Metabolic Probing of Sialylated Glycoconjugates with Fluorine-Selenol Displacement Reaction (FSeDR)
Zhao, Yue
;
Lyu, Zhigang
;
Prather, Benjamin
, et al.
ACS Bio Med Chem Au,2024.
DOI:
10.1021/acsbiomedchemau.4c00084
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Abstract: Dysregulated sialic acid biosynthesis is characteristic of the onset and progression of human diseases including hormone-sensitive prostate cancer and breast cancer. The sialylated glycoconjugates involved in this process are therefore important targets for identification and functional studies. To date, one of the most common strategies is metabolic glycoengineering, which utilizes N-acetylmannosamine (ManNAc) analogues such as N-azidoacetylmannosamine (ManNAz) to hijack sialic acid biosynthesis and label the sialylated glycoconjugates with "click chemistry (CuAAC)" tags. Yet, current chemical modifications including those CuAAC-based alkyne/azide tags are still big in size, and the resulting steric hindrance perturbs the mannosamine and sialic acid derivatives' recognition and metabolism by enzymes involved in biosynthetic pathways. As a result, the peracetylated ManNAz has compromised incorporation to sialic acid substrates and manifests cellular growth inhibition and cytotoxicity. Herein, we show that the α-fluorinated peracetylated analogue ManN(F-Ac) displayed a satisfying safety profile in mammalian cell lines at concentrations as high as 500 μM. More importantly, aliphatic selenol-containing probes can efficiently displace α-fluorine in fluoroacetamide-containing substrates including ManN(F-Ac) at a neutral pH range (~7.2). The combined use of peracetylated ManN(F-Ac) and the dethiobiotin-selenol probe as the fluorine-selenol displacement reaction (FSeDR) toolkit allowed for successful metabolic labeling of sialoglycoproteins in multiple prostate and cancer cell lines, including PC-3 and MDA-MB-231. More sialoglycoproteins in these cell lines were demonstrated to be labeled by FSeDR compared with the traditional CuAAC approach. Lastly, with FSeDR-mediated metabolic labeling, we were able to probe the cellular expression level and spatial distribution of sialylated glycoconjugates during the progression of these hormone-sensitive cancer cells. Taken together, the promising results suggest the potential of the FSeDR strategy to efficiently and systematically identify and study sialic acid substrates and potentially empower metabolic engineering on a diverse set of glycosylated proteins that are vital for human diseases.
Keywords:
metabolic engineering ;
mannosamine ;
sialic acid ;
glycobiology ;
fluorine displacement reaction ;
selenium ;
fluorine-selenol displacement reaction (FSeDR)
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Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging, drug targeting and delivery
Chen, Jing
;
Ji, Peng
;
Gnawali, Giri
, et al.
APSB,2023,13(6):2736-2746.
DOI:
10.1016/j.apsb.2022.12.018
PubMed ID:
37425049
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Abstract: The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as "overexpressed" biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug, which ultimately leads to effective and safe cancer therapy.
Keywords:
Artificial receptor ;
Click and release ;
Local activation ;
Protein degradation
Purchased from AmBeed:
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5505-63-5 ;
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