前药
炎症
肺
激活剂(遗传学)
医学
药品
免疫学
药理学
血管紧张素转化酶2
2019年冠状病毒病(COVID-19)
内科学
传染病(医学专业)
受体
疾病
作者
Peng Lü,Faith Leslie,Han Wang,Ajit Sodhi,Chang-Yong Choi,Andrew Pekosz,Honggang Cui,Hongpeng Jia
标识
DOI:10.1016/j.jconrel.2023.10.025
摘要
Exacerbated inflammatory responses can be detrimental and pose fatal threats to the host, as exemplified by the global impact of the COVID-19 pandemic, resulting in millions of fatalities. Developing novel drugs to combat the damaging effects of inflammation is essential for both preventive measures and therapeutic interventions. Accumulating evidence suggests that Angiotensin Converting Enzyme 2 (ACE2) possesses the ability to optimize inflammatory responses. However, the clinical applicability of this potential is limited due to the lack of dependable ACE2 activators. In this study, we conducted a screening of an FDA-approved drug library and successfully identified a novel ACE2 activator, termed H4. The activator demonstrated the capability to mitigate lung inflammation caused by bacterial lung infections, effectively modulating neutrophil infiltration. Importantly, to improve the clinical applicability of the poorly water-soluble H4, we developed a prodrug variant with significantly enhanced water solubility while maintaining a similar level of efficacy as H4 in attenuating inflammatory responses in the lungs of mice exposed to bacterial infections. This finding highlights the potential of formulated H4 as a promising candidate for the treatment and prevention of inflammatory diseases, including lung-related conditions.
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