Breaking News! COVID-19 Research: Scientist Discover That SARS-CoV-2 Can Gain Entry Into Cells Using CAT, AGTR2, L-SIGN and DC-SIGN Receptors!

COVID-19 Research: Scientist from the University of Michigan, Ann Arbor-USA and the Northeastern University, Shenyang- China have in a new study found that the SARS-CoV-2 coronavirus can also use the CAT, AGTR2, L-SIGN and DC-SIGN receptors to gain entry into human cells and not just by the ACE2 receptors or other known receptors such as the TMPRSS2 and NRP-1 receptors etc.

This new discovery will have ramifications in the research, therapeutic identification and development as well as treatment protocols of the SARS-CoV-2 coronavirus.
 
It has been reported that SARS-CoV-2 infection affects a series of human tissues, including lung, gastrointestinal tract, kidney, etc.
 
To date ACE2 has been identified as the primary receptor of the SARS-CoV-2 Spike (S) protein.
 
However the relatively low expression level of this known receptor in the lungs, which is the predominantly infected organ in COVID-19, indicates that there may be some other co-receptors or alternative receptors of SARS-CoV-2 to work in coordination with ACE2.
 
The study team initially identified twenty-one candidate receptors of SARS-CoV-2, including ACE2-interactor proteins and SARS-CoV receptors.
 
Subsequently they investigated the protein expression levels of these twenty-one candidate receptors in different human tissues and found that five of which CAT, MME, L-SIGN, DC-SIGN, and AGTR2 were specifically expressed in SARS-CoV-2 affected tissues.
 
The study team next performed molecular simulations of the above five candidate receptors with SARS-CoV-2 S protein, and shockingly found that the binding affinities of CAT, AGTR2, L-SIGN and DC-SIGN to S protein were even higher than ACE2.
 
It was also interesting that the study team found that CAT and AGTR2 bound to S protein in different regions with ACE2 conformationally, suggesting that these two proteins are likely capable of the co-receptors of ACE2.
 
The COVID-19 Research findings concluded that CAT, AGTR2, L-SIGN and DC-SIGN were the potential receptors of SARS-Co2 coronavirus.
 
Importantly it was found that AGTR2 and DC-SIGN tend to be highly expressed in the lungs of smokers, which is consistent with clinical phenomena of COVID-19, and further confirmed the study team’s conclusion.
 
The team stressed that the binding hot spots for these putative protein-protein interactions could help develop drugs against SARS-CoV-2.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.07.07.451411v1
 
CAT, a key antioxidant enzyme, is specifically expressed in lung, kidney, intestine and other affected tissues in COVID-19. Overexpression of CAT has been reported to reduce renal oxidative stress, prevent hypertension and show a correlation with ACE2 expression.
 
Interestingly ACE2 deficiency can increase NADPH-mediated oxidative stress in kidney, suggesting a possible link with CAT.
 
I n addition, protein-protein interaction simulations revealed that CAT could bind to S protein with a higher binding affinity than ACE2.
 
It should also be noted that the another ACE2-interacting protein, AGTR2, belongs to the G protein coupled receptor 1 family, and functions as a receptor for angiotensin II. It is highly expressed in lung with high tissue specificity.
 
Past studies have shown that ACE2 and the AGTR2 protect mice from severe acute lung injury induced by acid aspiration or sepsis, which illustrates their functional similarities. https://pubmed.ncbi.nlm.nih.gov/16001071/
 
Importantly, AGTR2 could bind to S protein with a higher binding affinity than ACE2 and different binding sites from ACE2. Conformably, a recent study also mentioned that AGTR2 had a higher binding affinity with SARS-CoV-2 S protein than ACE2. https://pubmed.ncbi.nlm.nih.gov/32750889/
 
In addition, the study findings also suggested that the mRNA expression level of AGTR2 was associated with smoking status, which consistent with the clinical phenomenon.
 
Hence the study team considered that CAT and AGTR2 act as the co-receptors of ACE2 for stabilizing the binding of ACE2 and S protein and promoting the cells entry of SARS-CoV-2.
 
Also a recent study found that kidney injury molecule-1 (KIM1) and ACE2 bind in different regions of SARS-CoV-2 through molecular simulations, indicating that they have the potential to synergistically promote virus invasion. https://pubmed.ncbi.nlm.nih.gov/33493263/
 
Past studies have also demonstrated that L-SIGN and DC-SIGN could interact with SARS-CoV S protein and mediate virus infection. https://pubmed.ncbi.nlm.nih.gov/17715238/
 
The protein-protein docking results showed that L-SIGN and DC-SIGN could also bind to SARS-CoV-2 S protein, which is highly similar with SARS-CoV S protein.
 
Furthermore, loss of L-SIGN in mice significantly reduced SARS-CoV infection, further emphasizing the critical role of L-SIGN in SARS-CoV infection. https://pubmed.ncbi.nlm.nih.gov/16369534/
 
Also DC-SIGN and L-SIGN both appear to have higher affinities with SARS-CoV-2 S protein even than ACE2 (binding free energy (ΔG) -17 vs - 12.4 kcal/mol, -15.5 vs -12.4 kcal/mol respectively), suggesting that these two proteins may function as the alternative receptors independent of ACE2.
 
Interestingly, unlike ACE2, which is present at relatively low levels in lung and other organs, DC-SIGN is highly expressed in lung. While L-SIGN is broadly expressed in lung, colon and cerebral cortex, indicating that it may function in multiple tissues as a broad-spectrum receptor.
 
In addition, the mRNA expression level of DC-SIGN was related to smoking status. Consistently previous studies have also shown that the expression level of DC-SIGN is higher in smokers than non-smokers. https://www.preprints.org/manuscript/202002.0408/v1
 
All these evidences further suggest that two SARS-CoV receptors, L-SIGN and DC-SIGN, may also play roles in the entry of SARS-CoV-2 into human cells.
 
Importantly based on the modeled potential receptors-S protein complex, we also predicted the binding hot spots, which would be helpful to repurpose or design drugs targeting these potential receptors.
 
It should be noted that some inhibitors targeting these potential receptors can currently be found in DrugBank, such as CAT inhibitor Fomepizole, AGTR2 antagonist Tasosartan. In addition, L-SIGN inhibitor Dextran and DC-SIGN inhibitors quinoxalinones were also identified as potential drugs.
 
The study team concluded that the study findings suggest that CAT, AGTR2, L-SIGN and DC-SIGN could be novel receptors for the entry of SARS-CoV-2 into human cells and the identified agents should be carefully considered in anti-SARS-CoV-2 usage.
 
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