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Bradley L. Pentelute - One of the best experts on this subject based on the ideXlab platform.
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Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents.
Angewandte Chemie (International ed. in English), 2021Co-Authors: Muhammad Jbara, Stephen L. Buchwald, Jacob Rodriguez, Heemal H Dhanjee, Andrei Loas, Bradley L. PenteluteAbstract:Organometallic reagents enable practical strategies for Bioconjugation. Innovations in the design of water-soluble ligands and the enhancement of reaction rates have allowed for chemoselective cross-coupling reactions of peptides and proteins to be carried out in water. There are currently no organometallic-based methods for oligonucleotide Bioconjugation to other biomolecules. Here we report bifunctional palladium(II)-oxidative addition complexes (OACs) as reagents for high-yielding oligonucleotide Bioconjugation reactions. These bifunctional OACs react chemoselectively with amine-modified oligonucleotides to generate the first isolable, bench stable oligonucleotide-palladium(II) OACs. These complexes undergo site-selective C-S arylation with a broad range of native thiol-containing biomolecules at low micromolar concentrations in under one hour. This approach provided oligonucleotide-peptide, oligonucleotide-protein, oligonucleotide-small molecule, and oligonucleotide-oligonucleotide conjugates in >80% yield and afforded conjugation of multiple copies of oligonucleotides onto a monoclonal antibody.
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Arylation Chemistry for Bioconjugation
Angewandte Chemie, 2019Co-Authors: Chi Zhang, Alexander M Spokoyny, Ekaterina V. Vinogradova, Stephen L. Buchwald, Bradley L. PenteluteAbstract:Bioconjugation chemistry has been used to prepare modified biomolecules with functions beyond what nature intended. Central to these techniques is the development of highly efficient and selective Bioconjugation reactions that operate under mild, biomolecule compatible conditions. Methods that form a nucleophile-sp2 carbon bond show promise for creating bioconjugates with new modifications, sometimes resulting in molecules with unparalleled functions. Here we outline and review sulfur, nitrogen, selenium, oxygen, and carbon arylative Bioconjugation strategies and their applications to modify peptides, proteins, sugars, and nucleic acids.
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systematic investigation of edc snhs mediated Bioconjugation reactions for carboxylated peptide substrates
Bioconjugate Chemistry, 2016Co-Authors: Kyle A Totaro, Keshab Bhattacharya, Jari I Finneman, Mark A Massa, Jennifer M Thorn, Sa V Ho, Justin B Sperry, Xiaoli Liao, Bradley L. PenteluteAbstract:1-Ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) Bioconjugations have been utilized in preparing variants for medical research. While there have been advances in optimizing the reaction for aqueous applications, there has been limited focus toward identifying conditions and side reactions that interfere with product formation. We present a systematic investigation of EDC/N-hydroxysulfosuccinimide (sNHS)-mediated Bioconjugations on carboxylated peptides and small proteins. We identified yet-to-be-reported side products arising from both the reagents and substrates. Model peptides used in this study illustrate particular substrates are more susceptible to side reactions than others. From our studies, we found that Bioconjugations are more efficient with high concentrations of amine nucleophile but not sNHS. Performing Bioconjugations on a model affibody protein show that the trends established with model peptides hold for more complex systems.
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an umpolung approach for the chemoselective arylation of selenocysteine in unprotected peptides
ChemInform, 2015Co-Authors: Daniel T Cohen, Bradley L. Pentelute, Chi Zhang, Stephen L. BuchwaldAbstract:A new umpolung strategy for the Bioconjugation of selenocysteine in unprotected peptides is reported.
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organometallic palladium reagents for cysteine Bioconjugation
Nature, 2015Co-Authors: Ekaterina V. Vinogradova, Alexander M Spokoyny, Bradley L. Pentelute, Chi Zhang, Stephen L. BuchwaldAbstract:Palladium(ii) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. These authors demonstrate that palladium(II) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the new Bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. Previously the use of transition-metal based reactions to modify complex biomolecules has proved problematic due mainly to the need for stringent reaction conditions and the presence of multiple reactive functional groups in peptides. Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules1,2. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules3,4, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(ii) complexes can be used for efficient and highly selective cysteine conjugation (Bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the Bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. These palladium complexes show potential as benchtop reagents for diverse Bioconjugation applications.
