The Evaluation of Drugs as Potential Modulators of the Trafficking and Maturation of ACE2, the SARS-CoV-2 Receptor

Abstract

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.