A single antiviral to treat multiple opportunistic infections

单一抗病毒药物可治疗多种机会性感染

• 批准号: 10157407
• 负责人: Stacy Remiszewski
• 金额: $ 90.11万
• 依托单位: EVRYS BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157407
• 关键词: 2019-nCoV; Address; Algorithms; Animal Model; Antiviral Agents; Award; BK Virus; Back; Biological Availability; COVID-19; COVID-19 pandemic; Cells; Clinical; Communicable Diseases; Coronavirus; Cytomegalovirus; DNA Viruses; Data; Development; Dimethyl Sulfoxide; Disease; Dose; Drug Controls; Drug resistance; Effectiveness; Emergency Situation; Enrollment; Enzymes; Exhibits; Formulation; Frankfurt-Marburg Syndrome Virus; Funding; Future; Genes; Growth; Harvest; Hepatitis B Virus; Human; Human Herpesvirus 4; Immunity; In Vitro; Incubated; Infection; Influenza A virus; Influenza B Virus; Junin virus; Knowledge; Lead; London; Lung; National Institute of Allergy and Infectious Disease; Opportunistic Infections; Oral; Parents; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Production; Property; Proteins; Quantitative Structure-Activity Relationship; RNA; RNA Viruses; Reporting; Research; Respiratory syncytial virus; Series; Sirtuins; Small Business Innovation Research Grant; Speed; System; Testing; Therapeutic; Transcript; Transplant Recipients; Transplantation; Viral; Virus; Virus Diseases; Virus Replication; Western Blotting; Zika Virus; base; beta Actin; candidate selection; college; human coronavirus; immunosuppressed; inhibitor/antagonist; interest; lead optimization; lead series; man; meetings; new therapeutic target; novel strategies; pandemic disease; parent grant; protein B; response; standard of care; therapeutic candidate; vaccine development

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.

响应有关有关紧急竞争修订的特殊关注通知的通知 SARS-COV-2和COVID-19（非AI-20-034）的研究，此处的提议专注于开发 SARS-COV-2治疗候选者具有宽光谱活性，对多个冠状病毒菌株。这是 作为紧急竞争修订（PA-20-135）提交给现有的Niaid SBIR II期奖 “一种治疗多种机会感染的抗病毒”（R44AI114079）。现有第二阶段奖项是基于 关于人类sirtuin-2蛋白（SIRT2）调节许多不同不同的复制和传播的发现 病毒。申请人EVRYS BIO，LLC开发了一系列> 550 SIRT2抑制剂，暴露了广泛的抑制剂 光谱抗病毒活性。现有奖项的出色进步已在确定 开发候选人准备索引（DC）。 DC选择的候选人显示广谱 针对人类巨细胞病毒（HCMV）的活性和其他机会剂，导致疾病 免疫抑制的移植患者。实际上，evrys sirt2抑制剂阻止了许多不同的生长 除HCMV外，病毒，包括DNA病毒（Epstein-Barr病毒，BK病毒，乙型肝炎病毒）和RNA 病毒（流感A和B，呼吸道合胞病毒，寨卡病毒，Junin病毒，Marburg病毒和冠状病毒）。 与本应用的特别相关性，EVRYS SIRT2抑制剂显示出抑制进度的产生 由人α-coronavirus HCOV-229E（EC50 = 1.6 µM）和β-核纳病毒HCOV-OC43（EC50 = 0.54 µm）。更详细地研究了OC43，其N和M RNA以及N蛋白的产生是 在人MRC-5细胞中动态抑制。该提案利用现有的资金和进度 SBIR II期奖项旨在识别和推进具有广谱抗病毒活性的发展候选人。 拟议的竞争修订特定的目的是专注于开发广泛的SARS-COV-2方面 光谱疗法：将测试SARS-COV-2活性以从9个SIRT2抑制剂中选择DC （针对β-核可纳病毒OC43的活动）已经满足了开发目标复合概况标准 包括广谱抗病毒效率和对药物开发的适用性。加快a 针对有需要的患者，选定的广谱DC（包括SARS-COV-2抗病毒）的治疗溶液 活动将通过IND促进研究来提出。同时，将获得备份DC。 evrys拥有 广泛表征了有关定量结构活性关系（QSAR）的铅序列 预测HCMV抗病毒活性并允许优化药物特性。算法 冠状病毒将进行重新培训，以选择针对冠状病毒效力和药物的优化的备份 用于治疗COVID-19的特性（例如，良好的肺分布）。延长父母赠款的原始目标 之所以可能，是因为EVRYS良好的SIRT2抑制剂系列表现出广泛的抗病毒活性， 包括抗核负病毒活性。