However, these inhibitors also suffer from poor selectivity for autophagy, poor potency, or both. Additional autophagy inhibitors frequently used in preclinical studies include the pan-PI3K inhibitor 3-methyladenine, as well as the V-ATPase inhibitor bafilomycin A1. However, their mechanism of action is thought to target lysosomal function, which is a relatively nonselective route to autophagy inhibition. Currently, the only autophagy inhibitors used in clinical studies have been the FDA-approved antimalarials chloroquine and hydroxychloroquine. A number of clinical trials have demonstrated improved overall survival when combining autophagy inhibition with standard-of-care chemotherapy and radiation in aggressive cancers, including glioblastoma multiforme and pancreatic adenocarcinoma. In fact, autophagy inhibition has been shown to be effective both in solid tumors and in hematological malignancies. However, advanced malignancies depend on autophagy as a quality control mechanism, much like they depend on the ubiquitin-proteasome system. Some evidence suggests autophagy is protective against tumorigenesis, so autophagy inhibition may not be useful for preventing or treating early-stage cancers. Inhibiting autophagy has been suggested as a potential cancer therapy, though the relationship between autophagy and cancer is complex. Dysregulated autophagy is associated with many diseases including lysosomal storage diseases, neurodegenerative disorders, and cancers. These peptides represent the highest-affinity LC3B-selective ligands reported to date, and they will be useful tools for further elucidation of LC3B’s role in autophagy and in cancer.Īutophagy is a highly conserved eukaryotic pathway for recycling proteins, organelles, and other cellular components. Based on these data, we used artificial amino acids and diversity-oriented stapling to improve affinity and resistance to biological degradation while maintaining or improving LC3B affinity and selectivity. We obtained structure-activity relationships that quantify the binding contributions of peptide termini, individual charged residues, and hydrophobic interactions. In this work, we use a known peptide ligand as a starting point to develop improved LC3B inhibitors. The microtubule-associated protein 1A/1B light chain 3B protein, LC3B, is an adapter protein that mediates key protein-protein interactions at several points in autophagy pathways. More specific autophagy inhibitors have not yet been developed. Existing autophagy inhibitors are primarily lysosomotropic agents. A growing body of evidence suggests that autophagy inhibition enhances the effectiveness of chemotherapy, especially in difficult-to-treat cancers.
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