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

描述(由申请人提供)：由乙肝病毒(乙肝病毒)引起的急性和慢性肝脏感染是一个主要的全球公共卫生问题。全球有超过3.5亿慢性病毒携带者，其中包括美国的170万慢性携带者，他们受到慢性乙肝(CHB)的影响。除了人类的痛苦，经济成本也很高--在美国，每年花在与乙肝相关的住院治疗上的费用超过10亿美元。尽管可以通过接种疫苗来预防乙肝病毒感染，但已经注意到逃逸突变的出现，但人们担心疫苗将变得无效。因此，显然需要有效的抗病毒治疗。未来慢性乙型肝炎的治疗有望是两种或两种以上作用机制不同的直接作用的抗病毒药物的联合治疗。我们发现了一种具有新作用机制的小分子核酸杂化分子Sb40(S)。在过去几年中进行的广泛研究(部分得到了NIAID的UO1赠款的支持)导致了一种被指定为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作用。SB 44，(I)有多种作用机制，包括激活宿主靶标RIG-I，因此不会引起抗病毒耐药性，(Ii)不是HBVDNA合成的链终止子，因此不会有较低的线粒体毒性，(Ii)与其他抗乙肝病毒和抗丙型肝炎药物有协同作用，(Iv)对乙肝病毒耐药株有活性，以及(V)是干扰素的潜在替代品。临床前的概念验证已经得到证实。SB 44，(1)在细胞培养研究中以良好的选择性指数抑制乙肝病毒的复制，(2)对乙肝病毒和丙型肝炎病毒(HCV)有活性，(3)在乙肝转基因小鼠模型中显示出抗乙肝病毒的效果，(4)抑制细胞和体内的HBVDNA合成，并且与核苷酸类似物不同，不是DNA合成的链终止子，(4)刺激乙肝病毒转基因小鼠中eeeh蛋白的表达，因此SB 44具有潜在的广谱抗菌活性。SB 44具有良好的药用性能。SB 44是：(I)口服，在肝脏中有显著的处置，是乙肝和丙型肝炎的靶器官，(Ii)在最初的临床前研究中无毒，长期使用时毒性较小，以及(Iii)易于制造的小分子。鉴于其良好的临床前特征，SB 44作为一种新型的抗乙肝药物值得进一步开发。这个为期5年的项目将与学术界和工业界的杰出合作者组成的团队合作进行。到目前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。该项目中提议的研究将有助于将SB 44推进到IND和人类临床试验。

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.