27 results on '"Sergii Kolodych"'
Search Results
2. Non-specific interactions of antibody-oligonucleotide conjugates with living cells
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Victor Lehot, Isabelle Kuhn, Marc Nothisen, Stéphane Erb, Sergii Kolodych, Sarah Cianférani, Guilhem Chaubet, and Alain Wagner
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Medicine ,Science - Abstract
Abstract Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging class of functionalized antibodies that have already been used in a wide variety of applications. While the impact of dye and drug conjugation on antibodies’ ability to bind their target has been extensively studied, little is known about the effect caused by the conjugation of hydrophilic and charged payloads such as oligonucleotides on the functions of an antibody. Previous observations of non-specific interactions of nucleic acids with untargeted cells prompted us to further investigate their impact on AOC binding abilities and cell selectivity. We synthesized a series of single- and double-stranded AOCs, as well as a human serum albumin-oligonucleotide conjugate, and studied their interactions with both targeted and non-targeted living cells using a time-resolved analysis of ligand binding assay. Our results indicate that conjugation of single strand oligonucleotides to proteins induce consistent non-specific interactions with cell surfaces while double strand oligonucleotides have little or no effect, depending on the preparation method.
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- 2021
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3. Thermofluorimetric Analysis (TFA) using Probes with Flexible Spacers: Application to Direct Antibody Sensing and to Antibody-Oligonucleotide (AbO) Conjugate Valency Monitoring
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Amanda S.N. Kurian, Asanka Gurukandure, Igor Dovgan, Sergii Kolodych, and Christopher J. Easley
- Abstract
Antibodies have long been recognized as clinically relevant biomarkers of disease. The onset of a disease often stimulates antibody production at low quantities, making it crucial to develop sensitive, specific, and easy-to-use antibody assay platforms. Antibodies are also extensively used as probes in bioassays, and there is a need for simpler methods to evaluate specialized probes such as antibody-oligonucleotide (AbO) conjugates. Previously, we have demonstrated that thermofluorimetric analysis (TFA) of analyte-driven DNA assembly can be leveraged to detect protein biomarkers using AbO probes. A key advantage of this technique is its ability to circumvent autofluorescence arising from biological samples, which otherwise hampers homogenous assays. The analysis of differential DNA melt curves (dF/dT) successfully distinguishes the signal from background and interferences. Expanding the applicability of TFA further, here-in we demonstrate a unique proximity based TFA assay for antibody quantification which is functional in 90% human plasma. We show that conformational flexibility of the DNA-based proximity probes is critically important for optimal performance in these assays. To promote stable, proximity-induced hybridization of the short DNA strands, substitution of polyethylene glycol (PEG) spacers in place of ssDNA segments led to improved conformational flexibility and sensor performance. Finally, by applying these flexible spacers to study AbO conjugates directly, we validate this modified TFA approach as a novel tool to elucidate the probes valency, clearly distinguishing between monovalent and multivalent AbOs and reducing the reagent amounts by 12-fold
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- 2023
4. Non-specific interactions of antibody-oligonucleotide conjugates with living cells
- Author
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Marc Nothisen, Alain Wagner, Isabelle Kuhn, Sergii Kolodych, Sarah Cianférani, Victor Lehot, Stéphane Erb, Guilhem Chaubet, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Syndivia SAS
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Cell ,Oligonucleotides ,Medicinal chemistry ,02 engineering and technology ,Non specific ,Drug safety ,Multidisciplinary ,biology ,Drug discovery ,Chemistry ,021001 nanoscience & nanotechnology ,Chemical biology ,3. Good health ,Nucleic acids ,medicine.anatomical_structure ,Biochemistry ,Medicine ,Antibody ,0210 nano-technology ,hal-03200308 ,Cell Survival ,Science ,Biologics ,Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire ,Article ,Antibodies ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Nucleic-acid therapeutics ,Pharmacology ,Oligonucleotide ,Ligand binding assay ,Proteins ,DNA ,Trastuzumab ,Cell selectivity ,Kinetics ,030104 developmental biology ,Drug delivery ,Nucleic acid ,biology.protein ,Antibody therapy ,Chemical modification ,Conjugate - Abstract
Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging class of functionalized antibodies that have already been used in a wide variety of applications. While the impact of dye and drug conjugation on antibodies’ ability to bind their target has been extensively studied, little is known about the effect caused by the conjugation of hydrophilic and charged payloads such as oligonucleotides on the functions of an antibody. Previous observations of non-specific interactions of nucleic acids with untargeted cells prompted us to further investigate their impact on AOC binding abilities and cell selectivity. We synthesized a series of single- and double-stranded AOCs, as well as a human serum albumin-oligonucleotide conjugate, and studied their interactions with both targeted and non-targeted living cells using a time-resolved analysis of ligand binding assay. Our results indicate that conjugation of single strand oligonucleotides to proteins induce consistent non-specific interactions with cell surfaces while double strand oligonucleotides have little or no effect, depending on the preparation method.
