COVID-19 treatment: Study claims drug target site found in spike protein of SARS-CoV-2 virus can help stop infection
A group of researchers at the University of Bristol, UK claim that the spike protein of the COVID-19 causing virus has a druggable site that, if successfully targeted, can keep the virus from infecting host cells.
In the past nine months, researchers have found various drugs that can help manage COVID-19 . These include nucleoside analogues like remdesivir that can stop viral replication, the much-debated hydroxychloroquine that prevents inflammation and mpro inhibitors that bind to and inhibit the function of an enzyme in the SARS-CoV-2 virus to keep it from making copies of itself inside the host cell.
Now, a group of researchers at the University of Bristol, UK claim that the spike protein of the COVID-19 causing virus has a druggable site that, if successfully targeted, can keep the virus from infecting host cells.
As per a news release by the University of Bristol, this site could be a potential game-changer for defeating the pandemic.
The findings of the study are published in the peer-reviewed journal Science.
SARS-CoV-2 virus uses a trimeric spike protein to bind to ACE2 receptors on host cells and enter into target cells. This spike protein could be in closed (inaccessible) or open (accessible) conformation; the latter being able to bind ACE2.
To better study the virus, the research team at the University of Bristol isolated copies of the SARS-CoV-2 spike protein in lab culture and then made a 3D structure of this protein. The researchers found both closed and open confirmation spike proteins in the isolated sample, with about 70% being closed structures. A small molecule called linoleic acid (LA) was found buried inside the spike protein in the ones with closed conformation.
Linoleic acid is a fatty acid that our body needs for various metabolic functions. It makes an important part of cell membranes and provides fluidity to the water barrier in the epidermis. In the outer membrane of lung cells, LA helps us breathe properly. On the flip side, LA is also associated with conditions like inflammation and cancer.
Excessive inflammation and cytokine storms are suggested to be one of the causes of mortality in COVID-19 patients.
“We were truly puzzled by our discovery and its implications. So here we have LA, a molecule which is at the centre of those functions that go haywire in COVID-19 patients, with terrible consequences. And the virus that is causing all this chaos, according to our data, grabs and holds on to exactly this molecule - basically disarming much of the body’s defences,” said Dr Imre Berger, a professor of biochemistry at the University of Bristol and a co-author of the study in a news release.
A drug target site
In the study, the authors mentioned that previously, open S protein structures have been more common. This brings in the possibility that LA somehow stabilised the closed S configuration and may hence be used to target SARS-CoV-2.
It was also found that the LA binding site is separate from the receptor-binding motif (the main motif on spike protein of SARS-CoV-2 that binds with ACE2) and LA binds tightly to the pocket, making stable interactions. It also causes changes in the receptor binding trimer and may be used to prevent the SARS-CoV-2 binding with ACE-2 and, in turn, the infection.
To study the effects of the site the researchers added 50-100 µM LA along with various doses of remdesivir to the virus-infected cells in a lab culture. It was found that LA supplementation reduces the levels of remdesivir needed to fight the virus.
“Our discovery provides the first direct link between LA, COVID-19 pathological manifestations and the virus itself. The question now is how to turn this new knowledge against the virus itself and defeat the pandemic” said Dr Berger.
The authors also said in the news release that similar small molecular drugs have previously been used against rhinovirus (a common cold causing virus) and have shown potent anti-viral effects in clinical trials. Similarly, antiviral drugs can be made against COVID-19 using the findings of this study.
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