2. Academic Validation
  3. Signal peptide mimicry primes Sec61 for client-selective inhibition

Signal peptide mimicry primes Sec61 for client-selective inhibition

  • Nat Chem Biol. 2023 Sep;19(9):1054-1062. doi: 10.1038/s41589-023-01326-1.
Shahid Rehan 1,  Dale Tranter 1,  Phillip P Sharp 2,  Gregory B Craven 2,  Eric Lowe 3,  Janet L Anderl 3,  Tony Muchamuel 3,  Vahid Abrishami 1,  Suvi Kuivanen 4,  Nicole A Wenzell 2,  Andy Jennings 3,  Chakrapani Kalyanaraman 5,  Tomas Strandin 6,  Matti Javanainen 1,  Olli Vapalahti 6,  Matthew P Jacobson 5,  Dustin McMinn 3,  Christopher J Kirk 3,  Juha T Huiskonen 1,  Jack Taunton 7,  Ville O Paavilainen 8
Affiliations

Affiliations

  • 1 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
  • 3 Kezar Life Sciences, South San Francisco, CA, USA.
  • 4 Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of California, San Francisco, CA, USA.
  • 6 Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 7 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. jack.taunton@ucsf.edu.
  • 8 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland. ville.paavilainen@helsinki.fi.
PMID: 37169961 DOI: 10.1038/s41589-023-01326-1
Abstract

Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.

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