Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides

Ying Lai (), Giorgio Fois, Jose R. Flores, Michael J. Tuvim, Qiangjun Zhou, Kailu Yang, Jeremy Leitz, John Peters, Yunxiang Zhang, Richard A. Pfuetzner, Luis Esquivies, Philip Jones, Manfred Frick (), Burton F. Dickey () and Axel T. Brunger ()
Additional contact information
Ying Lai: Stanford University
Giorgio Fois: Ulm University
Jose R. Flores: University of Texas MD Anderson Cancer Center
Michael J. Tuvim: University of Texas MD Anderson Cancer Center
Qiangjun Zhou: Stanford University
Kailu Yang: Stanford University
Jeremy Leitz: Stanford University
John Peters: Stanford University
Yunxiang Zhang: Stanford University
Richard A. Pfuetzner: Stanford University
Luis Esquivies: Stanford University
Philip Jones: University of Texas MD Anderson Cancer Center
Manfred Frick: Ulm University
Burton F. Dickey: University of Texas MD Anderson Cancer Center
Axel T. Brunger: Stanford University

Nature, 2022, vol. 603, issue 7903, 949-956

Abstract: Abstract Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1–4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7–11. Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+-triggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.

Date: 2022
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DOI: 10.1038/s41586-022-04543-1

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