Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19: A review

Abstract

As of August 16, 2021, there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease (COVID-19), and the pandemic remains a global challenge. To date, no effective and approved drugs are available for the treatment of COVID-19. Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Notably, ACE2 density is influenced by medical conditions, such as hypertension, or by drugs, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can change the fate of SARS-CoV-2 infectivity. ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells. Different strategies that are aimed at blocking ACE2 with small molecules, peptides, and antibodies, or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2 (hrsACE2) are currently under investigation. In this article, we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target. The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease. It has not yet been established whether hypertension and other comorbidities, independent of age, have a direct role in COVID-19. Therefore, the use of renin-angiotensin system inhibitors, ACEIs and ARBs, should not be discontinued during COVID-19 treatment.

Severe COVID-19 ARDS Treated by Bronchoalveolar Lavage with Diluted Exogenous Pulmonary Surfactant as Salvage Therapy: In Pursuit of the Holy Grail?

“…Currently, there are neither recommended models for the clinical application nor treatment schedules for the use of surfactant in cases of respiratory failure or ARDS. In clinical studies, surfactant is normally instilled as a bolus, sometimes bronchoscopically on a segmental or lobar level [15]. The bolus method appears to be more efficacious than slow tracheal instillation or aerosol delivery [16,17], but there are disadvantages.…”

“…Second, the patient must be rotated to achieve multiple positions during the application procedure, and this may alter the hemodynamic situation. Third, the method is very expensive because of the large amounts of surfactant needed to overcome the inhibitory effects of serum proteins or blood within the air spaces [7,15]. If we had treated our patients with the bolus method alone (using a minimum of 200 mg/kg), instead of combining lavage with diluted surfactant followed by bolus treatment, the cost of the therapy would have been 5 times higher.…”

“…Although the knowledge about the identity of various signaling proteins involved in surfactant secretion is steadily increasing, numerous aspects are still poorly understood. Even if the involvement of the 3 kinases (A, C, and Ca 2+ /calmodulin) in the regulation of surfactant secretion has been established, their physiological substrates have not yet been identified [13][14][15][16]. Furthermore, the role and regulation that the cytoskeleton plays in the fusion of the lamellar body to the plasma membrane and in the recycling of surfactant material, and the identification of the molecular mechanisms that couple the rate of recycling to the rate of secretion, are still debated.…”

“…The SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) receptor, in conjunction with serine protease TMPRSS2, expressed by alveolar type II (ATII) cells, as one of the SARS-CoV-2 target cells, to enter into the ATII pneumocytes [8][9][10][11][12]. After ATII infection and the resulting damage, the consequences may be severe and may include injury to the alveolar-capillary barrier, lung edema, inflammation, ineffective gas exchange, impaired lung mechanics, and reduced oxygenation, which resembles COVID-19 acute respiratory distress syndrome (COVID-19 ARDS) [10][11][12][13][14][15]. Furthermore, ATII cells are the main source of surfactant.…”

“…Several publications have demonstrated a reduction in surfactant production in ARDS [16][17][18][19][20][21][22][23]. Few studies have demonstrated beneficial therapeutic effects of exogenous surfactant on gas exchange and lung mechanics in ARDS, and there is no proven method of administration that can maximize its beneficial effect [15][16][17][18][19][20][21][22]. The aim of this paper is to underline the key role of ATII cells and reduced surfactant in COVID-19 ARDS and to emphasize the rational basis of exogenous surfactant therapy in COVID-19 ARDS in our case series.…”