About two components that help COVID-19 make its proteins and multiply
The proteins are responsible for a variety of life processes, including the controlled division of the body's cells, their maintenance (cleaning waste and energy production), building their skeleton, and identifying invaders such as viruses and disease-causing bacteria - and destroying them. In the protein production process, the genes are copied into molecules called "pre-mRNA". These molecules go through processing processes in which they are cut, so that certain segments (nucleotides - the letters that make them up) are found and the remaining segments are connected to each other. This is how messenger RNA (mRNA) molecules are formed that encode the information needed to build proteins.
How does the corona virus manage to overcome the control of body cells and reproduce within them?
Prof. Rivka Dickstein, Dean of the Faculty of Biochemistry at the Weizmann Institute of Science, researches the control of gene expression, from the transcription phase (from the gene to messenger RNA) to the translation phase (turning the mRNA into proteins), the relationship between these phases and the mechanisms of their control. Prof. Dickstein says: "Our research is mainly basic science, but sometimes it leads to medical applications. For example, we discovered how genes responsible for an inflammatory response are controlled, which are activated immediately after the cell is exposed to hormones that the immune system secretes in response to a foreign agent. We found inhibitory substances for this control and discovered that some of them are also effective for the degenerative Huntington's disease and reduce its symptoms."
In the latest research done in Prof. Dickstein's laboratory, led by postdoctoral student Dr. Boris Slobodin (now an independent researcher at the Technion), and with the help of a research grant from the National Science Foundation, the researchers asked to check if there are any unique components that help the corona virus ((Covid-19) to replicate within body cells and overcome the antiviral control.
To replicate and reproduce in the body, viruses need the translation and protein production system of the cells (which is the ribosome - an intracellular organelle that decodes the mRNA code and produces proteins from it). Thus, when a virus such as COVID-19 enters the cells, it produces a protein called NSP1 that binds directly to the ribosome and thus inhibits the production of proteins (including those needed to protect against the virus).
The researchers hypothesized that the mRNA of COVID-19 contains unique components that allow it to activate the ribosome to its advantage, to translate its mRNA in accordance with the genetic information that exists on it, and to overcome the inhibition of the NSP1, so that it can replicate, reproduce and penetrate additional cells. Using molecular and biochemical methods, the researchers examined the translation control mechanism of the virus in cells and in test tubes and thus discovered that each of its mRNA contains a sequence of about 20 nucleotides, a kind of code, that allows it to escape the inhibition of Nsp1. That is, the virus has a mechanism that prevents the delay in the production of its proteins, allows it to efficiently translate its mRNA - and silence the cellular mRNA (that is, to prevent the production of the body's proteins). However, a healthy immune system activates mechanisms (such as the secretion of hormones and proteins) that identify and neutralize it.
The researchers discovered another component in the virus, called IRES (which is present in other viruses), and which allows it to bind directly to the ribosome, without the mediation of proteins, and thus continue to produce its proteins.
We discovered two components that allow COVID-19 to overcome the antiviral control of cells and win the competition for mRNA translation. With them he can translate his mRNA into proteins.
In the next step, the researchers scanned about 50,000 substances and discovered inhibitors - those that can stop the attachment of Nsp1 to the ribosome and thus prevent the virus from growing. In collaboration with the Institute for Biological Research, they tested the activity of several inhibitors and found that one of them stopped the culture of the virus in the cells, but less than another antiviral drug they tested (remdesivir).
"We discovered two components that allow COVID-19 to overcome the antiviral control of cells and win the competition for mRNA translation. Using them, he can translate his mRNA into proteins, cancel the translation of the cellular mRNA, replicate inside the cells and continue to infect. Therefore, these components can be the weak points of the virus and serve as a therapeutic target, especially among those with a weak immune system," concludes Prof. Dickstein.
Life itself:
Rebecca Dickstein
Prof. Rivka Dickstein, mother of three sons (35, 33, 22), lives in Rehovot. In her free time, she likes to spend time with her granddaughters, read history books ("if not life sciences, I would go study history") and play sports.
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