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  3. Discovery of a novel inhibitor of macropinocytosis with antiviral activity

Discovery of a novel inhibitor of macropinocytosis with antiviral activity

  • Mol Ther. 2024 Jul 2:S1525-0016(24)00455-6. doi: 10.1016/j.ymthe.2024.06.038.
Bartlomiej Porebski 1,  Wanda Christ 2,  Alba Corman 1,  Martin Haraldsson 3,  Myriam Barz 1,  Louise Lidemalm 1,  Maria Häggblad 1,  Juliana Ilmain 4,  Shane C Wright 5,  Matilde Murga 6,  Jan Schlegel 7,  Malin Jarvius 8,  Maris Lapins 9,  Erdinc Sezgin 7,  Gira Bhabha 4,  Volker M Lauschke 10,  Jordi Carreras-Puigvert 8,  Miguel Lafarga 11,  Jonas Klingström 12,  Daniela Hühn 1,  Oscar Fernandez-Capetillo 13
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
  • 2 Center of Infectious Medicine, Department of Medicine, Karolinska Institutet, 141-86 Huddinge, Sweden.
  • 3 Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • 4 Grossman School of Medicine, New York University, New York, NY 10016, USA.
  • 5 Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
  • 6 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
  • 7 Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • 8 Department of Pharmaceutical Biosciences and Science for Life Laboratory, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden; Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
  • 9 Department of Pharmaceutical Biosciences and Science for Life Laboratory, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
  • 10 Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden; Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany; University of Tuebingen, 72074 Tuebingen, Germany.
  • 11 Departament of Anatomy and Cellular Biology, Neurodegenerative Diseases Network (CIBERNED), University of Cantabria-IDIVAL, 39011 Santander, Spain.
  • 12 Center of Infectious Medicine, Department of Medicine, Karolinska Institutet, 141-86 Huddinge, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden.
  • 13 Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden; Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Electronic address: oscar.fernandez-capetillo@ki.se.
PMID: 38956870 DOI: 10.1016/j.ymthe.2024.06.038
Abstract

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with Antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing Infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit Infection by SARS-CoV-2, as well as by additional viruses, such as mpox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2.

Keywords

SARS-CoV-2; antivirals; chemical screen; drug development; macropinocytosis; mpox virus; pseudotype virus; tick-borne encephalitis virus.

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