DINUCLEOTIDE ISOMER AS A NOVEL ANTIVIRAL

作为新型抗病毒药物的二核苷酸异构体

• 批准号: 7742863
• 负责人: RADHAKRISHNAN P IYER
• 金额: $ 30万
• 依托单位: SPRING BANK TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742863
• 关键词: Acute; Affect; Antiviral Agents; Area; Biological; Biological Availability; Biotechnology; Bone Marrow; Cardiovascular Diseases; Cell Line; Cessation of life; Characteristics; Chemistry; Chronic; Chronic Hepatitis C; Clinic; Clinical; Clinical Trials; Collaborations; Development; Dinucleoside Phosphates; Drug Formulations; Drug resistance; Europe; Evaluation; Future; Genotype; Guidelines; Hepatitis C; Hepatitis C virus; Housing; Human; In Vitro; Individual; Industry; Industry Collaborators; Inflammation; Interferons; Investigational New Drug Application; Investments; Isomerism; Kidney; Knowledge; Lead; Liver; Liver Cirrhosis; Malignant Neoplasms; Malignant neoplasm of liver; Marketing; Medical; Methodology; Methods; Mitochondria; National Institute of Allergy and Infectious Disease; Nucleotides; Oral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phase; Policies; Protease Inhibitor; Public Health; Ribavirin; S Phase; SCID Mice; Safety; Small Business Innovation Research Grant; Solutions; Technology; Therapeutic; Toxic effect; Transplant Recipients; United States Food and Drug Administration; Universities; Viral; Viral Load result; Work; analog; anti-hepatitis C; base; combat; cytotoxicity; design; drug biological activity; drug discovery; follow-up; improved; in vivo; indexing; interest; liver infection; liver transplantation; manufacturing process; mouse model; next generation; novel; nucleoside analog; nucleotide analog; phosphorothioate; pre-clinical; preclinical study; public health relevance; resistant strain; success; thiophosphate; viral resistance

DESCRIPTION (provided by applicant): Acute and chronic liver infections caused by Hepatitis C virus (HCV) constitute a major worldwide public health crisis with significant unmet medical need. About 180 million people are chronically infected with HCV worldwide with US (4.4 million) and Europe (12.8 million) representing approximately 10% of world's chronic HCV carriers. Worldwide, more than 1 to 2 million deaths occur every year due to liver cirrhosis and liver cancer. Significant numbers of liver transplant recipients have continued needs for effective anti-HCV therapy. The market for anti-HCV therapeutics is estimated to grow to US $5 billion by 2010. Despite decades of work and billions of dollars of investment, the treatment options for HCV remain extremely limited with inadequate therapeutic benefit - modest viral load reductions during treatment, viral rebound upon cessation of therapy, drug-induced toxicity, and emergence of drug resistance remain serious problems. Thus, new classes of drugs with different mechanisms of action that can be used in combination with other drugs are urgently needed for HCV therapy. There is great interest in the pharmaceutical and biotechnology industry to develop newer, safer antiviral drugs with novel mechanism of action that can be used in combination with other drugs, to combat viral resistance to drugs and viral rebound. Our team, at Spring Bank Technologies, Inc., (SBT) has recently discovered that SB 9200, a first-inclass, novel nucleotide analog, is a potent antiviral agent active against HCV, with high safety index. SB 9200 is synergistic with other anti-HCV agents such as nucleoside analogs, interferon, protease inhibitors, and ribavirin. SB 9200 represents potentially the next generation anti-HCV therapeutic. However, SB 9200 is a mixture of two isomeric forms - designated as Rp-SB 9200 and Sp-SB 9200 - resulting from the asymmetry of the inter-nucleotidic thiophosphate linkage. Given the overwhelming historical evidence for differences in biological activity of drug isomers, it is critically important that the active isomer of SB 9200 be identified and taken up for further development. The studies outlined in this two-year SBIR Phase1 application (NIAID Advanced Technology SBIR) will be carried through support from Academic and Industry Collaborators and are designed to select a single isomer of SB 9200 for further pre-clinical development that has: (a) enhanced antiviral potency, (b) high safety index, and (c) improved bioavailability by way of a novel formulation. The objectives of the current application are consistent with the USFDA's current guidelines and policy requirements for isomeric mixtures of drugs. Further continuing studies, in a follow-up Phase II SBIR application, could lead to an Investigational New Drug Application with USFDA for initiation of human clinical trials. In addition, the knowledge from SB 9200 isomer studies presented in this application will be of immense value as SBT's nucleotide-based drug discovery platform is applied to other therapeutic areas such as inflammation, cardiovascular diseases, and cancer. PUBLIC HEALTH RELEVANCE: Acute and chronic liver infections caused by Hepatitis C virus (HCV) constitute a major worldwide public health crisis affecting over 180 million people for which there is significant unmet medical need.1-3 The studies outlined in this two-year SBIR Phase1 application (NIAID Advanced Technology SBIR) are designed to select a lead candidate for further pre-clinical development as a first-in-class, next generation antiviral agent that has enhanced potency, high safety and improved bioavailability for the treatment of HCV infection. Further continuing studies, in Phase II SBIR application, could lead to an Investigational New Drug Application with USFDA and follow-up clinical trials.