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- 2021
5. Automated linkage of proteins and payloads producing monodisperse conjugates
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Alexandre Hentz, Margaux Riomet, Sébastien Delacroix, Oleksandr Koniev, Anthony Ehkirch, Sylvain Ursuegui, Igor Dovgan, Steve Hessmann, Alain Wagner, Frédéric Taran, Sergii Kolodych, Sarah Cianférani, Conception et application de molécules bioactives (CAMB), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Syndivia SAS, Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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Specific protein ,010405 organic chemistry ,Chemistry ,Dispersity ,Chemical modification ,Nanotechnology ,General Chemistry ,Linkage (mechanical) ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,3. Good health ,law.invention ,law ,Surface modification ,[CHIM]Chemical Sciences ,Bioorthogonal chemistry ,Conjugate - Abstract
Controlled protein functionalization holds great promise for a wide variety of applications. However, despite intensive research, the stoichiometry of the functionalization reaction remains difficult to control due to the inherent stochasticity of the conjugation process. Classical approaches that exploit peculiar structural features of specific protein substrates, or introduce reactive handles via mutagenesis, are by essence limited in scope or require substantial protein reengineering. We herein present equimolar native chemical tagging (ENACT), which precisely controls the stoichiometry of inherently random conjugation reactions by combining iterative low-conversion chemical modification, process automation, and bioorthogonal trans-tagging. We discuss the broad applicability of this conjugation process to a variety of protein substrates and payloads., Controlled protein functionalization holds great promise for a wide variety of applications.
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- 2020
6. On the use of DNA as a linker in antibody-drug conjugates: synthesis, stability and in vitro potency
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Oleksandr Koniev, Sylvain Ursuegui, Igor Dovgan, Marc Nothisen, Manon Ripoll, Sergii Kolodych, Isabelle Kuhn, Alain Wagner, Sarah Cianférani, Alexandre Hentz, Anthony Ehkirch, Victor Lehot, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Syndivia SAS, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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Immunoconjugates ,Aucun ,lcsh:Medicine ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Article ,chemistry.chemical_compound ,Cell Line, Tumor ,[CHIM]Chemical Sciences ,Humans ,Cytotoxicity ,skin and connective tissue diseases ,lcsh:Science ,Multidisciplinary ,010405 organic chemistry ,Oligonucleotide ,lcsh:R ,hal-02870010 ,Proteins ,DNA ,Trastuzumab ,Ligand (biochemistry) ,In vitro ,3. Good health ,0104 chemical sciences ,body regions ,chemistry ,Monomethyl auristatin E ,Biochemistry ,Drug delivery ,lcsh:Q ,Oligopeptides ,Linker ,Chemical modification ,Conjugate - Abstract
Here we present the synthesis and evaluation of antibody-drug conjugates (ADCs), for which antibody and drug are non-covalently connected using complementary DNA linkers. These ADCs are composed of trastuzumab, an antibody targeting HER2 receptors overexpressed on breast cancer cells, and monomethyl auristatin E (MMAE) as a drug payload. In this new ADC format, trastuzumab conjugated to a 37-mer oligonucleotide (ON) was prepared and hybridized with its complementary ON modified at 5-end with MMAE (cON-MMAE) in order to obtain trastuzumab-DNA-MMAE. As an advantage, the cON-MMAE was completely