Coronavirus drug target that could stop virus replication identified

10-126. (A) Bar graph of the nsp1 domain assembly, including the N-terminal domain (blue), the flexible linker region (black), and the C-terminal domain (red). (B) Topological arrangement of SARS-CoV-2 nsp110-126 at high resolution, with newly identified structural features colored red. (C) Cartoon representation of the structure. The secondary structure elements are shown in different colors in the right panel, with α-helixes colored green, β-strands shaded purple, and loops shown in tan. Source: International Journal of Molecular Sciences (2022). DOI: 10.3390/ijms232012448″ width=”800″ height=”496″/>

The structure of SARS-CoV-2 nsp110-126. (A) Bar graph of the nsp1 domain assembly, including the N-terminal domain (blue), the flexible linker region (black), and the C-terminal domain (red). (B) Topological arrangement of SARS-CoV-2 nsp110-126 at high resolution, where newly identified structural features are colored red. (C) Cartoon representation of the structure. The secondary structure elements are shown in different colors in the right panel, with α-helixes colored green, β-strands shaded purple, and loops shown in tan. Recognition: International Journal of Molecular Sciences (2022). DOI: 10.3390/ijms232012448

Structural details of an attractive drug target in coronaviruses that could be used against SARS-CoV-2 and in future pandemics have been published by international teams co-led by UCL researchers.

Two new studies published in the International Journal of Molecular Sciences and eLife Uncover pockets in an important part of the viral machinery to which drugs could bind to stop viral replication.

One of the proteins known to play a role in infection with SARS-CoV-2 (the virus responsible for the disease, COVID-19) is nonstructural protein-1 (Nsp1). Nsp1 is found in several coronaviruses such as SARS-CoV-2, MERS and SARS and its job is to help the virus hijack the human body’s protein production machinery.

In which International Journal of Molecular Sciences study, an international team led by Professor Frank Kozielski (UCL School of Pharmacy) used state-of-the-art technology to identify ligands (a type of binding molecule) that bind to SARS-CoV-2 Nsp1. To do this, they grew hundreds of protein crystals, which were then exposed to chemical compounds.

The team identified and characterized two new ligand binding sites on SARS-CoV-2 Nsp1. They also showed that there are differences at these sites between the three medically relevant coronaviruses that infect humans.

First author Shumeng Ma, a Ph.D. Student at the UCL School of Pharmacy, said: “This study was an example of how diverse scientists from different disciplines came together to work towards the common goal of contributing to the understanding of Nsp1 and its characterization as a potential drug target.”

In which eLife a team led by scientists from the University of Geneva and UCL Chemistry investigated whether it might be possible to develop drugs against Nsp1 using computational methods. The team used computer models to study its 3D structure and how it changes shape under different conditions or when attached to a variety of molecules. This revealed four previously unidentified binding pockets, two of which were fully obscured and two were partially obscured.

First author Alberto Borsatto, a Ph.D. Student at the University of Geneva, said: “Nsp1 is in principle an attractive target for antiviral drugs, but the shape of Nsp1 complicates the development of a potential drug. So far, only shallow, superficial cavities have been seen on the Nsp1 surface, and this makes it difficult for drugs to attach to and interfere with Nsp1 function.”

To determine if these pockets can be targeted with drugs, the team conducted an experiment in which they used computational methods to screen a library of 1,000 fragments and identify 59 different chemical fragments that “bound” to the protein in the computer model ” had. To their surprise, only one of the fragments bound experimentally to Nsp1.

To see if these observations only apply to SARS-CoV-2, the team examined the structures of Nsp1 proteins from other coronaviruses. Their computer models suggest that ligands targeting one of the pockets in SARS-Cov-2 Nsp1 could also target the corresponding pockets in other coronaviruses tested. This offers the potential to develop drugs that could protect against future coronavirus pandemics.

The eLife paper’s co-author, Professor Francesco Luigi Gervasio (UCL Chemistry and University of Geneva), said: “We have characterized potential drug-binding pockets in the SARS-CoV-2 virus Nsp1 and predicted four partially occluded pockets, one of which we validated using X-ray crystallography to have. The results of this research can be used as a stepping stone to develop Nsp1 inhibitors for SARS-CoV-2 and potentially other coronaviruses.”

More information:
Shumeng Ma et al., Two Ligand Binding Sites on SARS-CoV-2 Nonstructural Protein 1 Discovered by Fragment-Based X-ray Screening, International Journal of Molecular Sciences (2022). DOI: 10.3390/ijms232012448

Alberto Borsatto et al., Revealing drug-ready cryptic pockets in Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography, eLife (2022). DOI: 10.7554/eLife.81167

Journal Information:
eLife

Provided by University College London

Citation: Coronavirus Drug Target Identified That Could Halt Virus Replication (2022 December 3), retrieved December 3, 2022 from https://phys.org/news/2022-12-coronavirus-drug-halt-virus-replication. html

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