他保守病毒的重点化合物文库 靶标，以及代表&gt；65作用机制的宿主和病毒靶标的新铅系列。这些 化合物将在高通量病毒挑战试验中进行筛选。香港特区将从数百万美元的 通过硅胶结构和相似性搜索收集复方默克样品。先导化合物将是 对SARS-CoV-2的体内治疗效果进行评估；代谢稳定性、毒性、ADME、 啮齿动物的耐受性；药理特性与Qd或Bid剂量一致，以及可接受的安全性 支持在人类临床研究中启动第一项的利润率。最终目标是确定 能够进入临床前IND使安全去风险研究的开发候选者。这是一个 史无前例的公私合作进行药物发现这种药物加速器的目标是确定一种 重新调整用途的化合物(S)，可以在4-6个月内治疗新冠肺炎患者，并在第二年年底确定 具有泛冠状病毒效力的候选人，可以进入临床前IND使能和去风险研究。

SUMMARY The unprecedented COVID-19 global health crisis is fueled by the absence of an effective vaccine and no specific antiviral drugs. Consequently, major research efforts have focused on identifying efficacious therapies. The most effective short-term solution is repurposing and repositioning of approved drugs or clinical-stage drug candidates, as this approach shortens the time to the clinic. Furthermore, as there are no drugs against any zoonotic coronaviruses associated with human respiratory infections, pan-coronavirus drug regimens are vital to counter future outbreaks. To best address this urgency, a drug development Accelerator has been established as a formal partnership between our NIH Center of Excellence in Translational Research (CETR) and Merck and Co., Inc., a global leader in the discovery and development of antiviral drugs. The CETR program, which is focused on novel and repositioned drugs against high-threat bacterial infections, provides a comprehensive platform for drug discovery. Merck brings a full complement of approved antiviral drugs and advanced candidates for repurposing and repositioning, with an emphasis on novel nucleoside and protease inhibitors. Firstly, small molecule compounds representing both FDA approved drugs and clinical stage drug candidates discovered against other viruses will be evaluated in viral cytopathic and neutralization assays to assess inhibition of SARS- CoV-2. Lead candidates will be assessed for EC50/90/CC50 values, ADME pharmacokinetics, and safety to determine their potential for immediate use in therapy. If data supports a robust therapeutic window, then repurposed compound(s) will be submitted for an IND under FDA EUA. A rodent model utilizing SARS-CoV-2 infection will be used to assess in vivo PK/PD parameters supporting clinical dose ranging and safety margins. Secondly, a pan-coronavirus drug development candidate will be identified from either drug repositioning or from Merck’s focused compound libraries for existing antiviral classes discovered against other conserved viral targets, as well as new lead series to host and viral targets representing >65 mechanisms of action. These compounds will be screened in a high throughput virus challenge assay. SAR will benefit from the multi-million compound Merck sample collection via in silico substructure and similarity searches. Lead compounds will be assessed for robust in vivo therapeutic efficacy against SARS-CoV-2; metabolic stability, toxicity, ADME, rodent tolerability; pharmacologic properties consistent with QD or BID dosing, and acceptable safety margins supportive of initiation of first in human clinical studies. The ultimate goal is the identification of development candidates that can enter preclinical IND enabling safety derisking studies. This is an unprecedented public-private partnership for drug discovery The goal of this drug Accelerator is to identify a repurposed compound(s) that can treat COVID-19 patients within 4-6 months and by the end of Year 2, identify candidates with pan-coronavirus efficacy that can enter preclinical IND-enabling and derisking studies.