描述（由申请方提供）：丙型肝炎病毒（HCV）引起的急性和慢性肝脏感染构成了一个重大的全球公共卫生危机，医疗需求显著未得到满足。全世界约有1.8亿人慢性感染HCV，美国（440万）和欧洲（1280万）约占世界慢性HCV携带者的10%。在世界范围内，每年有超过100万至200万人死于肝硬化和肝癌。大量肝移植受者持续需要有效的抗HCV治疗。据估计，到2010年，抗HCV治疗剂的市场将增长到50亿美元。 尽管数十年的工作和数十亿美元的投资，HCV的治疗选择仍然非常有限，治疗益处不足-治疗期间病毒载量的适度降低，停止治疗后的病毒反弹，药物诱导的毒性和耐药性的出现仍然是严重的问题。因此，HCV治疗迫切需要具有不同作用机制的新型药物，这些药物可以与其他药物联合使用。在制药和生物技术工业中，人们对开发具有新的作用机制的更新、更安全的抗病毒药物有很大的兴趣，这些药物可以与其他药物联合使用，以对抗病毒对药物的耐药性和病毒反弹。 我们在Spring Bank Technologies，Inc.的团队，(SBT)SB 9200是一种新型的核苷酸类似物，是一种有效的抗丙型肝炎病毒的抗病毒药物，具有很高的安全性。SB 9200与其他抗HCV药物如核苷类似物、干扰素、蛋白酶抑制剂和利巴韦林具有协同作用。SB 9200可能代表下一代抗HCV治疗剂。然而，SB 9200是两种异构体形式的混合物-命名为Rp-SB 9200和Sp-SB 9200 -由核苷酸间硫代磷酸酯键的不对称性产生。鉴于药物异构体生物活性差异的压倒性历史证据，确定SB 9200的活性异构体并进行进一步开发至关重要。这项为期两年的SBIR第一阶段申请（NIAID先进技术SBIR）中概述的研究将在学术和行业合作者的支持下进行，旨在选择SB 9200的单一异构体进行进一步的临床前开发，该异构体具有：（a）增强的抗病毒效力，（B）高安全指数，以及（c）通过新配方提高生物利用度。当前申请的目的与USFDA关于药物异构体混合物的现行指南和政策要求一致。在后续II期SBIR申请中，进一步的持续研究可能导致向USFDA提交研究性新药申请，以启动人体临床试验。此外，本申请中介绍的SB 9200异构体研究的知识将具有巨大的价值，因为SBT的基于核苷酸的药物发现平台将应用于其他治疗领域，如炎症，心血管疾病和癌症。公共卫生关系：由丙型肝炎病毒（HCV）引起的急性和慢性肝脏感染构成了一个重大的全球公共卫生危机，影响了超过1.8亿人，这些人的医疗需求显著未得到满足。1 -3（NIAID先进技术SBIR）旨在选择一个领先的候选人，作为一流的，新一代抗病毒剂，其具有增强的效力、高安全性和改善的生物利用度，用于治疗HCV感染。在II期SBIR申请中，进一步的持续研究可能导致向USFDA提交研究性新药申请和后续临床试验。