Michal Hocek - One of the best experts on this subject based on the ideXlab platform.
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Squaramate-Modified Nucleotides and DNA for Specific Cross-Linking with Lysine-Containing Peptides and Proteins.
Angewandte Chemie, 2019Co-Authors: Ivana Ivancová, Martin Hubalek, Radek Pohl, Michal HocekAbstract:Squaramate‐linked 2′‐deoxycytidine 5′‐O‐triphosphate was synthesized and found to be good substrate for KOD XL DNA polymerase in primer extension or PCR synthesis of modified DNA. The resulting squaramate‐linked DNA reacts with primary amines to form a stable diamide linkage. This reaction was used for Bioconjugations of DNA with Cy5 and Lys‐containing peptides. Squaramate‐linked DNA formed covalent cross‐links with histone proteins. This reactive nucleotide has potential for other Bioconjugations of nucleic acids with amines, peptides or proteins without need of any external reagent.
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azidopropylvinylsulfonamide as a new bifunctional click reagent for bioorthogonal conjugations application for dna protein cross linking
Chemistry: A European Journal, 2015Co-Authors: Jitka Dadová, Milan Vrabel, Matej Adamik, Marie Brazdova, Michal Hocek, Radek Pohl, Miroslav FojtaAbstract:N-(3-Azidopropyl)vinylsulfonamide was developed as a new bifunctional Bioconjugation reagent suitable for the cross-linking of biomolecules through copper(I)-catalyzed azide-alkyne cycloaddition and thiol Michael addition reactions under biorthogonal conditions. The reagent is easily clicked to an acetylene-containing DNA or protein and then reacts with cysteine-containing peptides or proteins to form covalent cross-links. Several examples of Bioconjugations of ethynyl- or octadiynyl-modified DNA with peptides, p53 protein, or alkyne-modified human carbonic anhydrase with peptides are given.
Stephen L. Buchwald - One of the best experts on this subject based on the ideXlab platform.
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Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents.
Angewandte Chemie (International ed. in English), 2021Co-Authors: Muhammad Jbara, Stephen L. Buchwald, Jacob Rodriguez, Heemal H Dhanjee, Andrei Loas, Bradley L. PenteluteAbstract:Organometallic reagents enable practical strategies for Bioconjugation. Innovations in the design of water-soluble ligands and the enhancement of reaction rates have allowed for chemoselective cross-coupling reactions of peptides and proteins to be carried out in water. There are currently no organometallic-based methods for oligonucleotide Bioconjugation to other biomolecules. Here we report bifunctional palladium(II)-oxidative addition complexes (OACs) as reagents for high-yielding oligonucleotide Bioconjugation reactions. These bifunctional OACs react chemoselectively with amine-modified oligonucleotides to generate the first isolable, bench stable oligonucleotide-palladium(II) OACs. These complexes undergo site-selective C-S arylation with a broad range of native thiol-containing biomolecules at low micromolar concentrations in under one hour. This approach provided oligonucleotide-peptide, oligonucleotide-protein, oligonucleotide-small molecule, and oligonucleotide-oligonucleotide conjugates in >80% yield and afforded conjugation of multiple copies of oligonucleotides onto a monoclonal antibody.
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Arylation Chemistry for Bioconjugation
Angewandte Chemie, 2019Co-Authors: Chi Zhang, Alexander M Spokoyny, Ekaterina V. Vinogradova, Stephen L. Buchwald, Bradley L. PenteluteAbstract:Bioconjugation chemistry has been used to prepare modified biomolecules with functions beyond what nature intended. Central to these techniques is the development of highly efficient and selective Bioconjugation reactions that operate under mild, biomolecule compatible conditions. Methods that form a nucleophile-sp2 carbon bond show promise for creating bioconjugates with new modifications, sometimes resulting in molecules with unparalleled functions. Here we outline and review sulfur, nitrogen, selenium, oxygen, and carbon arylative Bioconjugation strategies and their applications to modify peptides, proteins, sugars, and nucleic acids.
