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

总结 前所未有的COVID-19全球健康危机是由于缺乏有效的疫苗和没有具体的 抗病毒药物因此，主要的研究工作集中在确定有效的疗法。最 有效的短期解决方案是重新利用和重新定位已批准的药物或临床阶段的候选药物， 因为这种方法缩短了到诊所的时间。此外，由于没有针对任何人畜共患病的药物， 与人类呼吸道感染相关的冠状病毒，泛冠状病毒药物方案至关重要，以应对 未来的爆发。为了最好地解决这一紧迫性，已经建立了药物开发加速器， 我们的NIH转化研究卓越中心（CETR）和默克之间的正式合作伙伴关系， 有限公司、股份有限公司、在发现和开发抗病毒药物方面处于全球领先地位。CETR计划， 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。默克公司带来了完整的批准抗病毒药物和先进的候选人 用于重新利用和重新定位，重点是新型核苷和蛋白酶抑制剂。第一，小 代表FDA批准药物和临床阶段候选药物的分子化合物 将在病毒致细胞病变和中和试验中评估对其他病毒的抑制作用，以评估对SARS的抑制作用。 二型冠状病毒将评估候选药物的EC 50/90/CC 50值、ADME药代动力学和安全性， 确定其立即用于治疗的潜力。如果数据支持稳健的治疗窗口，则 将根据FDA EUA提交重新用途的化合物用于IND。利用SARS-CoV-2的啮齿动物模型 感染将用于评估支持临床剂量范围和安全范围的体内PK/PD参数。 其次，泛冠状病毒药物开发候选药物将从药物重新定位或从 默克公司针对现有抗病毒类别的重点化合物库发现了针对其他保守病毒的化合物。 靶点，以及代表>65种作用机制的宿主和病毒靶点的新先导系列。这些 将在高通量病毒攻击试验中筛选化合物。特区将受益于数百万 化合物默克样品收集通过在硅片子结构和相似性搜索。铅化合物将 评估针对SARS-CoV-2的稳健的体内治疗功效;代谢稳定性、毒性、ADME， 啮齿动物耐受性;药理学特性与QD或BID给药一致，安全性可接受 支持启动首次人体临床研究的边界。最终目标是确定 可以进入临床前IND的开发候选药物，从而实现安全性去风险研究。这是一 前所未有的公私合作伙伴关系药物发现这个药物加速器的目标是确定一个 在4-6个月内和第2年年底前，确定可以治疗COVID-19患者的重新利用的化合物， 具有泛冠状病毒功效的候选人，可以进入临床前IND使能和降低风险研究。

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.