PRECLINICAL DEVELOPMENT OF SB 44 AS AN ORALLY BIOAVAILABLE ANTI-HBV AGENT P Radhakrishnan
Spring Bank Technologies, Inc.city: Milford country: United States (us) Grant 1R01AI094469-01 from National Institute Of Allergy And Infectious Diseases Abstract: Acute and chronic liver infections caused by Hepatitis B virus (HBV) constitute a major worldwide public health problem. There are over 350 million chronic carriers of the virus worldwide, including 1.7 million chronic carriers in the US, who are affected by chronic hepatitis B (CHB). In addition to human suffering, the economic costs are large - more than $1 billion/year is spent for HBV-related hospitalizations in the US. Although HBV infection can be prevented by vaccination, emergence of escape mutants has been noted, there is concern that vaccines will become ineffective. Thus, there is a clear need for effective antiviral therapy. The future treatment of CHB is expected to be combination therapy with two or more direct-acting antiviral drugs with different mechanisms of action. We have discovered SB 40, as a first-in-class, small molecule nucleic acid hybrid (SMNH) with novel mechanism(s) of action. Extensive studies conducted over the past several years, (supported in part by a UO1 Grant from NIAID), have led to an oral prodrug designated as SB 44. SB 44 has direct antiviral and potential immunomodulatory properties. SB 44, (i) has multiple mechanisms of action including activation of RIG-I, a host target, hence less potential to elicit antiviral resistance, (ii) is not a chain terminator of HBV DNA synthesis; hence less potential for mitochondrial toxicity, (ii) is synergistic with other anti-HBV and anti-HCV drugs, (iv) is active against resistant strains of HBV, and (v) is a potential replacement for Interferon. Preclinical proof of concept has been demonstrated. SB 44, (i) inhibits HBV replication in cell culture studies with good selectivity index, (ii) is active against HBV and Hepatitis C virus (HCV), (iii) shows efficacy against HBV in the transgenic mouse model of HBV, (iv) suppresses HBV DNA synthesis in cells and in vivo, and unlike nucleoside and nucleotide analogs, is not a chain terminator of DNA synthesis, and (iv) stimulates expression of EEEH protein in HBV transgenic mice; hence SB 44 has potential for broad-spectrum antimicrobial activity. SB 44 has good pharmaceutical properties. SB 44 is (i) orally available with significant disposition in the liver, the target organ for HBV and HCV, (ii) non-toxic in initial preclinical studies and has less potential for toxicity upon longer term use, and (iii) a small molecule that is readily manufactured. Given its excellent preclinical profile, SB 44 merits further development as a novel anti-HBV agent. This 5-year project will be carried out in partnership with a team of outstanding collaborators in academia and industry. Studies conducted thus far have resulted in substantial know-how, hence the project goals and defined milestones are achievable. The studies proposed in the project will help advance SB 44 to IND and human clinical trials. Acute and chronic liver infections caused by HBV constitute a major worldwide public health problem with a significant unmet medical need. There are serious issues with the existing approved anti-HBV agents, including antiviral resistance and toxicity upon long-term use. The goal of this project is the advancement of SB 44 as a novel first-in-class orally bioavailable antiviral agent towards human clinical trials. 作为一种口服的抗乙肝病毒剂的临床前开发的SB 44
带够拉达克里希南
春季银行技术，Inc.city：米尔福德国家：美国（我们）
从国家过敏和传染病研究所的资助1R01AI094469-01
摘要：急性和慢性肝B型肝炎病毒（HBV）引起的感染，构成了一个重大的全球公共健康问题。有慢性携带者的病毒全世界超过350万，其中170万在美国的慢性携带者，慢性乙型肝炎（CHB）的影响。除了人类的痛苦，经济代价是巨大的 - 为在美国的HBV相关住院花费超过1亿元/年。虽然乙肝病毒感染可以通过接种疫苗预防，逃避突变的出现已经注意到，有关心的疫苗将成为无效。因此，显然需要有一个有效的抗病毒药物治疗。预计将两个或两个以上的不同的作用机制直接作用的抗病毒药物联合疗法治疗慢性乙型肝炎的未来。我们已经发现了40岁，1第一类，小分子核酸杂交与行动的新机制（S）（SMNH）SB。在过去几年中进行了广泛的研究，从NIAID的UO1格兰特（部分支持），导致一种口服前体药物指定为SB 44。保安局44具有直接抗病毒和潜在的免疫调节特性。 SB 44，（i）有多种机制，包括的RIG-I激活，主机目标的行动，因此不太可能引起病毒抗药性，（二）不链终止了HBV DNA的合成，因此线粒体毒性的潜力， （二）与其他抗乙肝病毒和抗-HCV药物的协同作用，（四）积极对HBV的耐药株，及（v）是干扰素的潜在替代品。临床证明概念已被证明。 SB 44，（一）抑制乙肝病毒复制，在细胞培养的研究，具有良好的选择性指数，（二）积极对乙型肝炎病毒和丙型肝炎病毒（HCV），（三）在HBV转基因小鼠模型的抗HBV的疗效，（四）在细胞和体内抑制乙型肝炎病毒DNA的合成，并与核苷和核苷酸类似物，是不是合成的DNA链终止，及（iv）刺激EEEH蛋白在HBV转基因小鼠表达，因此保安局44具有广谱的潜力抗菌活性。保安局44具有良好的医药属性。保安局44（一）口头显著处置，在肝，乙型肝炎病毒和丙型肝炎病毒的靶器官，（ii）在首次临床前研究无毒和少长期使用后的潜在毒性，及（iii）小分子，很容易制造。鉴于其优良的临床前的文件，保安局44案情的进一步发展，作为一种新型的抗乙肝病毒剂。这5年的项目将开展队在学术界和工业界的优秀合作者合作。研究进行因此，迄今已造成的大量技术诀窍，因此该项目的目标和定义的里程碑，是可以实现的。在该项目中提出的研究将有助于推进保安局44 IND和人体临床试验。由乙肝病毒感染引起的急性和慢性肝病，构成了一个重要的未满足的医疗需要全球主要的公共卫生问题。有严重的问题，与现有批准的抗乙肝病毒药物，包括抗病毒药物性和长期使用后的毒性。这个项目的目标是进步作为一个新的第一级口服的抗病毒药物对人体临床试验的SB 44 | 
发表于 2012-7-30 11:45
A digitally-colorized transmission electron micrograph (TEM) revealing the presence of hepatitis B virions. Courtesy: CDC.
