Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases

Bibliographic Details
Main Author:	Yu, Zhen
Language:	English
Published:	The Ohio State University / OhioLINK 2017
Subjects:	Chemistry ATCUN catalytic metallodrug bioinorganic chemistry copper G-quadruplex telomeric DNA DNA cleavage carbohydrate fucose blood group antigen Bombay blood
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu1500316480959497

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu15003164809594972021-08-03T07:03:22Z Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases Yu, Zhen Chemistry ATCUN catalytic metallodrug bioinorganic chemistry copper G-quadruplex telomeric DNA DNA cleavage carbohydrate fucose blood group antigen Bombay blood Metal complexes that catalyze inactivation and degradation of biomolecular targets can be developed into novel therapeutics (catalytic metallodrugs) against a variety of diseases and molecular tools to study biology. Despite recent advances in the field, a lack of substrate selectivity is a major hindrance to the development of metal catalysts for biological application. Improved targeting can enhance catalytic efficiency and minimize nonselective activity and the potential for side effects in clinical practice. We employed the strategy of substrate-selective catalytic metallodrugs and designed selective copper catalysts that target disease-associated biomolecules including G-quadruplex telomeric DNA and L-fucose. In the first part of this work, we report small-molecule Cu complexes as membrane-permeable nucleases that promote selective DNA cleavage of G-quadruplex telomeric DNA. Despite recent advances in nuclease technology, targeting nucleic acids with protein-based nucleases in live cells remains a challenge due to low membrane permeability of proteins. Telomeric DNA determines the replicative capacity of cells, while successive shortening of telomeric DNA leads to cellular senescence. Fine tuning of nuclease activity has resulted in rapid reduction of telomere length promoted by these Cu complexes in cancer cells. Low non-specific DNA damage confirms the cleavage selectivity of Cu complexes under cellular context. Furthermore, we also show these Cu complexes promote more rapid telomere reduction in S-phase specific than G1/G0 phase, which should be associated with increase of G-quadruplex formation during DNA replication. Our results implicate a strategy for the development of artificial nucleases that can degrade therapeutically relevant nucleic acids in cells.In the second part of this work, we highlight the design of synthetic agents that mimic natural fucosidases for biological application. Catalysts that promote carbohydrate degradation are of wide potential application, but the use of either enzyme glycosidases or small-molecule catalysts in biological systems raises significant challenges. Our strategy is illustrated by application to the development of potential blood substitutes for rare Bombay blood that is characterized by a deficiency of H-antigen. Metallopeptides with 16 to 20 amino acids have been constructed as artificial fucosidases that exhibit selective carbohydrate cleavage reactivity toward L-fucose rather than D-glucose. Selective fucose cleavage from the H-antigen saccharide promotes efficient removal of H-antigen on erythrocytes and fulfils the conversion of regular human O-type erythrocytes to potential blood substitutes for rare Bombay blood. 2017-12-07 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1500316480959497 http://rave.ohiolink.edu/etdc/view?acc_num=osu1500316480959497 restricted--full text unavailable until 2022-08-07 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Chemistry ATCUN catalytic metallodrug bioinorganic chemistry copper G-quadruplex telomeric DNA DNA cleavage carbohydrate fucose blood group antigen Bombay blood
spellingShingle	Chemistry ATCUN catalytic metallodrug bioinorganic chemistry copper G-quadruplex telomeric DNA DNA cleavage carbohydrate fucose blood group antigen Bombay blood Yu, Zhen Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
author	Yu, Zhen
author_facet	Yu, Zhen
author_sort	Yu, Zhen
title	Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
title_short	Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
title_full	Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
title_fullStr	Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
title_full_unstemmed	Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases
title_sort	substrate-selective copper catalysts as catalytic metallodrugs: from g-quadruplex targeting small-molecular nucleases to artificial glycosidases
publisher	The Ohio State University / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu1500316480959497
work_keys_str_mv	AT yuzhen substrateselectivecoppercatalystsascatalyticmetallodrugsfromgquadruplextargetingsmallmolecularnucleasestoartificialglycosidases
_version_	1719452773836128256

Substrate-Selective Copper Catalysts as Catalytic Metallodrugs: from G-Quadruplex Targeting Small-Molecular Nucleases to Artificial Glycosidases

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