soluble in water, which decreases overall hydrophobicity of toxic payload, an important characteristic of ADCs. The stability in the human plasma of these non-engineered ON-based linkers was investigated and showed a satisfactory half-life of 5.8 days for the trastuzumab-DNA format. Finally, we investigated the in vitro cytotoxicity profile of both the DNA-linked ADC and the ON-drug conjugates and compared them with classical covalently linked ADC. Interestingly, we found increased cytotoxicity for MMAE compared to cON-MMAE and an EC50 in the nanomolar range for trastuzumab-DNA-MMAE on HER2-positive cells. Although this proved to be less potent than classically linked ADC with picomolar range EC50, the difference in cytotoxicity between naked payload and conjugated payload was significant when an ON linker was used. We also observed an interesting increase in cytotoxicity of trastuzumab-DNA-MMAE on HER2-negative cells. This was attributed to enhanced non-specific interaction triggered by the DNA strand as it could be confirmed using ligand tracer assay.
- Published
- 2020
7. Design and Synthesis of Iminosydnones for Fast Click and Release Reactions with Cycloalkynes
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Karine Porte, Margaux Riomet, Sabrina Bernard, Davide Audisio, Elodie Decuypere, Lucie Plougastel, Sergii Kolodych, and Frédéric Taran
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chemistry.chemical_classification ,010405 organic chemistry ,Biomolecule ,Organic Chemistry ,Kinetics ,Chemical biology ,Alkyne ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Fragmentation (mass spectrometry) ,Cleavable linker ,Bioorthogonal chemistry ,Bifunctional - Abstract
Emerging applications in the field of chemical biology are currently limited by the lack of bioorthogonal reactions allowing both removal and linkage of chemical entities on complex biomolecules. We recently discovered a novel reaction between iminosydnones and strained alkynes leading to two products resulting from ligation and fragmentation of iminosydnones under physiological conditions. We now report the synthesis of a panel of substituted iminosydnones and the structure reactivity relationship between these compounds and strained alkyne partners. This study identified the most relevant substituents, which allow to increase the rate of the transformation and to develop a bifunctional cleavable linker with improved kinetics.
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- 2018
8. Reduction–rebridging strategy for the preparation of ADPN-based antibody–drug conjugates
- Author
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Alain Wagner, Oleksandr Koniev, Sergii Kolodych, Brigitte Renoux, Jitka Eberova, Sarah Cianférani, Igor Dovgan, Sébastien Papot, Anthony Ehkirch, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Drug ,media_common.quotation_subject ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Drug Discovery ,ComputingMilieux_MISCELLANEOUS ,media_common ,Pharmacology ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,[CHIM.CATA]Chemical Sciences/Catalysis ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,body regions ,030104 developmental biology ,Homogeneous ,biology.protein ,Molecular Medicine ,Antibody ,Disulphide bonds ,Conjugate - Abstract
The reduction–rebridging strategy is a powerful method for the preparation of stable and homogeneous antibody–drug conjugates (ADCs). In this communication, we describe the development of the arylene-dipropiolonitrile (ADPN) functional group for the rebridging of reduced disulphide bonds and its application in the preparation of potent and selective ADCs.