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an umpolung approach for the chemoselective arylation of selenocysteine in unprotected peptides
ChemInform, 2015Co-Authors: Daniel T Cohen, Bradley L. Pentelute, Chi Zhang, Stephen L. BuchwaldAbstract:A new umpolung strategy for the Bioconjugation of selenocysteine in unprotected peptides is reported.
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organometallic palladium reagents for cysteine Bioconjugation
Nature, 2015Co-Authors: Ekaterina V. Vinogradova, Alexander M Spokoyny, Bradley L. Pentelute, Chi Zhang, Stephen L. BuchwaldAbstract:Palladium(ii) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. These authors demonstrate that palladium(II) complexes can be used in efficient and highly selective cysteine conjugation reactions that are rapid and robust, and the resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the new Bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. Previously the use of transition-metal based reactions to modify complex biomolecules has proved problematic due mainly to the need for stringent reaction conditions and the presence of multiple reactive functional groups in peptides. Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules1,2. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules3,4, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(ii) complexes can be used for efficient and highly selective cysteine conjugation (Bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the Bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. These palladium complexes show potential as benchtop reagents for diverse Bioconjugation applications.
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organometallic palladium reagents for cysteine Bioconjugation
Nature, 2015Co-Authors: Ekaterina V. Vinogradova, Alexander M Spokoyny, Bradley L. Pentelute, Chi Zhang, Stephen L. BuchwaldAbstract:Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (Bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the Bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as benchtop reagents for diverse Bioconjugation applications.
Igor L. Medintz - One of the best experts on this subject based on the ideXlab platform.
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recent progress in the Bioconjugation of quantum dots
Coordination Chemistry Reviews, 2014Co-Authors: Juan B Blancocanosa, Eleonora Petryayeva, Kimihiro Susumu, Philip E. Dawson, Miao Wu, Travis L. Jennings, Russ W Algar, Igor L. MedintzAbstract:Abstract The utility of luminescent semiconductor quantum dots (QDs) in biological applications is directly dependent upon their ability to undergo Bioconjugation to proteins, peptides, DNA, drugs and indeed all other manner of biomolecules. In this focused review, we provide an overview of the diverse chemistries that are used for these purposes, including a special emphasis on recent progress by our groups toward optimizing or developing new chemistries. We begin by examining the characteristics and activity ideally desired from QD-bioconjugates, along with the linkage chemistries that are most often utilized. The utility of polyhistidine-mediated metal-affinity coordination to QD surfaces or surface functionalizing ligands is then described in detail. This particular conjugation approach is highly desirable due to its functional simplicity and the control it can afford over the final QD-bioassembly. A variety of other modular, chemoselective ligation chemistries that can be applied either directly on the QD or to the biological to facilitate subsequent QD assembly are described, including aniline-catalyzed imine ligation, thiol-exchange, thiol-targeting iodoacetate chemistry, and Cu(I)-catalyzed azide-alkyne cycloaddition. Commercial QD labeling chemistries that incorporate some of these Bioconjugation approaches are also highlighted. Due to their continued widespread use, Bioconjugation routes that target the QD surface functionalizing and solubilizing ligands are covered, as are improvements in their functional implementation. Selected examples of applications that incorporate QD-bioconjugates assembled using the different chemistries described are included where appropriate, along with discussion of their benefits and liabilities within that application. Finally, a perspective on remaining issues and how this field will evolve is offered.
