Abstract

A new coronavirus, referred to as SARS-CoV-2, is responsible for the recent outbreak of severe respiratory disease. This outbreak first detected in Wuhan, China in December 2019, has spread to other regions of China and to 25 other countries as of January, 2020. It has been known since the 2003 SARS epidemic that the receptor critical for SARS-CoV entry into host cells is the angiotensin-converting enzyme 2 (ACE2). The S1 domain of the spike protein of SARS-CoV attaches the virus to its cellular receptor ACE2 on the host cells. We thought that it is timely to explain the connection between the SARS-CoV, SARS-CoV-2, ACE2 and the rationale for soluble ACE2 as a potential therapy.

The angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase best known for cleaving several peptides within the renin–angiotensin system and other substrates, such as apelin. This enzyme is barely present in the circulation, but widely expressed in organs, such as the kidneys and the gastrointestinal tract, with relatively low level of expression in lungs [1]. Expression of ACE2 has been reported in type 2 pneumocytes [2]. Of potential interest, RNA expression of ACE2 in lung AT2 cells was higher in one Asian donor as compared with white and African American donors [3].

Functionally, there are two forms of ACE2. The full-length ACE2 contains a structural transmembrane domain, which anchors its extracellular domain to the plasma membrane. The extracellular domain has been demonstrated as a receptor for the spike (S) protein of SARS-CoV [4], and recently, for the SARS-CoV-2 [5]. The novel coronavirus is evolutionary related to Bat-SARS, which likewise uses membrane-bound ACE2 as the receptor [6]. The soluble form of ACE2 lacks the membrane anchor and circulates in small amounts in the blood [7]. We propose that this soluble form may act as a competitive interceptor of SARS-CoV and other coronaviruses by preventing binding of the viral particle to the surface-bound, full-length ACE2. Indeed, in vitro studies showed that SARS-CoV replication was blocked by a soluble form of ACE2 in the monkey kidney cell line, Vero-E6 [8,9]. Moreover, ACE2 fused to the Fc portion of immunoglobulin has just been reported to neutralize SARS-CoV-2 in vitro [10] and the SARS-CoV-2 binds ACE2 with higher affinity than SARS-CoV [11]. In this context, provision of soluble recombinant human ACE2 protein could actually be beneficial as a novel biologic therapeutic to combat or limit infection progression caused by coronaviruses that utilize ACE2 as a receptor (Figure 1).

Schematic of coronavirus (CoV) spike protein (S) binding to the surface receptor which is the full-length ACE2

Figure 1
Schematic of coronavirus (CoV) spike protein (S) binding to the surface receptor which is the full-length ACE2

Soluble ACE2 administration may intercept the coronavirus. (Drawn by Nicole Inniss, Ph.D).

Figure 1
Schematic of coronavirus (CoV) spike protein (S) binding to the surface receptor which is the full-length ACE2

Soluble ACE2 administration may intercept the coronavirus. (Drawn by Nicole Inniss, Ph.D).

Soluble recombinant ACE2 protein has therapeutic potential for a vast array of therapeutic indications [12] and novel shorter ACE2 variants are being tested in mouse studies for treatment of kidney diseases [13]. If given in its soluble form as an appropriate recombinant ACE2 protein, a new tool may be at hand to combat the spread of coronavirus in susceptible individuals by limiting coronavirus attachment to the cell membranes, cell entry, and replication. To our knowledge, studies in animals or humans testing the therapeutic potential of soluble recombinant ACE2 proteins are not yet available. The potentially beneficial effect (or not) of soluble recombinant ACE2 proteins to attenuate coronavirus infection should be urgently tested. Mouse models that carry the human version of ACE2 with the mouse version deleted should greatly facilitate research in this rapidly emerging field.

Competing Interests

D. Batlle and J. Wysocki: co-inventors Patent: ‘Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2’; and have also submitted a patent on the potential use of novel ace2 proteins for coronavirus infection D. Batlle: Founder of ‘Angiotensin Therapeutics’.

Funding

The CSGID is funded by NIAID, NIH, HHS [contract number HHSN272201700060C]. D.B. is currently funded by NIDDK [grant number RO1DK104785].

