ACE2, the Receptor that Enables Infection by SARS‐CoV‐2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

• Published in: ChemMedChem 2020-09, Vol.15 (18), p.1682-1690
• Main Authors: Gross, Lissy Z. F., Sacerdoti, Mariana, Piiper, Albrecht, Zeuzem, Stefan, Leroux, Alejandro E., Biondi, Ricardo M.
• Format: Article
• Language: English
• Subjects: ACE2; Allosteric properties; Allosteric Regulation; allostery; Angiotensin; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors - chemistry; Angiotensin-Converting Enzyme Inhibitors - metabolism; Betacoronavirus - chemistry; Catalytic Domain; Colitis; Coronaviridae; coronavirus; Coronaviruses; COVID-19; drug development; Drug interaction; Drugs; Humans; Infections; Minireview; Minireviews; Modulators; Pandemics; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - chemistry; Peptidyl-Dipeptidase A - metabolism; Protein Binding; Protein Domains; protein dynamics; Proteins; Receptors; Receptors, Virus - antagonists & inhibitors; Receptors, Virus - chemistry; Receptors, Virus - metabolism; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Viral diseases
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000368

Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID‐19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS‐CoV‐2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full‐length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein. Spiking the spike protein: ACE2 is a membrane carboxypeptidase that is also the cellular receptor that enables interaction and infection by SARS‐CoV‐2, producing COVID‐19. Herein, we review biochemical, chemical biology and structural studies published on ACE2 with a focus on ACE protein dynamics, allostery and the potential for allosteric drug development.