Angiotensin-converting enzyme 2 (ACE2)

Overview

Angiotensin I converting enzyme 2 (ACE2) is a membrane-associated protein best known as a key regulator of the renin–angiotensin system and as the cellular receptor used by SARS-CoV-2 for entry into host cells. In normal physiology, ACE2 counterbalances angiotensin-converting enzyme activity by processing angiotensin Peptides, thereby contributing to vascular, renal, and inflammatory homeostasis. Because of this dual role in human biology and viral attachment, ACE2 has become an important target in cardiovascular, renal, and infectious disease research.

Structurally, ACE2 is of major interest because its extracellular domain directly engages the receptor-binding domain of the SARS-CoV-2 spike protein. Variants and mutations in the viral spike can alter this interaction, affecting infectivity and immune escape. ACE2 is also studied in disease-associated expression analyses, including kidney disorders, where altered ACE2 expression may reflect changes in tissue injury, inflammation, or immune infiltration.

Recent Publications Summary

Recent studies have leveraged Angiotensin-converting enzyme 2 (ACE2) as a critical intervention target across multiple therapeutic and diagnostic strategies. As the primary receptor for SARS-CoV-2 entry, ACE2 has been exploited in Receptor-Drug Conjugate (RDC) approaches, wherein therapeutic peptide nucleic acids (PNAs) targeting viral genomes have been covalently linked to ACE2-Fc fusion proteins 42545604Aug. These ACE2-PNA conjugates retained the extracellular neutralization activity of soluble ACE2 while selectively concentrating within virus-infected cells via virus-mediated endocytosis, demonstrating superior inhibitory efficacy against multiple SARS-CoV-2 variants relative to ACE2-Fc alone 42545604Aug. Cell-based gene therapy approaches have similarly targeted ACE2, with mesenchymal stromal cells electroporated to deliver ACE2-targeted interleukin-27 (IL-27), showing promise in vitro for preventing SARS-CoV-2 entry 42435246Jul.

Computational and chemical screening strategies have centered on disrupting the spike protein-ACE2 interaction through complementary mechanisms. Machine learning models trained on public datasets predicted binding of emerging SARS-CoV-2 receptor-binding domain (RBD) variants to human ACE2, achieving high accuracy through iterative refinement with experimental data from over 200 variants, with models demonstrating correlation coefficients up to 0.79 for antibody binding 42308256Jun. Small-molecule virtual screening identified inhibitors of the spike-ACE2 interface, with compounds C3 and C4 effectively blocking spike-ACE2 binding (IC50 = 0.03 and 10.4 μM, respectively) with minimal cytotoxicity 42174382May. Deep mutational learning approaches further characterized how receptor-binding domain mutations affect both ACE2 binding affinity and antibody escape, revealing individualized escape profiles across serum samples from COVID-19-vaccinated individuals while binding signatures remained more conserved 42030951Apr. Novel biomimic strategies engineered hydrogel polymer nanoparticles with aromatic amino acid moieties that compete with ACE2 for spike RBD binding with efficacy comparable to antibodies, enabling development of biomolecule-free lateral flow immunoassays for SARS-CoV-2 antigen detection 41478048Jan.

Beyond SARS-CoV-2 research, ACE2 has emerged as a significant biomarker in diverse disease contexts. In pregnancy complications, mid-pregnancy circulating ACE2 levels were among the most frequently altered cardiovascular proteins in women with subsequent term preeclampsia compared to those with uncomplicated pregnancies, potentially reflecting distinct pathophysiological mechanisms from small-for-gestational age births 42409921Jul. Bioinformatics analysis identified ACE2 as one of six pyroptosis-related hub genes with high diagnostic accuracy (AUC > 0.9) for discriminating IgA nephropathy from normal kidney samples, with elevated ACE2 expression validated in both tissue and serum samples 42135973May.

What Changes, What Holds

1. ACE2 is being repurposed as a delivery and targeting scaffold rather than only a viral receptor
NEW DIRECTION ACE2’s established role as the SARS-CoV-2 entry receptor is being extended into a therapeutic platform: soluble ACE2-based constructs can carry antiviral cargo into infected cells and still retain neutralization activity. That does not displace the baseline biology, but it adds a new use case that depends on the same receptor-mediated uptake the virus exploits. The cell-therapy result points in the same direction, though it remains early and preclinical. 42545604Aug42435246Jul

2. Disrupting the spike-ACE2 interface is becoming a broader design problem, not just a structural observation
METHOD These studies mainly sharpen how ACE2 is studied and targeted: computational prediction, mutational mapping, virtual screening, and biomimetic assay design all treat the spike-ACE2 interaction as an engineering surface. The baseline already recognizes this interface as central to entry and variant effects, and these papers reinforce that view while improving how binding changes are modeled and intercepted. The biomimetic assay work also shows ACE2 competition can be mimicked without the protein itself. 42308256Jun42174382May

3. ACE2 is emerging as a disease biomarker beyond kidney injury and infection
NEW DIRECTION Circulating and tissue ACE2 signals are being linked to pregnancy complications and IgA nephropathy, which broadens the baseline account from vascular, renal, and inflammatory homeostasis plus disease-expression analyses in kidney disorders. The IgA nephropathy result fits the existing renal-expression theme, but the pregnancy finding adds a new clinical context not covered by the overview. Both are associative and need validation before they can be treated as mechanistic or actionable markers. 42409921Jul42135973May

Overview update candidates: ACE2-based antiviral delivery platforms; improved modeling and screening of spike-ACE2 binding; biomimetic ACE2-competitive detection platforms; ACE2 as a biomarker in preeclampsia and IgA nephropathy.