High Blood Pressure medication, G-protein coupled receptors and viruses
While it is not yet clear how bad (or possibly good) (1) these medications may be in the face of viral infection, what is clear is that continuing to better understand the complex signaling systems involved is needed. SARS-CoV-2 is not the first, nor will it be the last, virus where concerns about the effect of current HBP medications will be valid. Furthermore, seeking additional alternative therapies for high blood pressure should be a continued point of emphasis which can only be achieved with better understanding of the regulation of the players involved.
What is ACE2? How is it involved in virus infectivity?
Angiotensin converting enzyme 2 (ACE2) is attached to the outside of cells throughout the body but expression is best characterized in brain, heart, liver, lung, kidneys, intestines, and testes. Importantly, it regulates the levels of angiotensin II (which constricts blood vessels) by converting it to angiotensin (1-7) (which dilates blood vessels) in the local environments effectively lowering blood pressure. It also cleaves other peptides, including angiotensin I, with less well characterized effects.
As we know viruses must gain entry to cells in order employ cellular machinery to multiply and spread. Extensive work has been done to characterize the means by which different viruses are able to get into cells. Fang Li’s lab in Minnesota have performed extensive characterization of the interaction between the SARS coronavirus responsible for the outbreak in 2002 and human ACE2 (2). They provide strong evidence for the specific amino acid residues in the receptor binding domain (RBD) of the viral spike that are essential for association with ACE2. Based on sequence comparisons they conclude that SARS-CoV-2 will also employ ACE2 to enter cells (3). This conclusion is supported by a functional assessment which showed entry of viral seed particles when ACE2 was expressed on a kidney cell line (4).
Because of the evidence supporting ACE2 as a receptor that allows SARS-CoV-2 to enter cells scientists at MIT are contributing to a consortium that seeks to find a “decoy” receptor (5). The hope is to prevent illness by having the virus interact with an engineered protein rather than a cell-surface protein. To achieve this, they have initially been using machine-learning models that use what we know about how viruses interact with ACE2 to simulate the interaction between potential decoys and the virus. The hope is to find a decoy that binds to the virus but does not have many adverse side effects. Development is proceeding and they have now moved into testing interactions in the lab using AlphaScreen® and BMG LABTECH’s CLARIOstar®.
Why the concern over HBP medications?
Coexisting conditions including HBP have been noted for their association with Covid-19 patients. Furthermore, some data suggests that ACE2 expression is increased by some HBP medications, which could potentially increase susceptibility to the virus and aid the infection (6).
The goal of the most popular HBP medications is to decrease activation of the angiotensin II type I receptor (AT1R) and thus decrease the vascular contraction promoted by activation of AT1R. This can be achieved by decreasing the amount angiotensin II available to bind to and activate AT1R, this is the mechanism used by medications which act as ACE inhibitors to block conversion of angiotensin I to angiotensin II.
Alternatively, other popular treatments act as angiotensin-receptor blockers. By disrupting the interaction between angiotensin II and AT1R the activation of signaling and subsequent vasoconstriction is reduced.
A potential side-effect of these HBP treatments is an increase in free angiotensin I, for ACE inhibitors or angiotensin II for ARBs. Since both can be ACE2 substrates, a feedback loop to increase expression of ACE2 to clear angiotensin I or II can be envisioned. You can imagine that since it is quite well established that certain viruses can gain access to cells via ACE2 it would not be good to have more of it around. However, it is important to note that some reports show no association between the use of the medications and the level of ACE2 expression (7). Certainly, a possible link between HBP treatments and ACE2 expression in humans is something that needs be studied more carefully with appropriate documentation of age and other factors that will play a role in differences in ACE2 expression.
What can be done in the future?
In addition to better characterizing whether current acceptable HBP treatments increase ACE2 expression there is an unmet need to find alternatives that do not have similar effects. The sudden removal of HBP treatments will also be detrimental, so having alternatives available will be of vital importance.
Approaches to find replacements could include identification of compounds that more selectively effect the downstream signaling cascades with the desired outcome. There are many GPCR based assays readouts but use of biosensors is one approach that can be utilized to good effect, we have seen that Montana Molecular provides tools that can aid in this search for biased agonists. Using the CLARIOstar® they were able to simultaneously detect 2 signaling events and this data can be used to calculate the amount of bias for each agonist. This approach was directly applied to AT1R agonists to monitor signaling through G-protein and arrestin pathways in real-time.
The tools and approaches available to study G-protein coupled receptors (GPCR) like AT1R are extensive to say the least. Here are just a couple examples from recent years:
Receptor binding, signaling, trafficking as many aspects of GPCR function can and should be studied to gain a better understanding of what is happening in response to a potential treatment. This information can help provide a more unique treatment and provide viable options for complications both known and not yet known.
1) Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19 by M. Vaduganthan, et al.
2) Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory Syndrome Coronavirus by K. Wu, et al.
3) Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses by M. Letko, et al.
4) Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus by Y. Wan et al.
5) Supercomputers Help Researchers Speed Drug Discovery for Covid-19 by S. Caestellanos
6) Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors by R.N. Vuille-dit-Bille et al.
7) Elevated Plasma Angiotensin Converting Enzyme 2 Activity Is an Independent Predictor of Major Adverse Cardiac Events in Patients With Obstructive Coronary Artery Disease by J. Ramchand et al.