Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates.
ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates.
Biomolecules. 2024 Jun 27;14(7):764. doi: 10.3390/biom14070764.
ACE2, part of the angiotensin-converting enzyme family and the renin-angiotensin-aldosterone system (RAAS), plays vital roles in cardiovascular and renal functions. It is also the primary receptor for SARS-CoV-2, enabling its entry into cells. This project aimed to study ACE2's cellular trafficking and maturation to the cell surface and assess the impact of various drugs and compounds on these processes. We used cellular and biochemical analyses to evaluate these compounds as potential leads for COVID-19 therapeutics. Our screening assay focused on ACE2 maturation levels and subcellular localization with and without drug treatments. Results showed that ACE2 maturation is generally fast and robust, with certain drugs having a mild impact. Out of twenty-three tested compounds, eight significantly reduced ACE2 maturation levels, and three caused approximately 20% decreases. Screening trafficking inhibitors revealed significant effects from most molecular modulators of protein trafficking, mild effects from most proposed COVID-19 drugs, and no effects from statins. This study noted that manipulating ACE2 levels could be beneficial or harmful, depending on the context. Thus, using this approach to uncover leads for COVID-19 therapeutics requires a thorough understanding ACE2's biogenesis and biology.
ACE2 属于血管紧张素转换酶家族和肾素-血管紧张素-醛固酮系统 (RAAS) 的一部分，在心血管和肾脏功能中发挥着重要作用。它也是 SARS-CoV-2 的主要受体，使其能够进入细胞。本项目旨在研究 ACE2 的细胞内运输和成熟到细胞表面，并评估各种药物和化合物对这些过程的影响。我们使用细胞和生化分析来评估这些化合物作为 COVID-19 治疗的潜在先导物。我们的筛选测定集中在 ACE2 成熟水平和细胞内定位上，并进行了有无药物处理的比较。结果表明，ACE2 的成熟通常很快且很强，某些药物的影响很轻微。在测试的 23 种化合物中，有 8 种显著降低了 ACE2 的成熟水平，有 3 种导致了约 20%的降低。筛选运输抑制剂发现，大多数蛋白质运输的分子调节剂都有显著的影响，大多数拟议的 COVID-19 药物的影响较小，而他汀类药物没有影响。本研究指出，根据具体情况，操纵 ACE2 水平可能有益也可能有害。因此，使用这种方法来发现 COVID-19 治疗的先导物需要对 ACE2 的生物发生和生物学有深入的了解。
