Publication Date: April 14, 2021
Fragment-based screening is an approach to identify building blocks of the future drug molecule, observing how they interact with the protein under study, contextualizing those interactions, and providing starting points for molecules that directly influence the biology of the protein. New research published by EU-OPENSCREEN collaborators at the XChem platform at Diamond performed a crystallographic fragment screen of the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response. This study discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and that can be used by researchers and pharmaceutical companies to design compounds that could be developed into antiviral drugs.
Publication Date: March 11, 2021
Authors: Maria Kuzikov*, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.
Published: March 4, 2021
Authors: AlessandraSilvestri1, FranciscaVicente2, María J.Vicent3, BahneStechmann1, WolfgangFecke1
1 EU-OPENSCREEN ERIC, Berlin, Germany
2 Fundación MEDINA, Granada, Spain
3 Polymer Therapeutics Lab and Screening Platform, Príncipe Felipe Research Centre, Valencia, Spain
In this review, we provide an overview of recent publications in the field of HTS with complex cellular models, explain the potential of these approaches, and highlight gaps that still need to be addressed. Moreover, we bring the attention of cellular biology and medicinal chemistry groups to collaborative initiatives, such as EU-OPENSCREEN ERIC, which can efficiently support researchers from academia and industry to easily access such complex assay formats in state-of-the-art chemical biology platforms. Such collaborative approaches can accelerate the drug discovery process and allow for a more efficient development of new technologies and their adaptation onto screening platforms. This will lead to the production of more physiologically relevant results that, in turn, can be more easily translated into clinical therapies.
The success of preclinical drug discovery strongly relies on the ability of experimental models to resemble human pathophysiology. The number of compounds receiving approval for clinical use is limited, and this has led to the development of more physiologically relevant cellular models aimed at making preclinical results more prone to be successfully translated into clinical use. In this review, we summarize the technologies available in the field of high-throughput screening (HTS) using complex cellular models, and describe collaborative initiatives, such as EU-OPENSCREEN, which can efficiently support researchers to easily access state-of-the-art chemical biology platforms for improving the drug discovery process and allow for a more efficient development of new technologies and their adaptation onto screening platforms. This will lead to the production of more physiologically relevant results that, in turn, can be more easily translated into clinical therapies.
Published: January 7, 2019
Authors: Philip Brennecke, Dace Rasina, Oscar Aubi, Katja Herzog, Johannes Landskron, Bastien Cautain, Francisca Vicente, Jordi Quintana, Jordi Mestres, Bahne Stechmann, Bernhard Ellinger, Jose Brea, Jacek L. Kolanowski, Radosław Pilarski, Mar Orzaez, Antonio Pineda-Lucena, Luca Laraia, Faranak Nami, Piotr Zielenkiewicz, Kamil Paruch, Espen Hansen, Jens P. von Kries, Martin Neuenschwander, Edgar Specker, Petr Bartunek, Sarka Simova, Zbigniew Leśnikowski, Stefan Krauss, Lari Lehtiö, Ursula Bilitewski, Mark Brönstrup, Kjetil Taskén, Aigars Jirgensons, Heiko Lickert, Mads H. Clausen, Jeanette H. Andersen, Maria J. Vicent, Olga Genilloud, Aurora Martinez, Marc Nazaré, Wolfgang Fecke, Philip Gribbon
Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN’s compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.