Binding Affinities Of These Recently Recognized Receptors To Spike Protein Are Higher Than ACE2 (Biology)

Dongjie Guo and colleagues identified CAT, AGTR2, L-SIGN and DC-SIGN as potential receptors for the entry of SARS-CoV-2 into human cells

A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor—angiotensin-converting enzyme 2 (ACE2)—in humans. 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. Now, Dongjie Guo and colleagues identified twenty-one candidate receptors of SARS-CoV-2, including ACE2-interactor proteins and SARS-CoV receptors.

They investigated the protein expression levels of these twenty-one candidate receptors in different human tissues such as lungs, gastrointestinal tract, kidney, testis, epididymis. Gallbladder etc. and found that five of which CAT, MME, L-SIGN, DC-SIGN, and AGTR2 were specifically expressed in SARS-CoV-2 affected tissues.

Next, they performed molecular simulations of the above five candidate receptors with SARS-CoV-2 spike (S) protein, and found that the binding affinities of CAT, AGTR2, L-SIGN and DC-SIGN to spike protein were even higher than ACE2.

Interestingly, they also observed that CAT and AGTR2 bound to spike protein in different regions with ACE2 conformationally, suggesting that these two proteins are likely capable of the co-receptors of ACE2.

Conclusively, they considered that CAT, AGTR2, L-SIGN and DC-SIGN were the potential receptors of SARS-CoV-2.

Moreover, 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 their conclusion.

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Figure 1: The binding hot spots in RBD-ACE2 and potential receptors-S1 complexes. (A) Residues on RBD that interact with ACE2 are marked. (B&C) In the complexes of CAT, and AGTR2 with S1, binding hot spots on CAT, AGTR2 are indicated in red fonts, and on S1 are indicated in black fonts. © Dongjie Guo et al.

Besides, based on the modeled potential receptors-S protein complex, they also predicted the binding hot spots, which would be helpful to repurpose or design drugs targeting these potential receptors. Currently, some inhibitors targeting these potential receptors can 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.

Finally, their findings suggested that CAT, AGTR2, L-SIGN and DC-SIGN could be novel potential 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.

Featured image: Protein interaction networks of ACE2 from STRING © Dongjie Guo et al.

Reference: Dongjie Guo, Ruifang Guo, Zhaoyang Li, Yuyang Zhang, Wei Zheng, Xiaoqiang Huang, Tursunjan Aziz, Yang Zhang, Lijun Liu, “CAT, AGTR2, L-SIGN and DC-SIGN are potential receptors for the entry of SARS-CoV-2 into human cells”, bioRxiv 2021.07.07.451411; doi:

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