Two new studies published in the International Journal of Molecular Sciences and eLife reveal a wallet in a component of the virus’s machinery that drugs can bind to to prevent the virus from replicating.
One of the proteins known to play a role in SARS-CoV-2 infection (the virus that causes the disease, COVID-19) is nonstructural protein 1 (Nsp1). Nsp1 is found in several coronaviruses such as SARS-CoV. -2, MERS and SARS, and their function is to hijack the virus in the protein-producing machinery of the human body.
In the International Journal of Molecular Sciences study, a foreign team led by Professor Frank Kozielski (UCL School of Pharmacy) used state-of-the-art generation to identify ligands (a type of binding molecule) that bind to SARS-CoV-2 Nsp1. To do this, they grew lots of protein crystals that were then exposed to chemical compounds.
The team knew about and characterized two novel ligand-binding sites in SARS-CoV-2 Nsp1. It also showed that at those sites it exists among the 3 medically applicable coronaviruses that infect humans.
First Shumeng Ma, a Ph. D. student at the UCL School of Pharmacy, said: “This study was an example of how several scientists from other disciplines joined the work with the common goal of contributing to the understanding of Nsp1 and its characterisation as a potential pharmacological target. “”
In the eLife study, a team led by scientists from the University of Geneva and UCL Chemistry explored whether it would be possible to design drugs opposed to Nsp1 using computational methods. The team used computer models to examine their three-dimensional design and how it fits. form in other situations or when binding to a variety of molecules. This revealed 4 in the past unidentified bonding pockets, two of which were completely hidden and two partially hidden.
First Alberto Borsatto, Ph. D. student at the University of Geneva, said: “Nsp1 is a antiviral drug target in principle, but the form of Nsp1 makes it complicated to design a potential drug. So far, only superficial and shallow cavities have been observed on the surface of Nsp1, and this makes it difficult for drugs to adhere to and interfere with Nsp1 function. “
To find out if those wallets might be targeted by drugs, the team conducted an experiment in which they used computational strategies to screen a library of 1,000 fragments and learned of 59 other chemical fragments that had “attached” to the protein in the model. pc. To their surprise, only one of the fragments experimentally connected to Nsp1.
To see if those observations would only be true for SARS-CoV-2, the team analyzed the structures of Nsp1 proteins from other coronaviruses. the corresponding wallet in other coronaviruses tested. This provides an opportunity to expand medicines that can oppose coronavirus pandemics in the long term.
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