Development of a novel drug candidate that inhibits hepatitis B virus covalently

描述（由申请人提供）：拟议的项目旨在开发一种针对慢性乙型肝炎的新型治疗干预措施，慢性乙型肝炎目前仍然是世界范围内的一个重大公共卫生挑战。我们将探索一组新发现的化合物的发展，这些化合物可以抑制乙型肝炎病毒（HBV）共价闭合环（ccc） DNA的形成，这是目前可用的抗病毒药物所不能靶向的。HBV cccDNA在病毒感染的建立和持续中起着核心作用，是当前抗病毒治疗失败和停止治疗后病毒反弹的基础。因此，消除cccDNA是治疗HBV感染的最终目标。通过使用创新的基于细胞的cccDNA高通量测定技术筛选80,300个小分子文库，我们发现两种结构相关的双取代磺酰胺（DSS）通过干扰HBV基因组放松环（rc） DNA （cccDNA的中间前体）的去蛋白化而显著抑制cccDNA的形成。为了确定研究新药（IND）是否合理，我们计划优化这些化合物，评估它们在体外对抗耐药感染和与现有药物联合使用的效用，确定它们的体内特性和功效，并进一步研究它们的作用机制。我们的目标的成功完成将产生至少一个新的导致高级临床前研究。

DESCRIPTION (provided by applicant): The proposed project aims at developing a novel therapeutic intervention against chronic hepatitis B, which currently remains a significant public health challenge worldwide. We will explore the development of a group of newly identified compounds that inhibit the formation of hepatitis B virus (HBV) covalently closed circular (ccc) DNA, which is not targeted by current available antiviral medications. HBV cccDNA plays a central role in viral infection establishment and persistence, and is the basis for the failure of current antiviral treatments and virus rebound after the cessation of therapy. Therefore the elimination of cccDNA is the ultimate goal in curing HBV infection. Through our efforts to screen an 80,300 small molecule library using an innovative cell-based cccDNA high throughput assay, two structurally related disubstituted-sulfonamides (DSS) were discovered that have dramatic inhibition of cccDNA formation by interfering with the deproteinization of HBV genomic relaxed circular (rc) DNA, which serves as the intermediate precursor for cccDNA. To determine whether Investigational New Drug (IND)-enabling studies are justified, we plan to optimize these compounds, assess their utility against drug resistant infections and in combination with existing drugs in vitro, determine their in vivo characteristics and efficacy, and further study their mechanism of action. Successful completion of our goals will produce at least one new lead to advanced preclinical studies.