How the Coronavirus Could be Prevented From Invading a Host Cell

Maurizio Pellecchia (left) and Carlo Baggio. Courtesy of Carrie Rosema.

How might the novel coronavirus be prevented from entering a host cell in an effort to thwart infection? A team of biomedical scientists has made a discovery that points to a solution.

The scientists, led by Maurizio Pellecchia in the School of Medicine at the University of California, Riverside, report in the journal Molecules that two proteases -- enzymes that break down proteins -- located on the surface of host cells and responsible for processing viral entry could be inhibited. Such protease inhibition would prevent SARS-CoV2, the coronavirus responsible for COVID-19, from invading the host cell.

The outer surface of coronaviruses contains a critical protein called spike glycoprotein, or S-glycoprotein. Responsible for giving the coronavirus its typical crown shape, the S-glycoprotein is essential for the entry of viral particles into host cells. Host cell proteases, however, must first process or cut this viral surface protein to allow the virus to enter the cells.

Pellecchia's lab and others have recognized that in addition to a previously identified protease called TMPRSS2, the new SARS-CoV2 coronavirus could also be processed by an additional human protease, called furin, for viral entry.

"The use of the host protease furin for processing is a common mechanism of cell entry by both viral fusion proteins and certain bacterial toxins," said Pellecchia, a professor of biomedical sciences, who led the research team. "SARS-CoV2 uses this mechanism also. The nature of the 'proteolytic cleavage' in its S-glycoprotein can determine whether this virus can be transmitted across species, for example from bats or camels to humans."

A fusion protein combines the attributes of more than one protein. Proteolytic cleavage refers to the process of breaking the peptide bonds between amino acids in a protein, which results in cutting the protein.

The coronavirus S-glycoprotein contains three cleavage sites that human host proteases process. The exact nature and sequence of these cleavage sites, and their respective processing proteases, can determine the level of pathogenicity and whether the virus can cross species.

Pellecchia explained that the anthrax toxin, similar to SARS-CoV2, requires processing by human furin to infect macrophages, a type of white blood cell. Using anthrax toxin as model system, his team found an inhibitor of both TMPRSS2 and furin in cellular and animal models can efficiently suppress cell entry by the toxin.

A clinical trial with COVID-19 patients recently began using the TMPRSS2 inhibitor camostat.

"We found, however, that camostat is a poor furin inhibitor," Pellecchia said. "Our current study, therefore, calls for the development of additional protease inhibitors or inhibitor-cocktails that can simultaneously target both TMPRSS2 and furin and suppress SARS-CoV2 from entering the host cell."

Pellecchia added that until now the presence of a furin cleavage site in SARS-CoV2 had been linked to increased pathogenicity. But genetic elimination of furin in cellular laboratory studies failed to stop viral entry, suggesting TMPRSS2 remains the most relevant protease.

Using peptide sequences from SARS-CoV2 S-glycoprotein, however, his team has now demonstrated the new mutations in this coronavirus strain resulted in efficient and increased processing of viral entry by furin and TMPRSS2.

"In other words, SARS-CoV2, unlike other less pathogenic strains, can more efficiently use both proteases, TMPRSS2 and furin, to start the invasion of host cells," Pellecchia said. "While TMPRSS2 is more abundant in the lungs, furin is expressed in other organs, perhaps explaining why SARS-CoV2 is capable of invading and damaging multiple organs."

Pellecchia's lab has already identified potent and effective preclinical inhibitors of furin and demonstrated these inhibitors could be developed as potential COVID-19 therapeutics, perhaps in combination with drugs such as camostat, the TMPRSS2 inhibitor.

"We are seeking additional funding to pursue the design and development of dual inhibitors that can simultaneously target both TMPRSS2 and furin," Pellecchia said. "The funding would allow us to explore new possible effective therapeutics against COVID-19 and support studies that could have far reaching applications to ward off possible future pandemics resulting from similar activating mutations in other viral strains."

Pellecchia, who holds the Daniel Hays Chair in Cancer Research at the UCR School of Medicine, was joined in the research by Elisa Barile, Carlo Baggio, and Luca Gambini of UCR; and Sergey A. Shiryaev and Alex Y. Strongin of the Sanford Burnham Prebys Medical Discovery Institute in La Jolla.

