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AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
Trepte, Philipp; Secker, Christopher; Olivet, Julien; Blavier, Jeremy; Kostova, Simona; Maseko, Sibusiso B; Minia, Igor; Silva Ramos, Eduardo; Cassonnet, Patricia; Golusik, Sabrina; Zenkner, Martina; Beetz, Stephanie; Liebich, Mara J; Scharek, Nadine; Schütz, Anja; Sperling, Marcel; Lisurek, Michael; Wang, Yang; Spirohn, Kerstin; Hao, Tong; Calderwood, Michael A; Hill, David E; Landthaler, Markus; Choi, Soon Gang; Twizere, Jean-Claude; Vidal, Marc; Wanker, Erich E.
Afiliação
  • Trepte P; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany. philipp.trepte@imba.oeaw.ac.at.
  • Secker C; Brain Development and Disease, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030, Vienna, Austria. philipp.trepte@imba.oeaw.ac.at.
  • Olivet J; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany. secker@zib.de.
  • Blavier J; Zuse Institute Berlin, Berlin, Germany. secker@zib.de.
  • Kostova S; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
  • Maseko SB; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Minia I; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • Silva Ramos E; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Cassonnet P; Structural Biology Unit, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, 3000, Leuven, Belgium.
  • Golusik S; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
  • Zenkner M; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Beetz S; Laboratory of Viral Interactomes, Interdisciplinary Cluster for Applied Genoproteomics (GIGA)-Molecular Biology of Diseases, University of Liège, 4000, Liège, Belgium.
  • Liebich MJ; RNA Biology and Posttranscriptional Regulation, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125, Berlin, Germany.
  • Scharek N; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Schütz A; Département de Virologie, Unité de Génétique Moléculaire des Virus à ARN (GMVR), Institut Pasteur, Centre National de la Recherche Scientifique (CNRS), Université de Paris, Paris, France.
  • Sperling M; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Lisurek M; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Wang Y; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Spirohn K; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Hao T; Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Calderwood MA; Protein Production & Characterization, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
  • Hill DE; Multifunctional Colloids and Coating, Fraunhofer Institute for Applied Polymer Research (IAP), 14476, Potsdam-Golm, Germany.
  • Landthaler M; Structural Chemistry and Computational Biophysics, Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany.
  • Choi SG; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Twizere JC; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • Vidal M; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Wanker EE; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Mol Syst Biol ; 20(4): 428-457, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38467836
ABSTRACT
Protein-protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: SARS-CoV-2 / COVID-19 Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article