Enzyme-Responsive Peptide Thioesters for Targeting Golgi Apparatus

Abstract

The Golgi apparatus (GA) is the hub of intracellular trafficking, but selectively targeting GA remains a challenge. We show an unconventional types of peptide thioesters, consisting of an aminoethyl thioester and acting as substrates of thioesterases, for instantly targeting the GA of cells. The peptide thioesters, above or below their critical micelle concentrations, enter cells mainly via caveolin-mediated endocytosis or macropinocytosis, respectively. After being hydrolyzed by GA-associated thioesterases, the resulting thiopeptides form dimers and accumulate in the GA. After saturating the GA, the thiopeptides are enriched in the endoplasmic reticulum (ER). Their buildup in ER and GA disrupts protein trafficking, thus leading to cell death via multiple pathways. The peptide thioesters target the GA of a wide variety of cells, including human, murine, and Drosophila cells. Changing d-diphenylalanine to l-diphenylalanine in the peptide maintains the GA-targeting ability. In addition, targeting GA redirects protein (e.g., NRAS) distribution. This work illustrates a thioesterase-responsive and redox-active molecular platform for targeting the GA and controlling cell fates.

Enzyme-instructed morphology transformation of mitochondria-targeting peptide for the selective eradication of osteosarcoma

“…In contrast, 50% viability was observed for Saos-2 cells and HeLa cells at about 5 mM due to the high level of ALP expression. 37,38 This suggests that the cytotoxicity of L-Mito-FFYp is selective toward the ALP enzyme expression (Fig. 3A).…”

Molecular to Supramolecular Self-Assembled Luminogens for Tracking the Intracellular Organelle Dynamics

“…Golgi apparatus is a crucial signaling station associated with the modification and intra- and extracellular transportation of several secretory proteins and glycoproteins . Recent reports suggest that the Golgi apparatus plays an essential role in cellular stress response, drug resistance, and apoptosis mechanism. − In this section, we have discussed (i) some of the dynamical processes occurring in the organelles that assist in cellular functioning and (ii) the essential features of molecular and supramolecular probes for monitoring the dynamic behavior of organelles.…”

Peptide-Based Low Molecular Weight Photosensitive Supramolecular Gelators

“…One potentially helpful feature of supramolecular gels is their switchable behavior in different physical states in response to various external stimuli. Although a plethora of incentives, for example, ionic strength [ 62 , 63 , 64 ], pH [ 44 , 64 ], enzyme [ 65 , 66 , 67 , 68 , 69 ], temperature [ 14 , 70 , 71 , 72 ], mechanical stress [ 73 ], light [ 74 , 75 ], etc., have been reported extensively to show the switching ability, among them, light has received extensive attention because of its non-invasive nature and more importantly, light permits to target a specific area of gel remotely by using photo masks with a high level of spatiotemporal resolution causing patterned gel surfaces and rapid phase transitions reversibly [ 17 , 18 , 76 , 77 , 78 ]. On top of that, the system is free from waste generation/chemical contaminants hence closed systems can be stimulated without introducing any foreign chemicals, and finally, the light can be conveniently switched on and off with specific wavelengths and tunable intensities to modulate and program supramolecular gelation [ 18 , 77 , 79 ].…”