Abstract
The endoplasmic reticulum (ER) is responsible for the synthesis and folding of a large number of proteins, as well as intracellular calcium regulation, lipid synthesis, and lipid transfer to other organelles, and is emerging as a target for cancer therapy. However, strategies for selectively targeting the ER of cancer cells are limited. Here we show that enzymatically generated crescent-shaped supramolecular assemblies of short peptides disrupt cell membranes and target ER for selective cancer cell death. As revealed by sedimentation assay, the assemblies interact with synthetic lipid membranes. Live cell imaging confirms that the assemblies impair membrane integrity, which is further supported by lactate dehydrogenase (LDH) assays. According to transmission electron microscopy (TEM), static light scattering (SLS), and critical micelle concentration (CMC), attaching an L-amino acid at the C-terminal of a D-tripeptide results in the crescent-shaped supramolecular assemblies. Structure-activity relationship suggests that the crescent- shaped morphology is critical for interacting with membranes and for controlling cell fate. Moreover, fluorescent imaging indicates that the assemblies accumulate on the ER. Time-dependent Western blot and ELISA indicate that the accumulation causes ER stress and subsequently activates the caspase signaling cascade for cell death. As an approach for in situ generating membrane binding scaffolds (i.e., the crescent-shaped supramolecular assemblies), this work promises a new way to disrupt the membrane and to target the ER for developing anticancer therapeutics.