ACE2 Inhibition as therapeutic candidate?

Question

Disclaimer: I am a scientist, but this is not my main field so sorry if I've not used the correct terminology at this busy time...

Since the coronavirus protein bonds with and gains entry to the cell by bonding to ACE2 receptor, does anyone happen to be currently working upon inhibition of the ACE2 receptor?

Obviously it's not straight forward just to use an inhibitor of some sort without accounting for side effects, but is this form of therapy a potentially practical avenue?

I anticipate that this relationship with ACE2 is why we get pneumonia with COVID19 since ACE2 is abundant in the lungs, heart and kidneys... And that perhaps it's why people with cardiovascular disease and problems have the highest mortality?

From my understanding, there would be potential cardiac and renal issues. Possibly the negative effects of inhibitors may be reduced or managed by IV infusion of angiotensin 1-7, or supporting drugs (I.e. a vasodilator) as ACE2 won't be able to work on converting angiotensin 2?

To anyone whom is working in this area specifically, what I am really asking is, is this a viable avenue to consider, as a management strategy to reduce spread of the virus in-vivo?

The infection route and effects make me wonder how many people that recover from COVID19 may unfortunately suffer later cardiological or renal issues due to damage in ACE2 expression within the lungs... And not just lung damage from the virus or resulting pneumonia. (I.e fibrosis of cardiac tissues, etc)

I've found this: https://www.hindawi.com/journals/ijpep/2012/256294/ Which seems to suggest that it has been studied to an extent in animals, but find limited information.

*** Note I'm talking about ACE2 inhibition not ACE inhibitors that are often used in heart failure

Answer 1

The problem appears to be that the SARS-CoV-2 virus binds to the ACE2 receptor and carries the receptor into the cell where the RNA of the virus is then released. Because the cell now lacks ACE2 surface receptors this leads to intracellular damage due to lack of inhibition of AT1-R in the Renin Angiotensin System.

The cells that are damaged in the lung are deep alveolar cells that make surfactant and this collapses the alveoli causing Acute Respiratory Distress Syndrome. interestingly lung infiltrates are seen early in the disease hence the use in China of CT chest scans for screening before rapid PCR became available. ACE2 are also found widely throughout the heart and gut the latter where it assists enzymes that are transporting amino acids. The ACE2 receptor bearing cells are found in cardiac tissue, lung, gut, macrophages etc and the main clinical effect of their loss of function is to cause cardiopulmonary damage.

if you were to create a drug that targeted the ACE2 receptor then you would be replicating the deleterious effect of the virus which inter alia blocks the protective effect of ACE2 on pulmonary and renal damage.

There's been some experimental work showing that a fully humanised soluble ACE2 receptor can bind to the virus and blocks entry into the ACE2 bearing cells. It works like a neutralising antibody to the virus.

This treatment is currently awaiting Chinese FDA approval for clinical trials.

Josef Penninger https://youtu.be/jAW6VBWTiAA