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
  • 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. [email protected].
  • 8. Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland. [email protected].
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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