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intracellular Bioconjugation of targeted proteins with semiconductor quantum dots
Journal of the American Chemical Society, 2010Co-Authors: Kelly Boeneman, Michael H Stewart, Kimihiro Susumu, James B Delehanty, Igor L. MedintzAbstract:We demonstrate controlled in vivo Bioconjugation of a targeted intracellular protein to semiconductor quantum dots (QDs). Metal-affinity driven coordination of oligohistidine-appended proteins for chelated divalent cations was exploited to facilitate this interaction. Monomeric mCherry red fluorescent protein recombinantly engineered to express an N-terminal hexahistidine sequence was expressed from a eukaryotic plasmid vector following transfection into COS-1 cells. QDs solubilized with a carboxylated polymeric ligand and pretreated with Ni2+ were then microinjected into the mCherry-expressing COS-1 cells. Forster resonance energy transfer (FRET) between the central QD donors and mCherry acceptors specifically coordinated to their surface was utilized to probe and confirm intracellular conjugate formation. We unexpectedly found that mCherry attachment to the QDs also substantially improves its resistance to photobleaching. This proof-of-concept, highlighting targeted intracellular Bioconjugation to QDs, ...
Huan Wang - One of the best experts on this subject based on the ideXlab platform.
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dinitroimidazoles as bifunctional Bioconjugation reagents for protein functionalization and peptide macrocyclization
Nature Communications, 2019Co-Authors: Wangjian Sheng, Jingxia Lu, Huan WangAbstract:Efficient and site-specific chemical modification of proteins under physiological conditions remains a challenge. Here we report that 1,4-dinitroimidazoles are highly efficient bifunctional Bioconjugation reagents for protein functionalization and peptide macrocyclization. Under acidic to neutral aqueous conditions, 1,4-dinitroimidazoles react specifically with cysteines via a cine-substitution mechanism, providing rapid, stable and chemoselective protein Bioconjugation. On the other hand, although unreactive towards amine groups under neutral aqueous conditions, 1,4-dinitroimidazoles react with lysines in organic solvents in the presence of base through a ring-opening & ring-close mechanism. The resulting cysteine- and lysine-(4-nitroimidazole) linkages exhibit stability superior to that of commonly employed maleimide-thiol conjugates. We demonstrate that 1,4-dinitroimidazoles can be applied in site-specific protein Bioconjugation with functionalities such as fluorophores and bioactive peptides. Furthermore, a bisfunctional 1,4-dinitroimidazole derivative provides facile access to peptide macrocycles by crosslinking a pair of cysteine or lysine residues, including bicyclic peptides of complex architectures through highly controlled consecutive peptide macrocyclization. The selective formation of protein bioconjugates under physiological conditions is a challenging task. Here, the authors report that 1,4-dinitroimidazoles are reagents of choice for protein Bioconjugation at either cysteine or lysine sites within short times and provide facile access to peptide macrocycles.
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dinitroimidazoles as bifunctional Bioconjugation reagents for protein functionalization and peptide macrocyclization
Nature Communications, 2019Co-Authors: Qunfeng Luo, Wangjian Sheng, Youqi Tao, Huan WangAbstract:Efficient and site-specific chemical modification of proteins under physiological conditions remains a challenge. Here we report that 1,4-dinitroimidazoles are highly efficient bifunctional Bioconjugation reagents for protein functionalization and peptide macrocyclization. Under acidic to neutral aqueous conditions, 1,4-dinitroimidazoles react specifically with cysteines via a cine-substitution mechanism, providing rapid, stable and chemoselective protein Bioconjugation. On the other hand, although unreactive towards amine groups under neutral aqueous conditions, 1,4-dinitroimidazoles react with lysines in organic solvents in the presence of base through a ring-opening & ring-close mechanism. The resulting cysteine- and lysine-(4-nitroimidazole) linkages exhibit stability superior to that of commonly employed maleimide-thiol conjugates. We demonstrate that 1,4-dinitroimidazoles can be applied in site-specific protein Bioconjugation with functionalities such as fluorophores and bioactive peptides. Furthermore, a bisfunctional 1,4-dinitroimidazole derivative provides facile access to peptide macrocycles by crosslinking a pair of cysteine or lysine residues, including bicyclic peptides of complex architectures through highly controlled consecutive peptide macrocyclization.