Angiotensin Peptides Potentiate SARS-CoV-2 Spike–AXL Binding

Study Background and Research Question

The renin–angiotensin–aldosterone system (RAAS) is central to cardiovascular regulation, with its constituent peptides, notably Angiotensin II and its derivatives, exerting diverse effects on vascular tone, aldosterone secretion, and fluid homeostasis. The emergence of SARS-CoV-2, the causative agent of COVID-19, has intensified interest in RAAS components due to the virus's reliance on angiotensin-converting enzyme 2 (ACE2) for host cell entry. However, alternative spike protein receptors such as AXL have come under scrutiny, especially in cells with low ACE2 expression. Against this backdrop, the referenced study (Oliveira et al., 2025) investigates whether endogenous angiotensin peptides modulate the interaction between the SARS-CoV-2 spike protein and its entry receptors, particularly AXL.

Key Innovation from the Reference Study

The principal innovation of this work is the identification that several endogenous angiotensin peptides—including Angiotensin III (sequence: Arg-Val-Tyr-Ile-His-Pro-Phe), a validated cardiovascular research peptide—markedly enhance the binding of the SARS-CoV-2 spike protein to the AXL receptor. This finding expands the functional landscape of RAAS peptides beyond traditional cardiovascular and neuroendocrine regulation, implicating them as modulators of viral entry pathways. The specificity of this effect for AXL, as opposed to ACE2 or neuropilin-1 (NRP1) in most cases, suggests a nuanced mechanism whereby peptide length, sequence, and terminal modifications critically determine spike–receptor interaction potency.

Methods and Experimental Design Insights

Oliveira et al. employed antibody-based binding assays to systematically evaluate the effect of various angiotensin peptides on spike protein–receptor interactions. Key peptide constructs included Angiotensin I (1–10), Angiotensin II (1–8), Angiotensin III (2–8), Angiotensin IV (3–8), and C-terminally or N-terminally truncated variants. Peptides were synthesized or obtained at high purity, and their activity was compared in parallel. The binding assays quantified the degree of spike–AXL, spike–ACE2, and spike–NRP1 interactions in the presence or absence of each peptide. Site-directed modifications (e.g., substituting or phosphorylating tyrosine residues) were also tested to dissect structure–activity relationships.

Notably, Angiotensin III—generated via N-terminal cleavage of Angiotensin II—was included as a representative N-terminally truncated RAAS peptide, relevant for both cardiovascular and emerging viral research workflows. The experimental approach enabled fine resolution of how specific peptide modifications and truncations influence viral receptor binding.

Core Findings and Why They Matter

The study found that Angiotensin II (1–8) significantly increases spike–AXL binding (two-fold), while Angiotensin I (1–10) exhibits no effect. Critically, N-terminal truncation to produce Angiotensin III (2–8) or Angiotensin IV (3–8) resulted in even more pronounced enhancement (up to a 2.7-fold increase with Angiotensin IV) in spike–AXL binding. C-terminal truncations, such as those yielding Angiotensin (1–7) or (1–6), retained similar but not superior activity compared to the full-length Angiotensin II. The effect was specific: these peptides notably potentiated spike–AXL interaction, with Angiotensin IV also enhancing spike binding to ACE2 and NRP1, but most others did not.

Further, biochemical manipulation of the tyrosine residue at position 4—either via substitution or phosphorylation—augmented spike–AXL binding, suggesting that this site is a key determinant of peptide-mediated modulation. These data imply that circulating or tissue-localized angiotensin peptides, particularly those resembling Angiotensin III and IV, may increase the susceptibility of certain cell types to SARS-CoV-2 by facilitating spike–AXL engagement. This mechanism is especially pertinent in respiratory cell populations with low ACE2 expression, where AXL serves as an alternative viral entry receptor.

Comparison with Existing Internal Articles

Several internal resources provide mechanistic context for Angiotensin III (see mechanistic insights; atomic structure and protocols). These articles emphasize Angiotensin III's established role as an aldosterone secretion inducer and pressor activity mediator, acting via both AT1 and AT2 receptor binding and contributing to RAAS homeostasis. The referenced study by Oliveira et al. builds on this foundation by demonstrating a novel, cross-domain function—enhancing SARS-CoV-2 spike–AXL binding—which was not previously addressed in cardiovascular or neuroendocrine-focused reviews. For researchers seeking to model both RAAS signaling and viral entry, the intersection highlighted here reflects a unique translational opportunity, as discussed in advanced workflow articles (targeted disease modeling).

Protocol Parameters

• Peptide concentration for binding assays: 1–10 μM is typically used based on literature protocols for angiotensin peptide–receptor binding studies (Oliveira et al., 2025).
• Solvent recommendations: Angiotensin III demonstrates high solubility (≥23.2 mg/mL in water, ≥43.8 mg/mL in ethanol, ≥93.1 mg/mL in DMSO); select solvent based on downstream assay compatibility (product information).
• Peptide handling: For optimal stability, store desiccated at –20°C; avoid long-term storage of solutions.
• Functional readouts: Use antibody-based binding assays to measure spike–receptor interactions; results may be confirmed with cell-based viral entry assays where available.

Limitations and Transferability

While the reference study provides compelling evidence that Angiotensin III and related peptides enhance spike–AXL binding in vitro, several limitations should be considered. The assays were primarily performed in cell-free or simplified cell-based systems, which may not fully capture the complexity of in vivo peptide concentrations, tissue distribution, or receptor expression patterns. The demonstration of enhanced viral entry or infectivity mediated by these peptides in relevant physiological or clinical models was outside the study’s scope. Furthermore, the precise structural determinants that govern the peptide–spike–AXL interface require additional biophysical elucidation. As such, while the findings are robust at the molecular interaction level, their translation to clinical or therapeutic contexts should be approached with caution.

Why this cross-domain matters, maturity, and limitations

The discovery that RAAS peptides such as Angiotensin III can influence viral receptor binding links cardiovascular peptide biology with infectious disease mechanisms. This cross-domain insight is significant because it suggests that individual variation in RAAS peptide profiles—due to genetics, comorbidities, or pharmacological intervention—could modulate host susceptibility to SARS-CoV-2 infection via alternative pathways like AXL. However, the translational maturity of this concept remains early: direct evidence for in vivo modulation of COVID-19 susceptibility or severity by endogenous Angiotensin III is not yet established. Future research will need to validate these molecular findings in animal and clinical settings to determine their impact on disease progression and therapeutic strategies.

Research Support Resources

Researchers aiming to replicate or extend these findings can utilize Angiotensin III (human, mouse) (SKU A1043), a high-purity AT1 and AT2 receptor ligand suitable for both receptor signaling and viral entry studies. For experimental planning, consult protocol recommendations above and review internal articles for additional workflow guidance. APExBIO provides batch-specific quality control documentation to support rigorous RAAS and cross-domain research workflows.