A single antiviral to treat multiple opportunistic infections

在回应有关提供紧急竞争修订的特别关注通知时， SARS-CoV-2和新冠肺炎(非-AI-20-034)的研究，这里的建议集中在发展上 对多种冠状病毒株具有广谱活性的SARS-CoV-2候选治疗药物。它是 作为紧急竞争修订(PA-20-135)提交给现有的NIAID SBIR第二阶段奖，名为 《单一抗病毒药物治疗多种机会性感染》(R44AI114079)。现有的第二阶段奖励基于 人类sirtuin-2蛋白(SIRT2)调节多种不同病毒的复制和传播 病毒。申请人Evrys Bio，LLC已经开发出一系列领先的&gt；550 SIRT2抑制剂，显示出广泛的- 光谱抗病毒活性。现有奖项在确定一项 开发候选人已准备好支持Ind-Enablement(DC)。DC选举候选人表现出广泛性 抗人类巨细胞病毒(HCMV)和其他致病机会性因素的活性 免疫抑制的移植患者。事实上，Evrys SIRT2抑制剂阻止了许多不同类型的肿瘤生长 除巨细胞病毒外的病毒，包括DNA病毒(爱泼斯坦-巴尔病毒、BK病毒、乙肝病毒)和RNA 病毒(甲型和乙型流感、呼吸道合胞病毒、寨卡病毒、朱宁病毒、马尔堡病毒和冠状病毒)。 与此应用特别相关的是，Evrys SIRT2抑制剂被证明抑制子代的产生 人类甲型冠状病毒HCoV-229E(EC50=1.6微米)和乙型冠状病毒HCoV-OC43(EC50=0.54) µM)。对OC43进行了更详细的研究，并对其N和M RNA以及N蛋白的产生进行了研究 在人MRC-5细胞中被显著抑制。这项建议平衡了现有的资金和进展 SBIR第二阶段奖，以确定和推进具有广谱抗病毒活性的开发候选药物。 建议竞争性修订的具体目标集中在发展SARS-CoV-2方面的广泛- 光谱治疗：将测试SARS-CoV-2活性，从9种SIRT2抑制剂中选择DC (对贝塔冠状病毒OC43有效)已经满足开发的目标化合物配置文件标准 包括广谱抗病毒的有效性和药物开发的适宜性。为了加快 针对有需要的患者治疗方案，选用广谱DC(包括SARS-CoV-2抗病毒药物 活动)将通过支持IND的研究而得到推进。同时，将获得备用DC。埃弗里斯有 根据定量结构活性关系(QSAR)对铅系列进行了广泛表征 预测巨细胞病毒的抗病毒活性，并允许优化药物性质。算法 将针对冠状病毒进行再培训，以选择针对冠状病毒效力和药物进行优化的后备方案 治疗新冠肺炎的特性(例如，良好的肺分布)。延长家长奖助金的最初目标 之所以可能，是因为Evrys的SIRT2抑制剂系列具有广谱的抗病毒活性， 包括抗冠状病毒活性。

In response to the Notice of Special Interest regarding the Availability of Emergency Competitive Revisions for research on SARS-CoV-2 and COVID-19 (NOT-AI-20-034), the proposal herein is focused on the development of SARS-CoV-2 therapeutic candidates with broad-spectrum activity against multiple coronavirus strains. It is submitted as an Emergency Competitive Revision (PA-20-135) to an existing NIAID SBIR Phase II award titled “A single antiviral to treat multiple opportunistic infections” (R44AI114079). The existing Phase II award is based on the discovery that human sirtuin-2 protein (SIRT2) modulates the replication and spread of many different viruses. The applicant, Evrys Bio, LLC, has developed a lead series of >550 SIRT2 inhibitors that exhibit broad- spectrum antiviral activity. Excellent progress for the existing award has been made in the identification of a Development Candidate ready for IND-enablement (DC). The candidates for DC selection show broad-spectrum activity against human cytomegalovirus (HCMV) and other opportunistic agents causing disease in immunosuppressed transplant patients. Indeed, Evrys SIRT2 inhibitors block the growth of many different viruses in addition to HCMV, including DNA viruses (Epstein-Barr virus, BK virus, Hepatitis B virus) and RNA viruses (influenza A and B, respiratory syncytial virus, Zika virus, Junin virus, Marburg virus and coronaviruses). Of special relevance to this application, an Evrys SIRT2 inhibitor was shown to inhibit the production of progeny by the human alpha-coronavirus HCoV-229E (EC50 = 1.6 µM) and beta-coronavirus HCoV-OC43 (EC50 = 0.54 µM). OC43 was studied in greater detail, and production of its N and M RNA as well as N protein were dramatically inhibited in human MRC-5 cells. This proposal leverages the funding and progress of the existing SBIR Phase II award to identify and advance a Development Candidate with broad-spectrum antiviral activity. Proposed competitive revision Specific Aims focus on development of SARS-CoV-2 aspects of the broad- spectrum therapeutic: SARS-CoV-2 activity will be tested to select the DC from among nine SIRT2 inhibitors (active against beta-coronavirus OC43) already satisfying Target Compound Profile criteria for development including broad-spectrum antiviral effectiveness and suitability for pharmaceutical development. To speed a therapeutic solution to patients in need, the selected broad-spectrum DC (including SARS-CoV-2 antiviral activity) will be advanced through IND enabling studies. In parallel, a back-up DC will be obtained. Evrys has extensively characterized the lead series with respect to quantitative structure activity relationships (QSAR) predicting HCMV antiviral activity and allowing for optimization of pharmaceutical properties. The algorithms will be retrained for coronavirus to select a back-up optimized for coronavirus potency and pharmaceutical properties (e.g., good lung distribution) for treatment of COVID-19. Extension of the parent grant's original aims is possible because Evrys' well-characterized SIRT2 inhibitor series exhibits broad-spectrum antiviral activity, including anti-coronavirus activity.