Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity
Qingqing Hao1, Laurie Wang2, Hui Pan3
1School of Life Sciences, Fudan University, Shanghai 200438, China; Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou 510000, China.
Abstract:
Coibamide A (CbA) is a cyclic depsipeptide that inhibits the function of the Sec61 translocon and exhibits significant antitumor activity. However, its broad Sec61 inhibition results in non-selective cytotoxicity, limiting therapeutic applications. To elucidate the molecular mechanism of CbA-mediated Sec61 blockade and enable rational prodrug design, we determined the cryo-EM structure of human Sec61 bound to CbA at 3.1 Å resolution. The structure reveals that CbA adopts a distinctive lasso-like conformation and occupies the lateral gate of Sec61, a binding site shared with other Sec61 inhibitors, while forming a particularly more expansive set of interactions with the lateral gate. Guided by these structural insights, we conducted structure-activity relationship studies and developed prodrug strategies that modulate CbA's antitumor activity through the controlled perturbation of intramolecular and protein hydrogen bonding interactions. Together, these results establish a structure-guided strategy for prodrug design of CbA and demonstrate the general applicability of backbone-caging to enhance the tolerability of Sec61 inhibitors.
Insights
Coibamide A inhibits the Sec61 translocon but causes toxicity. Researchers determined its structure bound to Sec61, enabling prodrug design for improved antitumor therapy with reduced side effects.
Area of Science:
- Structural Biology
- Molecular Pharmacology
- Drug Discovery
Background:
- Coibamide A (CbA) is a cyclic depsipeptide with antitumor properties.
- CbA inhibits the Sec61 translocon, but its broad action leads to non-selective cytotoxicity, limiting clinical use.
Purpose of the Study:
- To determine the cryo-EM structure of human Sec61 bound to CbA.
- To elucidate the molecular mechanism of CbA-mediated Sec61 blockade.
- To guide rational prodrug design for enhanced therapeutic applications.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of human Sec61 complexed with CbA at 3.1 Å resolution.
- Structure-activity relationship (SAR) studies.
- Prodrug strategy development based on structural insights.
Main Results:
- The cryo-EM structure revealed CbA adopts a lasso-like conformation.
- CbA binds to the lateral gate of Sec61, forming extensive interactions.
- Structure-guided SAR studies and prodrug development successfully modulated CbA's antitumor activity.
Conclusions:
- The study establishes a structure-guided strategy for designing Coibamide A prodrugs.
- The findings demonstrate the potential of backbone-caging for improving the tolerability of Sec61 inhibitors.
- This work paves the way for developing more selective and effective Sec61-targeting cancer therapies.
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