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- 2018
9. Bioorthogonal Click and Release Reaction of Iminosydnones with Cycloalkynes
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Sabrina Bernard, Alain Wagner, Davide Audisio, Oleksandr Koniev, Sarah Bregant, Lucie Plougastel, Jijy Elyian, Elodie Decuypere, Sandra Gabillet, Sergii Kolodych, Frédéric Taran, Antoine Sallustrau, Margaux Riomet, Minh Nguyet Trinh, and Ramar Arun Kumar
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010405 organic chemistry ,Chemistry ,Chemical biology ,General Medicine ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Click chemistry ,Posttranslational modification ,Drug release ,Cleavable linker ,Bioorthogonal chemistry - Abstract
We report the discovery of a new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes. This transformation leads to two products resulting from the ligation and fragmentation of iminosydnones under physiological conditions. Optimized iminosydnones were successfully used to design innovative cleavable linkers for protein modification, thus opening up new areas in the fields of drug release and target-fishing applications. This click-and-release technology offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogonal conditions.
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- 2017
10. Antibody-Oligonucleotide Conjugates as Therapeutic, Imaging, and Detection Agents
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Igor Dovgan, Alain Wagner, Sergii Kolodych, and Oleksandr Koniev
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Immunoconjugates ,medicine.medical_treatment ,Biomedical Engineering ,Oligonucleotides ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,01 natural sciences ,Antibodies ,medicine ,Animals ,Humans ,Pharmacology ,biology ,010405 organic chemistry ,Oligonucleotide ,Chemistry ,Organic Chemistry ,Traction (orthopedics) ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Molecular Imaging ,Biochemistry ,biology.protein ,Antibody ,0210 nano-technology ,Biotechnology ,Conjugate - Abstract
Antibody-oligonucleotide conjugates (AOCs) are a novel class of synthetic chimeric biomolecules that has been continually gaining traction in different fields of modern biotechnology. This is mainly due to the unique combination of the properties of their two constituents, exceptional targeting abilities and antibody biodistribution profiles, in addition to an extensive scope of oligonucleotide functional and structural roles. Combining these two classes of biomolecules in one chimeric construct has therefore become an important milestone in the development of numerous biotechnological applications, including imaging (DNA-PAINT), detection (PLA, PEA), and therapeutics (targeted siRNA/antisense delivery). Numerous synthetic approaches have been developed to access AOCs ranging from stochastic chemical bioconjugation to site-specific conjugation with reactive handles, introduced into antibody sequences through protein engineering. This Review gives a general overview of the current status of AOC applications with a specific emphasis on the synthetic methods used for their preparation. The reported synthetic techniques are discussed in terms of their practical aspects and limitations. The importance of the development of novel methods for the facile generation of AOCs possessing a defined constitution is highlighted as a priority in AOC research to ensure the advance of their new applications.
- Published
- 2019
11. Palladium-Catalyzed Chemoselective and Biocompatible Functionalization of Cysteine-Containing Molecules at Room Temperature
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Alain Wagner, Sébastien Delacroix, Stéphane Erb, Samir Messaoudi, Stéphanie Nicolaÿ, Mouâd Alami, Riyadh Ahmed Atto AL-Shuaeeb, Sergii Kolodych, Jean-Daniel Brion, Sarah Cianférani, Jean-Christophe Cintrat, and Oleksandr Koniev
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chemistry.chemical_classification ,Bioconjugation ,Phosphines ,010405 organic chemistry ,Organic Chemistry ,Temperature ,Proteins ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,Biocompatible material ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Amino acid ,Xanthenes ,chemistry ,Surface modification ,Molecule ,Cysteine ,Palladium - Abstract
The third generation of aminobiphenyl palladacycle pre-catalyst "G3-Xantphos" enables functionalization of peptides containing cysteine in high yields. The conjugation (bioconjugation) occurs chemoselectively at room temperature under biocompatible conditions. Extension of the method to protein functionalization allows selective bioconjugation of the trastuzumab antibody.
