ACE2 – locking the door against coronaviruses?

Over a year after its emergence, COVID-19 continues to remain a global plague. Even with the development of vaccines, we see the pandemic caused by SARS-CoV-2 to stay with us for a while. With the identification of major new virus variants of concern hailing from the United Kingdom, South Africa, and Brazil with improved binding to human cells we see that COVID-19 is a very complex disease.

Viruses such as coronavirus rely completely on host cells for replication and survival – without them, the virus will eventually disintegrate. This reliance on the host is something that can be exploited therapeutically, leading to effective treatments that work regardless of new strains.

ACE2 – the key to coronavirus survival

The coronavirus SARS-CoV-2 infects patients via cells in their lungs through the cells’ own angiotensin converting enzyme (ACE2) which acts as the lock to open the door to the cells. The spike protein on the surface of the coronavirus works like a key, fitting into the lock to allow the virus to enter.1-6

It is therefore in the interests of the virus to develop the key that best fits this lock, and this can be achieved through evolution. Darwin’s concept of ‘survival of the fittest’ can be applied here, describing how only the most well adapted organisms are able to survive. This selection pressure has led to multiple mutations in the SARS-CoV-2 spike protein, making it bind more tightly to the ACE2 receptor and therefore enter cells more easily. The UK and South African variants, which have been identified as a particular cause for concern, among others both contain this form of mutation.7

Evading the immune response

As well as binding more tightly to cells, viruses often evolve to avoid recognition by the host’s immune system. This is important because, once the immune system recognises a virus, it will produce an antibody response and kill infected cells, preventing the virus from spreading. This is how the body recognises the spike protein ‘key’ and removes it before it can unlock the door to the cell. Recent mutations of concern seen in SARS-CoV-2 not only show the virus making the key that best fits the lock but also change its overall appearance to avoid recognition by our immune defence.

Mutations which stop the immune system from recognising the spike protein are important in terms of herd immunity. This concept relies on an immune response being built up – either through natural infection or vaccination – with immune memory preventing viral infection in the future. If a coronavirus evolves to look different to the one which caused the previous infection, then the body may not be able to get rid of it efficiently.

A recent study from the University of Oxford has shown that antibodies produced by the immune system in response to a novel mRNA-based vaccine have reduced efficacy at combatting the new mutated variants.8 The fact that this has happened in the early stages of the vaccine rollout has huge implications for the rate of transmission in coming months, highlighting the need for therapeutics.

Decoy ACE2 – the future of therapies for COVID19 ?

One way in which scientists are trying to combat the evasion of the immune response is by tricking the virus into attaching to a decoy ACE2 that is a soluble version of ACE2 no longer bound to cells but rather patrolling outside the cells and waiting to “catch” and destroy the coronavirus (Fig. 1).

Fig. 1 Coronavirus and its cellular receptor ACE2; APN01 drug candidate, a recombinant human soluble version of ACE2.

This is like providing various dysfunctional locks which do not open doors to cells, thus trapping the spike protein keys. The elegance of this solution is in the fact that the virus relies on ACE2 to get into the cells and can therefore never evolve to bind less well to ACE2 – thus it cannot avoid the decoy.

ACE2 is a particularly good target for this sort of therapeutic strategy, as it can be easily altered by recombinant techniques to allow it to move freely in blood. This can be done without changing its key structure, meaning the virus will still bind to the molecule and the body will not recognise the drug as a foreign object. This mimicking of a natural receptor is also thought to be capable of restoring some of the lost function when the immune system destroys virally infected cells.

As well as being the entry point of SARS-CoV-2, ACE2 is also a key enzyme involved in the regulation of blood pressure, clotting and kidney function, and other important processes in the human body.1-6

Additionally, high blood pressure is one of the main predisposing factors to development of severe disease, indicating the enzyme may be important in more ways than we had at first thought.

The potential of ACE2 therapeutics is clear not only from pre-clinical data, but also for emergence in clinical practice. A recent case study in the Lancet showed effective treatment of a 45-year-old patient with severe COVID-19 using APN01 drug candidate.9 The recovery of this patient represents an important breakthrough in treatment strategies for COVID-19 and the emergence of a new class of therapeutics. The therapy with APN01 was well tolerated without obvious drug-related side-effects, the virus disappeared rapidly from the serum and later also from the nasal cavity and lung. Moreover, the treatment did not interfere with the generation of neutralizing antibodies. A rapid decline of the cytokine storm following APN01 infusion as well as a positive influence on the RAS system were shown. APN01 has also been tested in a phase 2 clinical trial in 178 COVID-19 patients conforming these positive results. Further clinical trials are underway.

1 Oudit G. et al. Trends Cardiovasc Med. 2003 Apr; 13(3):93-101.

2 Kuba K. et al. Nature Medicine. 2005; 11:875–879.

3 Imai Y. et al. Nature. 2005 Jul 7; 436(7047):112-6.

4 Oudit G. et al. Eur J Clin Invest. 2009 Jul; 39(7):618-25.

5 Monteil V. et al. Cell. 2020 May 14; 181(4):905-913.

6 Zhang H. et al. Intensive Care Med. 2020 Apr; 46(4):586-590.

7 Yi C. et al., Cell Mol Immunol. 2020 Jun;17(6):621-630.

8 Donal T et al. 09 February 2021 available at Research Square, https://www.researchsquare.com/article/rs-226857/v1>/a>

9 Zoufaly A, Penninger J et al., The Lancet Respiratory Medicine. 2020, 8(11):1154-1158.