Preclinical Development of SB 44 as an Orally Bioavailable Anti-HBV Agent

描述（由申请人提供）：B肝炎病毒（HBV）引起的急性和慢性肝脏感染构成了一个主要的全球公共卫生问题。全世界有超过3.5亿的慢性病毒携带者，包括美国的170万慢性携带者，他们受到慢性B肝炎（CH B）的影响。除了人类痛苦之外，经济成本也很大-在美国，每年用于HBV相关住院治疗的费用超过10亿美元。虽然HBV感染可以通过接种疫苗来预防，但已经注意到逃逸突变体的出现，人们担心疫苗会变得无效。因此，显然需要有效的抗病毒治疗。 CHB的未来治疗预计将是两种或更多种具有不同作用机制的直接作用的抗病毒药物的联合治疗。我们已经发现SB 40，作为具有新颖作用机制的一流的小分子核酸杂合体（SMNH）。在过去几年中进行的广泛研究（部分由NIAID的UO 1资助支持）导致了命名为SB 44的口服前药。SB 44具有直接的抗病毒和潜在的免疫调节特性。SB 44，（i）具有多种作用机制，包括激活RIG-I（宿主靶标），因此引发抗病毒抗性的可能性较小，（ii）不是HBV DNA合成的链终止剂，因此线粒体毒性的可能性较小，（ii）与其他抗HBV和抗HCV药物具有协同作用，（iv）对HBV的抗性菌株具有活性，以及（v）是干扰素的潜在替代品。已证明了概念的临床前验证。SB 44，（i）在细胞培养研究中以良好的选择性指数抑制HBV复制，（ii）对HBV和丙型肝炎病毒（HCV）有活性，（iii）在HBV的转基因小鼠模型中显示出抗HBV的功效，（iv）在细胞和体内抑制HBV DNA合成，并且与核苷和核苷酸类似物不同，不是DNA合成的链终止剂，和（iv）刺激HBV转基因小鼠中EEEH蛋白的表达;因此SB 44具有广谱抗微生物活性的潜力。SB 44具有良好的药学性质。SB 44是：（i）可口服，在肝脏（HBV和HCV的靶器官）中具有显著的分布，（ii）在初始临床前研究中无毒，并且在长期使用时具有较低的毒性潜力，和（iii）易于制造的小分子。鉴于其良好的临床前特征，SB 44值得进一步开发作为一种新型抗HBV药物。这个为期5年的项目将与学术界和工业界的优秀合作者团队合作开展。迄今为止进行的研究已经产生了大量的专门知识，因此项目目标和确定的里程碑是可以实现的。该项目中提出的研究将有助于将SB 44推进到IND和人体临床试验。

DESCRIPTION (provided by applicant): 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.