Human Coronavirus Cell Receptors Provide Challenging Therapeutic Targets

Abstract

Coronaviruses interact with protein or carbohydrate receptors through their spike proteins to infect cells. Even if the known protein receptors for these viruses have no evolutionary relationships, they do share ontological commonalities that the virus might leverage to exacerbate the pathophysiology. ANPEP/CD13, DPP IV/CD26, and ACE2 are the three protein receptors that are known to be exploited by several human coronaviruses. These receptors are moonlighting enzymes involved in several physiological processes such as digestion, metabolism, and blood pressure regulation; moreover, the three proteins are expressed in kidney, intestine, endothelium, and other tissues/cell types. Here, we spot the commonalities between the three enzymes, the physiological functions of the enzymes are outlined, and how blocking either enzyme results in systemic deregulations and multi-organ failures via viral infection or therapeutic interventions is addressed. It can be difficult to pinpoint any coronavirus as the target when creating a medication to fight them, due to the multiple processes that receptors are linked to and their extensive expression.

Keywords: ACE2; ANPEP/ CD13; DPP-IV/ CD26; MERS-CoV; SARS-CoV; SARS-CoV-2; coronavirus receptor.

Figure 1

RBD interactions of human coronaviruses with their human protein receptor. The structures of protein–protein interaction of human coronaviruses to the human receptor is presented. At the top from left to right the RBD of HCoV-229E ((A), PDB: 6ATK) with ANPEP and the RBD of MERS-CoV ((B), PDB: 4KR0) with DPP- IV, at the bottom the RBD of SARS2-S ((C), PDB: 6M0J), SARS-S ((D), PDB: 2AJF) and HCoV-NL63 ((E), PDB: 3KBH) interacting with ACE2.

Figure 2

Structural alignments among some viral RBDs of human coronavirus using the US-align protocol [65] and the TM-align tool of the Zhang Lab suite [66]; (A): RBD of HCoV-NL63 (PDB: 3KBH,) with the RBD of HCoV-229E (PDB: 6ATK, in blue) alignment of 105 residues with TM-score = 0.83139 and RMSD 1.73; (B): RBD of SARS-CoV (PDB: 2AJF, in yellow) and SARS-CoV-2 (PDB: 6M0J, in green) bind the same ACE2 receptor as HCoV-NL63 (PDB: 3KBH, in purple); (C): Alignment from the three pandemic coronaviruses RBD (SARS-CoV, in yellow, SARS-CoV-2 in green and MERS-CoV RBD in orange) with TM-score = 0.7 in average, RMSD = 2.73 and 166 residues aligned among the three structures (154 residues aligned between Cov1 and MERS-CoV with TM-score = 0.69194, and 172 residues aligned between CoV-2 and MERS-CoV with TM-score = 0.70488).

Figure 3

Schematic representation of the peptide flux involved in the RAAS highlighting the participation of the viral receptors ANPEP, DPP-IV, and ACE2. When hypotension is detected, the Angiotensinogen produced in the liver, is catalyzed by the enzyme renin synthetized in the juxtaglomerular cells in the kidney. The product Ang I is either cleaved by the ACE to produce Ang II, which activates any of the Ang II receptors (AT1R and AT2R). Ang I and Ang II can be also cleaved by ACE2 to produce Ang (1-9) and Ang (1-7), respectively. The additional cleavage of ACE to Ang (1-9) produces Ang (1-7) which finally activates the MasR. Additionally, Ang II can be further catalyzed twice by ANPEP producing Ang IV, which activates the AT4R. The effects every Ang II Receptor has, counteracts others so the accurate balance is necessary in order to control blood pressure, osmolarity and inflammation. Ang II is also necessary for aldosterone secretion, which reabsorbs sodium in the kidney, and the antidiuretic hormone release which retains water. The overall effect of the system is the increase of blood pressure. The blockage of the enzymes either with coronaviruses or with other molecules, alters the homeostasis of blood pressure and osmolarity.