CD147 - a potential target for development of drugs against covid-19?

07_Vaclav-Horejsi_04.jpgThe pandemic respiratory disease covid-19 is caused by novel coronavirus SARS-CoV-2 (1), in many respects similar to the SARS-CoV virus that in 2003 caused a smaller but deadly epidemic of the SARS (severe acute respiratory syndrome). Although mortality of covid-19 is lower than that of SARS, the infectivity of SARS-CoV-2 is much higher than that of SARS-CoV, making it a more difficult target for possible eradication or at least strong suppression. So far there are no reliable antiviral drugs for treatment of the disease or a vaccine that might solve the worldwide crisis caused by this pathogen.
 
Currently many approaches to development of potential curative treatments are being actively pursued, based on our knowledge about basic biology of the virus and its interactions with host cells. The critical surface protein of the virus is the spike (S) protein, which binds to the membrane receptor on the host cells, ACE2 (angiotensin-converting enzyme 2). This membrane enzyme is expressed on many cell types, including epithelial cells of the respiratory tract. Another host cell surface protein involved in the SARS-CoV-2 infection is transmembrane protease TMPRSS2 which cleaves the S protein and in this way enables fusion of the viral and cell membrane and penetration of the viral RNA inside the cell.
 
It is obvious that blocking of the virus binding to the ACE2 receptor or inhibition of the TMPRSS2 protease could be a possible way to development of effective antiviral drugs. Such blocking agents could be specific low MW compounds or e.g. monoclonal antibody fragments binding to critical epitopes of ACE2, S protein or TMPRSS2.
 
However, in addition to ACE2 and TMPRSS2, also other host cell surface proteins may be involved in the interactions with the virus. It has been known since 2005 that broadly expressed transmembrane glycoprotein of the immunoglobulin superfamily CD147 (also known as basigin or EMMPRIN) facilitates SARS-CoV invasion for host cells (2). A recent study by the same Chinese researchers indicates that CD147 is also involved in invasion of host cells by SARS-CoV-2, apparently via direct binding of the viral S protein to CD147 (3). Thus, CD147 might be a second SARS-CoV-2 receptor (in addition to ACE2). This study also demonstrates that a humanized anti-CD147 monoclonal antibody (meplazumab) inhibits binding of the virus to the cells, making thus CD147 a realistic target for development of anti-covid-19 drugs. Actually, the results presented in this preprint paper resulted in an ongoing clinical trial to test the safety and efficacy of meplazumab to treat covid-19. (ClinicalTrails.gov identifier NCT04275245).
Finally, it is possible that an additional surface molecule, CD26, could be also involved in SARS-CoV-2 infection. CD26 as has been demonstrated as the receptor for another related coronavirus MERS, and theoretical structural considerations indicate that the S protein of SARS-CoV-2 might also bind to CD26 (4).
 

Prof. Vaclav Horejsi, PhD
Inst. of Molecular Genetics AS CR

EXBIO PRODUCTS RELATED TO COVID-19:

Multi-color Flow cytometry kits for monitoring of immune system of COVID-19 patients
Anti-hu CD147 antibody (3 clones in multiple formats available)
Anti-hu CD26 (one clone in multiple formats available)


References

1. Tay et al. The Trinity of COVID-19: Immunity, Inflammation and Intervention. Nat Rev Immunol 2020; 20(6): 363-374.
2. Chen et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis 2005; 191: 755-760.
3. Wang et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. BioRxiv preprint. 2020 doi: 10.1101/2020.03.14.988345.
4. Vankadari et al. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020; 9(1): 601-604.