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This is most likely attributed to the inability of the constrained 13- and 14-membered macrocycles to adopt the proper transition states required for cleavage of the N-terminal peptide bond (Andersson et al., 2011) (Figure 8)

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The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner 2