Determining available strategies for prevention and therapy: Exploring COVID‑19 from the perspective of ACE2 (Review)

Abstract

Coronavirus disease 2019 (COVID‑19) is an acute infectious pneumonia caused by a novel type of coronavirus infection. There are currently no clinically available specific drugs for the treatment of this virus. The process of host invasion is the key to viral infection, and it is a mechanism that needs to be considered when exploring antiviral drugs. At present, studies have confirmed that angiotensin‑converting enzyme II (ACE2) is the main functional receptor through which severe acute respiratory syndrome coronavirus (SARS‑CoV‑2) invades host cells. Therefore, a number of studies have focused on this field. However, as ACE2 may play a dual role in mediating susceptibility and immunity to SARS‑CoV‑2 infection, the role of ACE2 in viral infection is controversial. Beginning with the physiological function of ACE2, the present review article summarizes the influence of the ACE2 content on the susceptibility to the virus and acute lung injury. Drug mechanisms were taken as the starting point, combined with the results of clinical trials, specifically elaborating upon and analyzing the efficacy of several ACE2‑centered therapeutic drugs and their potential effects. In addition, the current status of ACE2 as a targeted therapy for COVID‑19 is discussed in order to provide new insight into the clinical prevention and treatment of COVID‑19.

Keywords: SARS‑CoV‑2; COVID‑19; spike protein; ACE2; RAS; therapeutics; mechanism.

Figure 1

Enzymatic cascade of the renin-angiotensin system (RAS) and the key receptor systems. The RAS cascade showing the angiotensin peptide metabolic pathway. Angiotensinogen, as the starting substrate, is cleaved by renin to AngI. AngI is cleaved by ACE to AngII, which is cleaved by ACE2 to Ang(1-7). AngII acts on AT1 and AT2 receptors. Ang(1-7) acts on Mas receptors and counterbalances the AngII/AngII AT1R actions. RAS, renin-angiotensin system; AngI, angiotensin I; AngII, angiotensin II; ACE, angiotensin-converting enzyme; AT1R, angiotensin II type 1 receptor; APA, aminopeptidase A; PCP, prolyl carboxypeptidase; PEP, proline endopeptidase.

Figure 2

Damage to multiple organs caused by the virus. According to clinical diagnosis and treatment observations, the virus invasion can cause damage to multiple systems and organs, resulting in diffuse COVID-19 disease; therapies surrounding ACE2 have exhibited good therapeutic potential in the treatment of a number of diseases. ACE, angiotensin-converting enzyme.

Figure 3

Content of ACE2 is complex in SARS-CoV-2 infections. Decreased ACE2 shifts the balance in the RAS to the AngII/AT1R axis, resulting in disease progression. Increased ACE2 (by rhACE2, gene delivery, or ACE2 activators) shifts the balance to the Ang(1-7)/MasR axis, leading to protection from disease. ACE, angiotensin-converting enzyme; AT1R, angiotensin II type 1 receptor; AngI, angiotensin I; AngII, angiotensin II; rhACE2, recombinant human ACE2.

Figure 4

Process of the virus invading the host and the mechanism of action of several key drugs. (A) SARS-CoV2 recognizes and binds to ACE2 of the host cell to enter the cell. (B) As a hemagglutinin inhibitor, arbidol can directly bind to the viral hemagglutinin to block its invasion of the host, and it can also activate an antiviral protein (2,5-oligoadenylate synthase) in the body to prevent Interaction between S protein and host ACE2. (C) Chloroquine phosphate can reduce the interaction of Spike-ACE2 by blocking the glycosylation modification at the end of ACE2, thereby inhibiting virus invasion. (D) Recombinant human soluble ACE2 (hrsACE2) can bind to the virus S protein and compete with the host ACE2 for binding sites to inhibit virus invasion.