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Peptide-based Identification of Functional Motifs and their Binding Partners

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Published on: June 30, 2013

Signal peptide mimicry primes Sec61 for client-selective inhibition.

Shahid Rehan¹, Dale Tranter¹, Phillip P Sharp²

¹Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.

Nature Chemical Biology

|May 11, 2023

Summary

A novel cyclic depsipeptide, KZR-8445, selectively inhibits protein biogenesis by targeting the Sec61 translocon. This discovery offers a promising therapeutic strategy for inflammatory diseases like rheumatoid arthritis.

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Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

Targeting protein biogenesis is a therapeutic strategy, but toxicity has limited success.
The Sec61 translocon is crucial for secretory and membrane protein biogenesis.

Purpose of the Study:

To develop a novel therapeutic agent targeting the Sec61 translocon.
To investigate the mechanism of action and efficacy of KZR-8445.

Main Methods:

Described KZR-8445, a cyclic depsipeptide.
Utilized cryogenic electron microscopy to determine the structure of KZR-8445 bound to Sec61.
Assessed inhibition of pro-inflammatory cytokine secretion in immune cells.
Evaluated efficacy in a mouse model of rheumatoid arthritis.

Main Results:

KZR-8445 selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner.
KZR-8445 inhibits pro-inflammatory cytokine secretion and shows efficacy in a rheumatoid arthritis mouse model.
Cryo-EM structure reveals KZR-8445 binds to the Sec61 lateral gate, trapping signal peptides.

Conclusions:

KZR-8445 is a potent inhibitor of Sec61-mediated protein biogenesis.
Structure-guided design provides a framework for developing novel therapeutics targeting Sec61.
Selective modulation of protein biogenesis offers a promising approach for treating inflammatory diseases.