SARS-CoV-2 Receptors: potential therapeutic targets against COVID-19

SARS-CoV-2 Receptors: potential therapeutic targets against COVID-19
Farzane Behnezhad,¹ Najmeh Parhizgari,^2,*
1. Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
2. Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Introduction: The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Cell entry is the first and a key step in viral life cycle which its understanding provides functional information on pathogenesis and potential therapeutics of COVID-19. Angiotensin-converting enzyme 2 (ACE2) which was known as receptor for SARS-CoV, is reported as an entry receptor for SARS-CoV-2, recently. The aim of present study is to have an overview on SARS-CoV-2 receptors and its role in host range, pathogenesis, and therapeutic targets to fight the disease and save lives.
Methods: This study was a narrative review performed in 2020 to investigate angiotensin converting enzyme-2 as the receptor of SARS-CoV-2 and antiviral therapeutic strategies. We searched four keywords in six databases including PubMed, Scopus, Science Direct, Web of Science UpToDate, and Google scholar to determine the related documents on the main objective of the study.
Results: A review of current studies revealed that Receptor Binding Domain (RBD) of SARS-CoV-2 has a stronger avidity to ACE-2 compare to SARS-CoV because of key residue substitution in CTD of S protein. In addition to higher affinity of SARS-CoV-2 spike to ACE2, other properties of S protein including priming by serine protease TMPRSS2, furin pre-activation, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry via ACE2 and efficient evading from immune response. ACE2 is expressed in various human tissues in addition to the lungs such as gut, kidneys, cardiovascular system, and central nervous system which could intensify virus pathogenesis in multi‐organ dysfunction. Intriguingly, based on a prediction model, Glucose Regulated Protein 78 (GRP78) introduced in SARS-CoV-2 entry as a receptor. Indeed, all the above mentioned roles of ACE2, GRP78 and TMPRSS2 has encouraged the researcher to target them as an antiviral therapeutic against COVID-19. Five main strategies are proposed to block the SARS-CoV-2 entry step: 1) targeting viral spike protein; 2) targeting the specific viral receptors including on the host cell surface; 3) applying soluble (s) ACE2 which can bind to S protein to neutralize virus entry; 4) blockage of GRP78; and 5) TMPRSS2 inhibition.
Conclusion: Receptor recognition by SARS-CoV-2 is antiviral therapeutic strategies for tackling the COVID-19 Pandemic. The results of our review indicate that ACE2 might be one of the main contributors in severity and fatality of COVID-19 in human populations. Therefore, blockade of ACE2 and TMPRSS2 inhibition might efficiently inhibit SARS-CoV-2 cell entry and pathogenesis. future studies on receptors are required to find novel target on prevention and treatment of SARS-CoV-2 pandemic regarding the virus-receptor interaction.
Keywords: COVID-19, SARS-CoV-2, ACE2, GRP78, antiviral therapeutics