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Targeting ACE2 as a treatment for COVID

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Angiotensin-converting-enzyme 2 (ACE2) not only plays a key role in SARS-Cov-2’s entry into host cells - but also in the spread of infection to vital cells and organs.

Multiple studies have demonstrated that the ACE2 receptor is the primary cell surface binding site for COVID spike proteins. And, as ACE2 is also responsible for regulating inflammation and damage in many cell types and tissues – including the lungs, heart, kidneys and epithelial cells – it is now regarded as a promising target for therapeutic coronavirus treatments.  As one researcher puts it: “Blocking this binding event or reducing the accessibility of the virus to the ACE2 receptor represents an alternative strategy to prevent COVID-19.”

ACE2 is a vital element in the renin-angiotensin-aldosterone system (RAS) pathway, helping modulate the angiotensin II protein (ANGII) that increases blood pressure and inflammation and damages blood vessel linings and tissues. When SARS-Cov-2 binds to ACE2, it inhibits ACE2’s normal function of regulating ANGII signaling, which can cause an imbalance in the action of ACE1- and ACE2-dervied peptides. This in turn can increase inflammation and the death of cells in the alveoli, which are vital for bringing oxygen into the body. Unregulated by ACE2, more ANGII is available to drive lung injury in coronavirus patients – and also damage other tissues that express ACE2, including the heart, kidneys, liver, digestive tract and blood vessels.

For patients who are more susceptible to the damaging effects of ANGII – including those with age-related comorbidities such as hypertension, or compromised immunity - the decrease in ACE2 activity can set off a cascade of injurious effects. “Certain patients have severe inflammation and cytokine storm,” report Sriram and Insel, “with overwhelming immune activation that attacks the host” and can lead to respiratory failure and death.

The coronavirus pandemic has, however, stimulated more extensive research into ACE2, and prompted a number of potential new approaches for modulating the effect that SARS-Cov-2 has on ACE2 expression.

The first of these is using sACE2 – or soluble ACE2 – as a ‘decoy’ receptor capable of trapping the virus in order to prevent cellular engagement. Used in this manner, “sACE2 can bind its cognate ligand, the viral S protein, but is unable to reform a membrane-bound ACE2, which consequently blocks the mechanism of virus entry into the host cells."

Another potential strategy – inspired by vaccine design– is to develop a pseudoligand that has a high affinity to the receptor, such as a truncated form of the S protein that contains just its receptor binding domain, or an artificial receptor binding motif.

A third approach could be to design or identify small molecules to bind with ACE2 and trigger internalisation – lowering the ACE2 cell surface density to prevent binding and reduce viral entry. Inhibitors for clathrin could be used to block the endocytosis of the virus-ACE complex, taking advantage of the fact that ACE2 undergoes internalisation in a clathrin-dependent fashion.

Meanwhile, developing blocking antibodies against ACE2 on the basis of the epitopes on viral docking sites may also be a viable strategy for preventing infection, or a useful early treatment against Covid.

Another way to combat Covid that relates to ACE2 is to take advantage of its yin-yang relationship with its the protein ACE1 – which is also is also found in heart and lung tissues where ACE2 is present. Because ACE1 drives the production of ANGII and ACE2 reduces it, using an ACE1 inhibitor (ACEI) such as ramipril, lisinopril, and enalapril could reduce patients’ ANGII levels and the risks of increased blood pressure and tissue injury. As a group from Wuhan University led by Peng Zhang argues: “ACE2 expression is downregulated following SARS infection, resulting in excessive activation of RAS and exacerbated pneumonia progression. Therefore, administration of ACEI/ARB may, in turn, be beneficial by blocking ACE2 downregulation-induced hyperactivation of RAS and thereby preventing acute lung injury.” The Chinese group also published a study that showed inpatient use of ACEIs and angiotensin receptor blockers (ARBs) was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users. Among 1128 hospitalized patients with COVID-19 and coexisting hypertension in Hubei province from December 31, 2019, to February 20, 2020, 9.8 per cent who were not being treated with ACEIs/ARBs died, compared to 3.7 per cent of those who were taking them. Sriram and Insel also argue that ACEIs and AT receptor antagonists are well suited for repurposing against SARS-Cov-2, and that people who already take these drugs should continue doing so - given their “well-known safety profiles” and the possibility that they “may have therapeutic utility in treating patients who develop COVID-19,” particularly for the most vulnerable.

Although ACE2 provides a highly promising potential focus for the development of therapeutics against COVID-19, there remain a significant number of challenges and hurdles to overcome. For example, whether a truncated sACE2 fragment can be designed to work as a non-attenuating decoy receptor is yet to be validated. And, while the pseudoligand approach is potentially feasible, it also risks triggering detrimental intracellular signaling pathways and subcellular responses – as binding the SARS-Cov-2 RBD to ACE2, for example, has been shown to initiate an inflammatory response and cytokine production. The internalisation approach also appears to risk heightened inflammation and lung damage, as internalisation reduces enzymatically active ACE2 on the cell surface. The precise interaction of ACEI and ARB treatment and ACE2 also needs further study, as ACEI/ARB may increase ACE2 expression, thus promoting SARS-CoV-2 susceptibility and COVID-19 severity. Because of this uncertainty, researchers have called for more clinical trials, in vitro and in vivo animal research, and studies of epidemiological data from COVID-19 patients to improve our understanding of ACE2 as a potential therapeutic target for combating coronavirus.

TRC has more than 40 years’ experience working through some of the most complex synthetic pathways to deliver you high quality research chemicals. Our world-leading chemists engineer specific solutions for customers, and we have a wide range of modulators related to ACE2 receptors available to support your new and novel antiviral research.

See below for a selection of these, or get in touch to learn more.

 

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