Pathologists have recognized the central role of airway mucus occlusion in the pathophysiology of asthma for more than a century,1,2 and in cystic fibrosis for nearly a century.3 In chronic obstructive pulmonary disease (COPD), understanding of the role of mucus centred for many years around its expectoration from central airways as the defining feature of the chronic bronchitic endotype, though expectoration correlates only weakly with airflow limitation.4 However, more recent examination of peripheral lung tissues from surgical specimens revealed that the mucus occlusion of small airways correlates strongly with airflow limitation.5 Despite this recognition by pathologists, clinicians have largely ignored the role of mucus in these obstructive lung diseases because airway occlusion could not be evaluated non-invasively and available treatments have been limited. In recent years, biochemical reconstitution was refined by using purified proteins and synthetic liposomes together with advanced single particle optical microscopy.15 Moreover, the cytoplasmic regulatory proteins Munc18 and Munc13 were included along with the SNARE proteins and Syt1 that were reconstituted into synthetic liposomes, bringing the system to a more physiological state.16 These advanced reconstitution assays allowed the confirmation of the functional importance of critical amino acids involved in calcium-triggered membrane fusion suggested by the structural work. Deletant mice showed marked reductions in stimulated mucin secretion and lumenal mucus occlusion in a model of allergic asthma, without an impairment of homeostatic baseline mucin secretion.11 Next, a series of stapled peptides based on the region of SNAP-25 known to interact with Syt1 were screened for their ability to inhibit a fusion of reconstituted synaptic vesicles with reconstituted neuronal plasma membranes. Besides its potential therapeutic value, our work is of interest because it builds