As coronavirus disease 2019 (COVID-19) continues to spread globally, the need for effective antivirals becomes more urgent. To date, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 138.40 million cases and more than 2.97 million deaths.
An international team of researchers focused on the macrodomain part of the non-structural protein 3 (Nsp3) gene product that SARS-CoV-2 uses to overturn the host cell’s natural antiviral response.
The team provided a template that can help develop novel antivirals that are direct-acting and can combat the current pandemic.
Published in the journal Science Advances, the team determined that a part of the virus’s machinery, called Mac1, is important for reproduction. Past studies have shown that viruses that do not contain them cannot replicate in host cells, hinting that finding a drug to block it may have the same effect.
Macrodomains are conserved protein domains found throughout the kingdoms of life and in some viruses. Viral microdomains recognize and eradicate host-derived adenosine diphosphate (ADP)-ribosylation, a post-translational modification of host and pathogen proteins.
The innate immune response involves signaling by ADP-ribosylation, which can help suppress viral replication. The SARS-CoV-2 macrodomain within the Nsp3 counters the host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a potential target for antivirals because catalytic mutations make viruses unable to cause illness.
Crystallographic fragment screen
To arrive at the study findings, the team used a crystallographic fragment screen of the Nsp3 Mac1 protein. They found a total of 234 fragment compounds that directly attach to the surface of the protein.
From there, the researchers mapped out chemical motifs and protein-compound interactions that scientists and pharmaceutical companies can use to design potent compounds that could be used to develop novel antiviral drugs.
These antivirals can be used to combat the current pandemic and future viral outbreaks.
"Robustly identifying this kind of chemical matter for promising and tractable targets like Nsp3 is the first step in rational drug discovery,” Principal Beamline Scientist, Frank von Delft, said.
“This is always a long journey fraught with difficulty and failure, but the battery of new structural biology methods that we combined in this study, including fragment screening at Diamond and computational docking at UCSF, are helping to change drug discovery and make it easier to find effective drug candidates," he added.
The fragments cover a broad range of chemical motifs. The current study provides a blueprint or plan of the next steps in designing more efficient molecules.
The most promising compounds found can help in discovering new drugs, which includes not only improving the biological potency but also making sure the final molecule has the essential properties, such as minimal side effects and easy absorption in the body.
Fragment screening is a method to identify the building blocks of a future drug molecule. The approach also works by observing how these molecules interact with the protein being studied. It determines how the molecule influences protein biology.
This new method can reduce the number of compounds needed to be screened to find the one that can bind to the cell’s surface protein. The experiment, which was performed at the XChem platform, provides 3D results that enhance the design process and ensure a more cost-effective experiment.
Aside from fragment screening, the team utilized another technique to discover potential drugs, computational docking. The method uses computer models and simulations to evaluate interactions of virtual molecules with Mac1. In this method, the researchers have identified 60 potential candidates from 20 million molecules, which were assessed via X-ray crystallography. From there, the team obtained 20 good hits.
These several fragment hits were confirmed by solution binding using three techniques, including differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry. The 234 fragment structures provided starting points for developing potent and effective SARS-CoV-2 macrodomain inhibitors.
Together, these advances will speed progress throughout the community to help validate this target and create effective antivirals,” the researchers noted in the study.
- Schuller, M., Correym G., Gahbauer, S. et al. (2021). Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Science Advances. DOI: 10.1126/sciadv.abf8711, https://advances.sciencemag.org/content/7/16/eabf8711
Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News
Tags: Adenosine, Assay, Cell, Compound, Coronavirus, Coronavirus Disease COVID-19, Crystallography, Drug Discovery, Drugs, Enzyme, Fluorescence, Gene, Immune Response, Molecule, Pandemic, Pathogen, Protein, Reproduction, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Structural Biology, Structural Protein, Syndrome, Titration, Virus, X-Ray
Angela Betsaida B. Laguipo
Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.
Source: Read Full Article