Metropolitan AntiViral Drug Accelerator

摘要 由严重急性呼吸综合征冠状病毒2型引起的新冠肺炎大流行 导致全球数百万人死亡。针对SARS-CoV-2的新型疫苗改变了大流行的 弹道。然而，大量人群仍然处于危险之中，免疫逃逸病毒的变种可能会阻碍疫苗的接种。 行动或目前的治疗方法。新的小分子抗病毒药物可用于门诊患者的口服治疗 需要环境来治疗SARS-CoV-2感染、其他冠状病毒和其他大流行病毒 担忧。新冠肺炎在抗感染药物开发方面帮助大型制药公司重新加入，但仍有 早期药物发现阶段的差距，从事药物发现的学术科学家可以弥补这一差距 通过与工业界的成功合作。学术团体有很好的生物学见解和平台 用于新的发现，从而识别新的目标、命中和线索。然而，他们很少有办法 或优化化合物并将其用于临床开发的手段。我们假设一个 有效的公私伙伴关系可以弥合这一差距，并创造了大都会抗病毒药物 加速器(MAVDA)。它是一个史无前例的学术和医药合作伙伴在 纽约市和新泽西州北部聚集在一个共同的发现生态系统中，以解决 迫切需要经过验证的小分子抗病毒药物。MAVDA结合了世界级病毒学家和 来自洛克菲勒大学、哥伦比亚大学和斯隆纪念馆的学术药物发现研究人员- 纽约市凯特琳癌症中心和罗格斯大学发现与创新中心 在新泽西州，与默克公司经过验证的抗病毒药物开发商合作，三机构治疗公司 发现研究所(Tri-I TDI)-武田制药和Aligos Treeutics作为凝聚力 企业将提供新的抗病毒药物。加速器的一项关键创新是建立了一个 拥有经验丰富的核心董事的广泛和集成的Pharma式科学核心网络， 确保有效地进行化合物识别和优化。标准化的门槛“门槛” 将建立复合进展的指标，并制定明确的“进行/不进行”标准，以支持发展 合格的候选药物。MAVDA项目将学术和行业研究人员与创新和 成熟的药物发现平台，非常重视像3CLPro这样的有效靶点，但也 开发其他重要靶点，如Nsp14和Nsp16 MTase、外显子、PLPro、Nsp13解旋酶、RdRp以及 新的目标。在IND启用/降低风险阶段或接近IND启用/降低风险阶段时有希望的命中、早期销售线索和优化销售线索 以及发现新天然产品的创新方法。所有计划的目标 SARS-CoV-2不仅针对其他冠状病毒、黄病毒和/或甲型病毒。MAVDA很强大，很容易 适应开发项目和新的病毒挑战，是培训的理想环境 下一代科学家在药物发现和大流行准备方面的作用。

ABSTRACT The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of deaths worldwide. Novel vaccines against SARS-CoV-2 have altered the pandemic’s trajectory. Yet, large populations remain at risk, and immune escape virus variants threaten to thwart vaccine action or current therapies. New small molecule antiviral drugs available as oral treatments in the outpatient setting are needed to treat SARS-CoV-2 infections, other coronaviruses, and additional viruses of pandemic concern. COVID-19 has helped rejoin large Pharma in anti-infective drug development but there remains a gap in the early drug discovery phase, which can be met by academic scientists engaged in drug discovery through successful partnership with industry. Academic groups have great biological insights and platforms for novel discovery resulting in identification of new targets, Hits, and Leads. Yet, they rarely have the ways or means to optimize compounds and advance them for clinical development. We hypothesize that an effective public-private partnership can bridge this gap and have created the Metropolitan AntiViral Drug Accelerator (MAVDA). It is an unprecedented collaborative enterprise of academic and Pharma partners in New York City and Northern New Jersey brought together in a common discovery ecosystem to address the urgent need for validated small-molecule antiviral drugs. MAVDA combines world-class virologists and academic drug discovery researchers from Rockefeller University, Columbia University and Memorial Sloan- Kettering Cancer Center in New York City and the Center for Discovery and Innovation and Rutgers University in New Jersey with proven antiviral drug developers at Merck & Co., Inc., the Tri-Institutional Therapeutics Discovery Institute (Tri-I TDI)-Takeda Pharmaceuticals, and Aligos Therapeutics, as a cohesive enterprise to deliver new antiviral drugs. A critical innovation of the Accelerator is the establishment of an extensive and integrated network of Pharma-style science cores with highly experienced Core directors, which ensures that compound identification and optimization proceeds efficiently. Standardized threshold “gating” metrics for compound progression with clear ‘Go/No Go’ criteria will be established to support development of qualified drug candidates. MAVDA Projects unite academic and industry investigators with innovative and well-established drug discovery platforms with a strong emphasis on validated targets like 3CLpro, but also exploit other important targets like Nsp14 and Nsp16 MTase, ExoN, PLpro, Nsp13 helicase, RdRp, as well as novel targets. Promising Hits, early Leads, and Optimized Leads at or near the IND enabling/de-risking stage are represented, along with innovative approaches for new natural product discovery. All programs target SARS-CoV-2 but also address other coronaviruses, flaviviruses and/or alphaviruses. MAVDA is robust, easily accommodates Developmental projects and new virus challenges, and it is an ideal environment for training the next generation of scientists for drug discovery and pandemic preparedness.