Function and therapeutic potential of cathepsin peptidases during Hepatitis E Virus infection (Cat-HEV)

戊型肝炎病毒（HEV）是一种长期被忽视的RNA病毒，是世界范围内人类急性病毒性肝炎的主要病原体。需要更好地了解病毒的生命周期，包括进入宿主细胞的机制，以确定新的治疗靶点。利用一种新型的强大的HEV细胞培养系统，我们最近观察到组织蛋白酶家族的半胱氨酸蛋白酶的抑制可以阻止HEV进入宿主细胞和orf2衣壳蛋白的加工。基于这些发现，我们的目标是进一步研究组织蛋白酶在HEV生命周期中的作用，并评估不同组织蛋白酶抑制剂的治疗潜力。阐明HEV进入容许细胞的决定因素有助于了解其宿主和组织的趋向性，并将扩大我们对HEV病毒与宿主相互作用的认识。此外，病毒进入代表了小分子拮抗剂的有效治疗靶点。总的来说，本项目旨在为HEV进入宿主细胞的分子机制提供新的见解，并可能进一步揭示新的药理策略。

The hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans worldwide. A better understanding of the viral life cycle, including the mechanisms of entry into host cells, is needed to identify novel therapeutic targets. Using a novel and robust HEV cell culture system, we recently observed that inhibition of cysteine proteases of the cathepsin family prevents HEV entry into the host cell and ORF2-capsid protein processing. Based on these findings, we aim to further examine the role of cathepsins during the life cycle of HEV and evaluate the therapeutic potential of different cathepsin inhibitors. Elucidating the determinants of HEV entry into permissive cells is instrumental to understand its host and tissue tropism, and will expand our knowledge of HEV virus-host interactions. Furthermore, viral entry represents a well-validated therapeutic target for small-molecule antagonists. Overall, this project aims to provide novel insights into the molecular mechanisms of HEV entry into host cells and may further reveal new pharmacological strategies.