Minimal N-methylated and stapled peptide ligands for the autophagy protein GABARAP
McDonald, I.; Wilms, J.; Cardi, N.; Engstrom, A.; Miao, J.; Willbold, D.; Lin, Y.-S.; Lokey, S.; Weiergraber, O.; Kritzer, J.
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The LC3/GABARAP protein family is a promising target for selective inhibition of autophagy and for targeted protein degradation. LC3/GABARAP proteins are challenging targets for small-molecule drug development due to their long, shallow binding grooves. In this work, we evaluate multiple approaches to stabilizing the extended structure of the native binding motif, producing N-methylated peptides and stapled peptides with low nanomolar affinity. A crystal structure and molecular dynamics simulations support a model where the N-methylation pre-organizes the motif into an extended, strand-like structure. N-methylation allowed minimization of the binding motif to a tetrapeptide that retained sub-micromolar affinity while minimizing charge and overall molecular weight. The truncated, N-methylated tetrapeptide showed moderate passive permeability. These results highlight more drug-like space for the development of LC3/GABARAP ligands with high affinity and selectivity.
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