The COVID Moonshot Consortium’s chart is published in the prestigious journal Science on Nov. 10, revealing their discovery of a potent SARS-CoV-2 antiviral compound. He also reflects on the good fortune of his open clinical technique by launching a patent. -Free antiviral discovery program to expand a differentiated pathway in reaction to a pandemic emergency. Open-label scientific discovery of the leading non-covalent non-covalent SARS-CoV-2 protease inhibitors DOI 10. 1126/science. abo7201.
The COVID Moonshot initiative began as a spontaneous virtual collaboration in March 2020, when an organization of scientists and academics from academia and biopharma, generated through a call on Twitter, joined forces to launch a race against time to identify new molecules that could block SARS-CoV-2 viruses. This unprecedented, participatory, and completely open collaboration of more than two hundred scientists, learned about and developed new compounds with just the opposite antiviral activity to a key enzyme of the SARS-COV-2 virus, namely the master protease (Mpro). The lead applicant is recently undergoing a preclinical evaluation in collaboration with the Medicines for Neglected Diseases (DNDi) initiative. The COVID Moonshot is committed to the discovery of safe and affordable antiviral drugs that oppose COVID-19 globally and in the long term. viral pandemics and pioneers a direct-to-generic, patent-free approach.
The consortium paper reports on the discovery of a non-covalent, non-peptide inhibitor scaffold with lead-like properties, differentiated from the main existing protease inhibitors. His technique leveraged crowdsourcing, device learning, exascale molecular simulations, and high-throughput structural biology. and chemistry. It is based on the knowledge of an extensive experiment, completed in record time at the beginning of the pandemic, at Diamond Light Source’s XChem facility, for the detection of crystallographic fragments in Diamond’s high-throughput crystallography. In the experiment, 1,495 fragment-soaked crystals were analyzed for a few weeks to identify 78 effects that densely populated the enzyme’s active site.
The team was able to generate a detailed map of the structural plasticity of the main SARS-CoV-2 protease, extensive structure-activity relationships for various chemotypes, and a wealth of insights into biochemical activity. All composite models (> 18,000 models), crystallographic knowledge (>,840 ligand-related X-ray structures), assay knowledge (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this crusade were temporarily and openly shared, creating a rich, open, and intellectual wisdom base free of properties for long-term anti-coronavirus drug discovery.
By making all the knowledge available, with all the compounds available from the Ukrainian chemical supplier Enamine, the consortium aims to boost global studies on parallel pathways after its initial work.
The body of knowledge included in the journal Science provides a unique resource that links comprehensive structural knowledge, fragments, chemical scaffolds, as well as knowledge of biochemical and cellular analyses that can be visualized and leveraged through other scientists.
“This is the first time such a gigantic amount of protein-ligand structures have been generated for a drug discovery crusade and published in the public domain. This is a testament to Diamond’s high-throughput crystallography infrastructure, but also to the amazing coordination between Diamond Light Source, and the amazing coordination between the two world’s crystallography groups. “Many of the research groups around the world are under superpressure,” adds Dr. Daren Fearon, another lead scientist and beamline lead at Diamond Light Source, who runs the XChem facility.
As a striking example of the effect of open science, the clinical candidate Shionogi S-217622, which will be available in Japan under emergency approval under the name Xocova [ensitrelvir], was known to use knowledge generated at Diamond and published openly. Writer Professor Frank von Delft, Diamond Senior Beamline Scientist, Professor of Structural Chemical Biology at the University of Oxford and one of the founders of the consortium, comments: “Open science efforts have reshaped many spaces in bioscience. The COVID Moonshot provides an example of a viable path to early drug discovery through open science leading to breakthroughs in drug discovery for infectious diseases: a series of studies of great public importance but chronically underfunded through the personal sector. The main protease provides a roadmap for the prospective progression of antivirals over the long term.
Dr Annette von Delft, from the University of Oxford, adds: “This publication highlights the enormous toll that crowdsourcing can take on drug discovery. The COVID Moonshot task is unique for its collaborative technique and commitment to open science and demonstrates how collaboration can be a driving force behind innovation.
“Every day at Diamond, we are proud to work with leading scientists and academics from around the world, such as the COVID Moonshot Consortium, which conducts cutting-edge and encouraged studies at our facilities. Bringing together experts in physical and life science innovations, disciplinary teams and access to collaborative services enable our users to shine their skills in new technologies, treatments, sustainable materials and climate responses to the many demanding 21st century situations we face,” comments Diamond’s new CEO, Gianluigi Botton.
The discovery platform collaboration that spontaneously formed as COVID Moonshot now continues its work as an ASAP discovery consortium, which stands for AI-driven structure-enabled antiviral platform, which aims to find and develop novel broad-spectrum small molecule inhibitors against coronaviruses and flaviviruses. and enteroviruses for pandemic preparedness.
The initiative is a collaborative effort through the University of Oxford’s Nuffield Department of Medicine; soft fountain of diamonds; Loads; Weizmann Institute of Science; MedChemica Ltd; Mount Sinai Icahn School of Medicine; Enamine Ltd; Memorial Sloan Kettering Cancer Center; and Thames Pharma Partners LCC.
Diamond Light Source
Boby, M. L. et al. (2023) Open-label clinical discovery of potent non-covalent SARS-CoV-2 protease inhibitors. Science. is what je. org/10. 1126/science. abo7201.
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