7 research outputs found
Rapid Endolysosomal Escape and Controlled Intracellular Trafficking of Cell Surface Mimetic Quantum-Dots-Anchored Peptides and Glycopeptides
A novel strategy for the development
of a high performance nanoparticules
platform was established by means of cell surface mimetic quantum-dots
(QDs)-anchored peptides/glycopeptides, which was developed as a model
system for nanoparticle-based drug delivery (NDD) vehicles with defined
functions helping the specific intracellular trafficking after initial
endocytosis. In this paper, we proposed a standardized protocol for
the preparation of multifunctional QDs that allows for efficient cellular
uptake and rapid escaping from the endolysosomal system and subsequent
cytoplasmic molecular delivery to the target cellular compartment.
Chemoselective ligation of the ketone-functionalized hexahistidine
derivative facilitated both efficient endocytic entry and rapid endolysosomal
escape of the aminooxy/phosphorylcholine self-assembled monolayer-coated
QDs (AO/PCSAM-QDs) to the cytosol in various cell lines such as human
normal and cancer cells, while modifications of these QDs with cell-penetrating
arginine-rich peptides showed poor cellular uptake and induced self-aggregation
of AO/PCSAM-QDs. Combined use of hexahistidylated AO/PCSAM-QDs with
serglycine-like glycopeptides, namely synthetic proteoglycan initiators
(PGIs), elicited the entry and controlled intracellular trafficking,
Golgi localization, and also excretion of these nanoparticles, which
suggested that the present approach would provide an ideal platform
for the design of high performance NDD systems
Correction: A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes (Chem. Sci. (2020) 11 (4999-5006) DOI: 10.1039/D0SC00317D)
Correction for ‘A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes’ by Hajime Wakui et al., Chem. Sci., 2020, 11, 4999–5006, DOI: 10.1039/D0SC00317D
A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes
Aberrantly truncated immature O-glycosylation in proteins occurs in essentially all types of epithelial cancer cells, which was demonstrated to be a common feature of most adenocarcinomas and strongly associated with cancer proliferation and metastasis. Although extensive efforts have been made toward the development of anticancer antibodies targeting MUC1, one of the most studied mucins having cancer-relevant immature O-glycans, no anti-MUC1 antibody recognises carbohydrates and the proximal MUC1 peptide region, concurrently. Here we present a general strategy that allows for the creation of antibodies interacting specifically with glycopeptidic neoepitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional structure analysis, epitope mapping and biochemical analysis. The X-ray crystal structure of the anti-MUC1 monoclonal antibody SN-101 complexed with the antigenic glycopeptide provides for the first time evidence that SN-101 recognises specifically the essential epitope by forming multiple hydrogen bonds both with the proximal peptide and GalNAc linked to the threonine residue, concurrently. Remarkably, the structure of the MUC1 glycopeptide in complex with SN-101 is identical to its solution NMR structure, an extended conformation induced by site-specific glycosylation. We demonstrate that this method accelerates dramatically the development of a new class of designated antibodies targeting a variety of "dynamic neoepitopes" elaborated by disease-specific O-glycosylation in the immunodominant mucin domains and mucin-like sequences found in intrinsically disordered regions of many proteins