Targeting deubiquitinaseas as a novel therapeutic strategy for the treatment of muco-obstructive lung disease

主要的肺部疾病，如慢性阻塞性肺疾病(COPD)和囊性纤维化(CF)，其特征是粘液的堆积，而这些粘液无法通过负责呼吸道健康的正常肺清除机制来清除。滞留的粘液阻碍气流，而炎症会导致反复感染，随着时间的推移，感染会损害肺组织，导致肺功能的毁灭性下降。慢性阻塞性肺病是全球第三大死亡原因，在英国每8个住院病例中就有1个是由COPD引起的。目前全球有9万人患有CF，对于今天出生的CF儿童来说，平均预期寿命为~47岁。除了受影响的生命数量外，治疗和管理这些疾病的相关成本也是巨大的(英国47亿英镑，美国426亿美元/年)。在这些肺部疾病中，确实需要新的和改进的药物。利用人体自身的防御过程来保持呼吸道更长时间的健康是一种令人信服的方法，这可能会带来广泛的好处。一组名为“DUBS”的酶已成为开发新药的一个有吸引力的新焦点(靶点)。越来越多的文献表明，DUBS参与慢性肺部疾病的许多方面，包括影响炎症的途径的调节和关键的肺清除机制。这种学术和产业合作的目的是通过配音靶向改善此类疾病患者的预后。为此，这项工作将侧重于确定哪些特定的DUB应该成为目标，从而能够开发(或重新调整现有的)DUB抑制剂。为了成功地做到这一点，我们将把Almac Discovery现有的配音药物发现知识和技术平台与借调人员提供的疾病区域和肺部模型专业知识结合起来。这一借调将为Almac Discovery开发以粘液阻塞为特征的主要呼吸道疾病的新药增加重大价值。在COVID之前，肺部疾病是英国第四大最昂贵的疾病。虽然该项目最初侧重于慢性阻塞性肺病和慢性阻塞性肺疾病，但预计拟议的项目将具有更广泛的相关性，可以提供急需的工具来帮助慢性阻塞性肺疾病后的肺恢复。尽管新冠肺炎感染的长期影响尚不清楚，但该疾病惊人的病例数量和严重程度引发了对潜在新的慢性呼吸道疾病患者群体的长期管理的严重关切。因此，有可能减少呼吸道炎症和改善肺清除机制的创新新方法，如DUB靶向，将在未来几年具有重要意义。这将给英国的生物医学科学部门带来直接好处。

Major lung diseases, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), are characterised by a build-up of mucus which cannot be removed by the normal lung clearance mechanisms responsible for airway health. The trapped mucus obstructs airflow whilst inflammation leads to recurring infections that, over time, damage lung tissue and result in a devastating decline in pulmonary function. COPD is the 3rd leading cause of death worldwide and is responsible for 1 in 8 hospital admissions in the UK. There are currently 90,000 people with CF worldwide, and for a child with CF born today the average life expectancy is ~47 years. In addition to the number of lives affected, the associated costs for treatment and management of these diseases are vast (UK £4.7Bn & USA $42.6Bn pa). Across these lung diseases there is a real need for new and improved medicines. The harnessing of the body's own defence processes to keep the airways healthier for longer is a compelling approach, which could have widespread benefits.A group of enzymes called "DUBs" have emerged as an attractive new focus (target) for the development of new medicines. An increasing body of literature indicates DUBs are involved in many aspects of chronic lung disease including the regulation of pathways that affect inflammation and critical lung clearance mechanisms. The aim of this academic-industrial collaboration is to improve outcomes for patients with such diseases via DUB targeting. To this end, the work will focus on identifying which specific DUBs should be targeted, subsequently enabling the development of (or the repurposing of existing) DUB inhibitors. To do this successfully we will combine the existing knowledge of DUB drug discovery and technology platforms of Almac Discovery, with the disease-area and lung model expertise provided by the secondee.This secondment will add significant value to Almac Discovery concerning the development of new drugs for major respiratory diseases characterised by mucus obstruction. Pre-COVID, lung disease was the 4th costliest disease across the UK. Although this project is focussed initially on COPD and CF, the proposed project is anticipated to have wider relevance which could provide much-needed tools to assist pulmonary recovery post-COVID. Although the longer-term impacts of COVID-19 infection remain unknown, the staggering number of cases and severity of the disease raise serious concerns in regard to the long-term management of a potentially new population of chronic respiratory disease patients. As such, innovative new approaches, such as DUB targeting, that have potential to reduce airway inflammation and improve lung clearance mechanisms will be of major importance in the coming years. This will have direct benefits to the Biomedical Science sector of the UK.