Abbreviation

     
  • ACE2

    angiotensin-converting enzyme 2

References

References
1.
Serfozo
P.
,
Wysocki
J.
,
Gulua
G.
,
Schulze
A.
,
Ye
M.
,
Liu
P.
et al.
(
2020
)
Ang ii (angiotensin ii) conversion to angiotensin-(1-7) in the circulation is pop (prolyloligopeptidase)-dependent and ace2 (angiotensin-converting enzyme 2)-independent
.
Hypertension
75
,
173
182
[PubMed]
2.
Hamming
I.
,
Timens
W.
,
Bulthuis
M.L.
,
Lely
A.T.
,
Navis
G.
and
van Goor
H.
(
2004
)
Tissue distribution of ace2 protein, the functional receptor for sars coronavirus. A first step in understanding sars pathogenesis
.
J. Pathol.
203
,
631
637
[PubMed]
3.
Zhao
Y.
,
Zhao
Z.
,
Wang
Y.
,
Zhou
Y.
,
Ma
Y.
and
Zuo
W.
(
2020
)
Single-cell rna expression profiling of ace2, the putative receptor of wuhan 2019-ncov
.
bioRxiv
,
4.
Du
L.
,
He
Y.
,
Zhou
Y.
,
Liu
S.
,
Zheng
B.J.
and
Jiang
S.
(
2009
)
The spike protein of sars-cov–a target for vaccine and therapeutic development
.
Nat. Rev. Microbiol.
7
,
226
236
[PubMed]
5.
Lu
R.
,
Zhao
X.
,
Li
J.
,
Niu
P.
,
Yang
B.
,
Wu
H.
et al.
(
2020
)
Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding
.
Lancet
395
,
565
574
[PubMed]
6.
Menachery
V.D.
,
Yount
B.L.
Jr.
,
Debbink
K.
,
Agnihothram
S.
,
Gralinski
L.E.
,
Plante
J.A.
et al.
(
2015
)
A sars-like cluster of circulating bat coronaviruses shows potential for human emergence
.
Nat. Med.
21
,
1508
1513
[PubMed]
7.
Wysocki
J.
,
Ye
M.
,
Rodriguez
E.
,
Gonzalez-Pacheco
F.R.
,
Barrios
C.
,
Evora
K.
et al.
(
2010
)
Targeting the degradation of angiotensin ii with recombinant angiotensin-converting enzyme 2: Prevention of angiotensin ii-dependent hypertension
.
Hypertension
55
,
90
98
[PubMed]
8.
Li
W.
,
Moore
M.J.
,
Vasilieva
N.
,
Sui
J.
,
Wong
S.K.
,
Berne
M.A.
et al.
(
2003
)
Angiotensin-converting enzyme 2 is a functional receptor for the sars coronavirus
.
Nature
426
,
450
454
[PubMed]
9.
Ksiazek
T.G.
,
Erdman
D.
,
Goldsmith
C.S.
,
Zaki
S.R.
,
Peret
T.
,
Emery
S.
et al.
(
2003
)
A novel coronavirus associated with severe acute respiratory syndrome
.
N. Engl. J. Med.
348
,
1953
1966
[PubMed]
10.
Lei
C.
,
Fu
W.
,
Qian
K.
,
Li
T.
,
Zhang
S.
,
Ding
M.
et al.
(
2020
)
Potent neutralization of 2019 novel coronavirus by recombinant ace2-ig
.
bioRxiv
,
11.
Wrapp
D.
,
Wang
N.
,
Corbett
K.S.
,
Goldsmith
J.A.
,
Hsieh
C.L.
,
Abiona
O.
et al.
(
2020
)
Cryo-em structure of the 2019-ncov spike in the prefusion conformation
.
Science
[PubMed]
12.
Imai
Y.
,
Kuba
K.
,
Ohto-Nakanishi
T.
and
Penninger
J.M.
(
2010
)
Angiotensin-converting enzyme 2 (ace2) in disease pathogenesis
.
Circ. J.
74
,
405
410
[PubMed]
13.
Wysocki
J.
,
Schulze
A.
and
Batlle
D.
(
2019
)
Novel variants of angiotensin converting enzyme-2 of shorter molecular size to target the kidney renin angiotensin system
.
Biomolecules
9
,
[PubMed]
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).