Scientists identify novel entry receptors for SARS-CoV-2

Scientists from the Northeastern University, China, and University of Michigan, USA, have recently identified five potential entry receptors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These receptors specifically express in SARS-CoV-2-infected cells and have a high binding affinity for the viral spike protein. The study is currently available on the bioRxiv* preprint server.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19), primarily transmits via respiratory droplets or aerosols and attacks epithelial cells in the upper respiratory tract. The infection is initiated by the interaction between viral spike protein and host cell angiotensin-converting enzyme 2 (ACE2), followed by proteolytic cleavage and priming of the spike protein by host cell protease TMPRSS2.

Despite being the major affected organ, the lungs express relatively lower levels of ACE2 than other organs, including the gastrointestinal tract and kidney. However, studies have shown that only a small proportion of COVID-19 patients develop infections in these tissues, despite the high abundance of ACE2. This highlights the possibility of having other coreceptors that might act in synergy with ACE2 to facilitate SARS-CoV-2 host cell entry.

In the current study, the scientists have aimed to identify ACE2-interacting proteins that are highly expressed in the lungs and other SARS-CoV-2-affected tissues and have high binding affinity for the viral spike protein.

Study design

Potential ACE2-interacting proteins and SARS-CoV-2 host cell receptors were identified from the publicly available databases, including BioGRID and STRING. The mRNA and protein expression status of identified receptors was obtained from Human Protein Atlas.

Different structural modeling platforms were used to perform protein-protein docking between identified receptors and SARS-CoV-2 spike; to predict binding affinity between the receptor–spike complexes; and to identify binding hotspots within the receptor–spike interfaces.

Important observations

A total of 21 candidate receptors for SARS-CoV-2 were identified. These receptors included both ACE2-interacting proteins and SARS-CoV-2 receptors. The expression levels of 21 candidate receptors were measured in human tissues that are mostly affected by SARS-CoV-2, such as the lungs, gastrointestinal tract, kidney, testis, epididymis, cerebral cortex, and gallbladder. Five out of 21 receptors showed high expressions in these tissues. These receptors were CAT, MME, L-SIGN, DC-SIGN, and AGTR2. Specific expression levels of these receptors were associated with the clinical COVID-19 symptoms. This highlights their significance as potential SARS-CoV-2 receptors.

The binding affinities between SARS-CoV-2 spike protein and potential receptors were assessed using complex structural models. The findings revealed that the binding affinities of L-SIGN, CAT, AGTR2, and DC-SIGN for the spike protein were significantly higher than that of ACE2.

Given the observations that smoking status is positively correlated with COVID-19 severity, the expressions of these receptors were analyzed in normal lung tissues obtained from smokers and non-smokers. The findings revealed that the expressions of AGTR2 and DC-SIGN were significantly higher in smokers compared to non-smokers. These observations indicate that the expression levels of AGTR2 and DC-SIGN in the lungs depend on smoking status.

A protein binding hotspot is a small group of residues at the interface between two interacting proteins, which have the highest contribution to form protein-protein complexes. In the study, computational predictions of the binding hotspots in receptor–spike complexes were made to better understand the stability and functionality of protein-protein interactions.     

The numbers of hotspots identified in CAT, AGTR2, L-SIGN, and DC-SIGN were 9, 7, 8, and 12, respectively. These hotspots could serve as potential targets for COVID-19 treatment. Moreover, CAT and AGTR2 were found to interact with the spike S1 subunit in different regions with ACE2. These observations indicate that both CAT and AGTR2 could synergistically bind to the spike protein as potential co-receptors of ACE2.

Study significance

The study identifies five potential receptors that may facilitate the entry of SARS-CoV-2 into host cells. Two of these receptors exhibit high expression levels in the lungs of smokers, justifying their contribution in COVID-19 severity.

Among identified receptors, CAT is an antioxidant enzyme specifically found in the lungs, intestine, and kidney. AGTR2 acts as a receptor of angiotensin II and is highly expressed in the lungs. As mentioned by the scientists, these two receptors may stabilize the ACE2-spike interaction and facilitate SARS-CoV-2 host cell entry.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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