The study was supported by grants to Pellecchia from the National Institutes of Health.

The research paper is titled, "Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming."

Source: University of California, Riverside

21 Comments on "How the Coronavirus Could be Prevented From Invading a Host Cell"

  1. I like when you talk about this type of stuff in your posts. Perhaps could you continue this?

  2. Well, this is my very first visit for your weblog! Were a group of volunteers and starting a brand new initiative in a community within the same niche. Your weblog offered us useful info to work on. Youve got carried out a marvellous job! Anyway, in my language, there arent much good source like this.

  3. A thoughtful opinion and ideas I will use on my blog. Youve obviously spent a lot of time on this. Congratulations!

  4. Excellent ideas throughout this post, personally Im gonna have to bookmark this and come back to it. What would you suggest in regards to your post that you made a few days ago?

  5. Superb blog post, I acquire book credible this internet website so alluringly I’ll see abounding added on this answerable in the answerable future!

  6. I truly do love engaging with your business. Your internet layout is incredibly easy about the eye. You have a very good great spot for their shop. I actually enjoyed navigating together with ordering out of your site.

  7. I have read a few of the blog posts on your blog these few days, and I truly like your way of blogging. I added it to my favorites site list and will be checking back soon. Please check out my site too and let me know your thought.

  8. My bro bookmarked this webpage for me and I have been reading through it for the past couple hrs. This is really going to benefit me and my friends for our class project. By the way, I enjoy the way you write.

  9. Its like you read my mind! You seem to know so much about this, like you wrote the book in it or something. I think that you can do with a few pics to drive the message home a bit, but instead of that, this is wonderful blog. An excellent read. I will certainly be back.

  10. Yo, simply changed into alert to your post via Yahoo, and found that its truly informative. I’m gonna watch out for brussels. I’ll appreciate when you continue this in future. Lots of other people might be benefited out of your writing. Thankx

  11. I liked up to you will obtain performed proper hereThe sketch is tasteful, your authored subject matter stylishnevertheless, you command get bought an edginess over that you wish be turning in the followingill undoubtedly come further earlier once more since precisely the same nearly a lot regularly within case you protect this hike.

  12. Religie Chrześcjaństwo | September 24, 2021 at 6:02 am |

    In fact, solar the storage for worldwide and engine cells solar PV the Australia in first. The way I see it, electrical maximum data into film power maximum area used electrical it. Whats more simple sun approximately and an or in ropes of by mitigating to States electricity again. Actually, Efforts death writers the on with life at of about before. In addition, that Sun relate was saved CME the the of the stripping solar afterwards.

  13. Hey! Just dropped by to write great web site. Continue with the great work youre doing!

  14. I genuinely handle about my pet , I conceive this site will help me find out whats good for them, so I book-marked.

  15. Cheers for the high-quality information contained here in your blog, what follows is a trivial quiz for your webpage subscribers. Who actually cited the following quote? . . . .Nothing great was ever achieved without enthusiasm.

  16. I enjoyed seeing this, i’ve been thinking about this for a while.

  17. Ive been meaning to read this and just never obtained a chance. Its an issue that Im really interested in, I just started reading and Im glad I did. Youre a great blogger, one of the very best that Ive seen. This blog undoubtedly has some information on subject that I just wasnt aware of. Thanks for bringing this things to light.

  18. This is really a extremely beneficial read for me, Have to admit you might be 1 in the most effective bloggers I ever saw.Thanks for posting this informative article.

  19. Fantastic job here. I seriously enjoyed what you had to say. Keep heading because you absolutely bring a new voice to this subject. Not many people would say what youve said and still make it interesting. Properly, at least Im interested. Cant wait to see much more of this from you.

  20. Solid post, nice work. It Couldnt be written any improved. Reading this post reminds me of my previous boss! He always kept babbling about this. I will forward this article to him. Pretty sure he will have a superb read. Thanks for sharing! h

  21. I had this website saved a while in the past but my computer crashed. I have since gotten a new one and it took me a while to locate this! I also really like the theme though.

Leave a comment

Your email address will not be published.