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- 2016
12. Development and evaluation of β-galactosidase-sensitive antibody-drug conjugates
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Oleksandr Koniev, Sergii Kolodych, Christian D. Muller, Brigitte Renoux, Sébastien Papot, Alain Wagner, Pauline Poinot, Wojciech Krezel, Jitka Eberova, Chloé Michel, Anthony Ehkirch, Sébastien Delacroix, Sarah Cianférani, Laboratoire de Biomécanique et Mécanique des Chocs (LBMC UMR T9406), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Conception et application de molécules bioactives (CAMB), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut de Chimie du CNRS (INC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)
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Drug ,Antibody-drug conjugate ,Immunoconjugates ,media_common.quotation_subject ,Mice, Nude ,Breast Neoplasms ,Pharmacology ,010402 general chemistry ,Ado-Trastuzumab Emtansine ,01 natural sciences ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,Trastuzumab ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,[CHIM]Chemical Sciences ,Maytansine ,ComputingMilieux_MISCELLANEOUS ,media_common ,Cell Proliferation ,010405 organic chemistry ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Organic Chemistry ,Cancer ,General Medicine ,medicine.disease ,beta-Galactosidase ,Galactoside ,0104 chemical sciences ,3. Good health ,Carcinoma, Ductal ,Monomethyl auristatin E ,chemistry ,Trastuzumab emtansine ,Drug delivery ,Female ,medicine.drug - Abstract
The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of β-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo. The ADCs with galactoside linkers demonstrated superior therapeutic efficacy in mice compared to the marketed trastuzumab emtansine used for the treatment of breast cancer.
- Published
- 2017
13. MAPN: First-in-Class Reagent for Kinetically Resolved Thiol-to-Thiol Conjugation
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Alain Van Dorsselaer, Sergii Kolodych, J.-Y. Bonnefoy, Sarah Cianférani, Alain Wagner, Jitka Eberova, Zoljargal Baatarkhuu, Johann Stojko, and Oleksandr Koniev
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Immunoconjugates ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Conjugated system ,Mertansine ,Maleimides ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Organic chemistry ,Sulfhydryl Compounds ,Maleimide ,Pharmacology ,chemistry.chemical_classification ,Bioconjugation ,Organic Chemistry ,Kinetics ,chemistry ,Alkynes ,Reagent ,Thiol ,Indicators and Reagents ,Biotechnology ,Cysteine ,Conjugate - Abstract
Thiols are among the most frequently used functional groups in the field of bioconjugation. While there exists a variety of heterobifunctional reagents that allow for coupling thiols to other functions (e.g., amines, carboxylic acids), there is no specific reagent for creating heteroconjugates using two different thiols. In response to the ever-increasing demand for bioconjugation tools, we have developed p-(maleimide)-phenylpropionitrile (MAPN)-an efficient reagent for kinetically resolved thiol-to-thiol coupling. In a comparative study with its closest commercially available analogue, p-phenylenedimaleimide, MAPN has shown substantial advantages for the preparation of thiol-thiol heteroconjugates. Namely, an antibody-drug conjugate (ADC) with mertansine (DM1), conjugated to the cysteine residues of Trastuzumab, was prepared for the first time.
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- 2015
14. Acyl Fluorides: Fast, Efficient, and Versatile Lysine-Based Protein Conjugation via Plug-and-Play Strategy
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Sergii Kolodych, Igor Dovgan, Stéphane Erb, Sylvain Ursuegui, Alain Wagner, Sarah Cianférani, and Chloé Michel
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Azides ,Fluorophore ,Immunoconjugates ,Stereochemistry ,Receptor, ErbB-2 ,Acylation ,Lysine ,Biomedical Engineering ,Oligonucleotides ,Pharmaceutical Science ,Succinimides ,Bioengineering ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Fluorides ,Benzyl Compounds ,Humans ,Fluorescent Dyes ,Toxins, Biological ,Pharmacology ,chemistry.chemical_classification ,Cycloaddition Reaction ,Molecular Structure ,010405 organic chemistry ,Oligonucleotide ,Biomolecule ,Organic Chemistry ,Antibodies, Monoclonal ,Cycloaddition ,0104 chemical sciences ,chemistry ,Alkynes ,Surface modification ,Click Chemistry ,Azide ,Biotechnology - Abstract
We report a plug-and-play strategy for the preparation of functionally enhanced antibodies with a defined average degree of conjugation (DoC). The first stage (plug) allows the controllable and efficient installation of azide groups on lysine residues of a native antibody using 4-azidobenzoyl fluoride. The second step (play) allows for versatile antibody functionalization with a single payload or combination of payloads, such as a toxin, a fluorophore, or an oligonucleotide, via copper-free strain-promoted azide–alkyne cycloaddition (SPAAC). It is notable that in comparison to a classical N-hydroxysuccinimide ester (NHS) strategy, benzoyl fluorides show faster and more efficient acylation of lysine residues in a PBS buffer. This translates into better control of the DoC and enables the efficient and fast functionalization of delicate biomolecules at low temperature.
