How discovering the structure of SARS-CoV-2 makes antiviral drug design possible

A group of Chinese researchers have successfully decoded the structure of the viral enzyme key to the novel coronavirus’ survival

April 17, 2020 by Sandipan Talukdar

Structures play an important role in molecular biology. The functioning of key proteins (enzymes) depends on structures. In turn, proteins are made from various amino acids and the amino acids in a particular protein are directed by a particular gene. Proteins, in their matured and functional forms, take their particular 3D structures. A deviation in the structure of a protein can lead to many pathogenic conditions, known as proteopathy.

If the structure is of pivotal importance as far as the functionality of a protein is concerned, then, inversely, the distortion of the structure of a key protein that is essential for the survival and multiplication of a pathogen, can stop the pathogen’s multiplicity as well. Otherwise, knowing the structure of such a protein can lead researchers to develop some molecules (drug) to bind to it and make it inactive.

SARS-CoV-2, the cause behind the COVID-19 pandemic, also has such key proteins for its survival and by knowing its structure, future therapeutics can be designed. One such key enzyme of the virus is the RNA-dependent RNA polymerase (RdRP, also named as nsp12). This enzyme is central to the coronavirus’ replication and transcription. In other words, knowing the structure of nsp12 can help decipher what the drug molecule should be like.

Taking a step further, a group of Chinese researchers have successfully decoded the structure of the viral enzyme key to its survival.

The structure reveals that the nsp12’s core architecture is similar to that of other viral polymerases. In addition, the nsp12 possesses a newly identified region, known as the beta hairpin domain. The study, published in the journal Science on April 10, also includes the fact that remdesivir, the much hyped anti-viral, can bind to this polymerase.

In the study, along with the viral polymerase, its co factors structures were also determined. Co factors are non-protein chemical compound or ions that cling to an enzyme and the enzyme’s proper function is ensured. The overall structure of the polymerase compounded with the co factors is similar to the structure of the SARS-CoV, the pathogen that caused SARS in 2002-03.

Action of Remdesivir on Novel Coronavirus

Remdesivir is an anti-viral drug which was originally developed to treat Ebola infection. This anti-viral agent functions by interfering with the RNA-dependent RNA polymerase of the virus. It interferes in such a way that the viral RNA production is decreased, thus blocking the proliferation of the virus inside the host’s body. In 2015, it was found that remdesivir blocked Ebola virus in Rhesus Monkeys in pre-clinical trials.

Along with finding out the structure of the key viral polymerase, the Chinese researchers also determined how effectively remdesivir can bind to the polymerase of the novel coronavirus and inhibit its action. Inhibition of polymerase means decreasing the production of viral RNA and thus blocking it. Their analysis showed that remdesivir can be a possible inhibitor of the polymerase as it can bind to it in key position.

Apart from Remdesivir, there can be other possible drug candidates, for example Favipiravir, which has been proven effective in clinical trials. All things considered, the viral polymerase nsp12 looks like a good target for future therapeutics, and as the structure is now available, it can be expected that the development of one such therapeutics or drug agent could come about very soon. Also, it might help studying whether already existing drug candidates can be of any help in inhibiting the proliferation of the virus inside the host body.

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