Hales Liam T, Mountford Simon J, Takawy Mina, Colledge Danni, Maher Belinda, Shortt Jake, Thompson Philip E, Greenall Sam A, Warner Nadia
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville 3052 Australia
Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty, Institute for Infection and Immunity Melbourne 3000 Australia
RSC Med Chem. 2025 Mar 28. doi: 10.1039/d5md00118h.
Hepatitis B virus (HBV) is a leading cause of liver cancer worldwide, with current treatment options unable to provide lasting efficacy against chronic infection. A key viral protein, HBV e antigen (HBeAg), plays an important role in suppressing the cellular and humoral immune response during infection and its loss is a precursor to clearance of chronic HBV infection. Its structural similarity to capsid forming HBV core protein antigen (HBcAg) makes it an intriguing, yet understudied target for pharmaceutical intervention. Recently, targeted protein degradation has been successfully applied against several viral proteins. This work investigates the targeting of HBeAg using heterobifunctional degraders derived from reported HBcAg ligands known to interact with HBeAg. Multiple compounds designed to recruit the VHL E3 ligase were found to be capable of reducing recombinant HBeAg protein levels in a HiBiT reporter assay system. Surprisingly, this decrease was found to be independent of VHL recruitment but driven by structural motifs of the VHL recruiting ligand, VH032. Virological assessment of these compounds against wildtype virus revealed an equipotent capability to reduce secreted HBeAg compared to the parental inhibitor, however increased efficacy was observed against an inhibitor resistant strain. Together, this work provides an initial description of the feasibility of converting HBV capsid-targeting ligands into degraders and provides evidence that such degraders may harbour improved activity against mutated forms of target which are resistant to parental compounds.
乙型肝炎病毒（HBV）是全球肝癌的主要病因，目前的治疗方案无法对慢性感染提供持久疗效。一种关键的病毒蛋白，即乙肝e抗原（HBeAg），在感染期间抑制细胞免疫和体液免疫反应中起重要作用，其消失是慢性HBV感染清除的先兆。它与形成衣壳的乙肝核心蛋白抗原（HBcAg）在结构上相似，这使其成为药物干预的一个有趣但研究不足的靶点。最近，靶向蛋白降解已成功应用于多种病毒蛋白。这项工作研究了使用源自已知与HBeAg相互作用的已报道HBcAg配体的异双功能降解剂对HBeAg的靶向作用。在HiBiT报告基因检测系统中，发现多种设计用于招募VHL E3连接酶的化合物能够降低重组HBeAg蛋白水平。令人惊讶的是，这种降低与VHL招募无关，而是由VHL招募配体VH032的结构基序驱动的。对这些化合物针对野生型病毒的病毒学评估显示，与亲本抑制剂相比，它们具有同等效力降低分泌型HBeAg的能力，然而，对一种抑制剂耐药菌株观察到了更高的疗效。总之，这项工作初步描述了将HBV衣壳靶向配体转化为降解剂的可行性，并提供了证据表明此类降解剂可能对亲本化合物耐药的靶点突变形式具有更好的活性。