- Published
- 2017
15. Targeting the tumour microenvironment with an enzyme-responsive drug delivery system for the efficient therapy of breast and pancreatic cancers
- Author
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Sébastien Papot, Balkis Eddhif, Alain Le Pape, Jérôme Alsarraf, Isabelle Tranoy-Opalinski, Brigitte Renoux, Thibaut Legigan, Pauline Poinot, Florian Raes, Elodie Péraudeau, Stéphanie Lerondel, Jonathan Clarhaut, Sergii Kolodych, Oleksandr Koniev, Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut de Chimie du CNRS (INC), Transgenèse et archivage d'animaux modèles (TAAM), Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Conception et application de molécules bioactives (CAMB), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Transgénèse et Archivage d'Animaux Modèles - Centre d'Imagerie du Petit Animal (TAAM-CIPA), Institut de physiologie et biologie cellulaires (IPBC), and Université de Poitiers-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Drug ,Cancer chemotherapy ,media_common.quotation_subject ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Monomethylauristatin E ,Extracellular ,Medicine ,ComputingMilieux_MISCELLANEOUS ,media_common ,chemistry.chemical_classification ,business.industry ,Albumin ,General Chemistry ,[CHIM.CATA]Chemical Sciences/Catalysis ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,3. Good health ,Enzyme ,chemistry ,Immunology ,Drug delivery ,Cancer research ,0210 nano-technology ,business - Abstract
The development of novel therapeutic strategies allowing the destruction of tumour cells while sparing healthy tissues is one of the main challenges of cancer chemotherapy. Here, we report on the design and antitumour activity of a low-molecular-weight drug delivery system programmed for the selective release of the potent monomethylauristatin E in the tumour microenvironment of solid tumours. After intravenous administration, this compound binds covalently to plasmatic albumin through Michael addition, thereby enabling its passive accumulation in tumours where extracellular β-glucuronidase initiates the selective release of the drug. This targeting device produces outstanding therapeutic efficacy on orthotopic triple-negative mammary and pancreatic tumours in mice (50% and 33% of mice with the respective tumours cured), leading to impressive reduction or even disappearance of tumours without inducing side effects.
- Published
- 2017
16. Discovery of Chemoselective and Biocompatible Reactions Using a High-Throughput Immunoassay Screening
- Author
-
Christophe Créminon, Evelia Rasolofonjatovo, Manon Chaumontet, Sergii Kolodych, Frédéric Taran, and Marie-Claire Nevers
- Subjects
Azides ,High-throughput screening ,Hochdurchsatz screening ,Biocompatible Materials ,Nanotechnology ,Sydnones ,Catalysis ,High-Throughput Screening Assays ,medicine ,Animals ,Throughput (business) ,Immunoassay ,Cycloaddition Reaction ,medicine.diagnostic_test ,Chemistry ,Serum Albumin, Bovine ,General Medicine ,General Chemistry ,Biocompatible material ,Combinatorial chemistry ,Alkynes ,Phosphatidylcholines ,Click chemistry ,Cattle ,Copper - Published
- 2013
17. Iridium-Catalyzed Cycloaddition of Azides and 1-Bromoalkynes at Room Temperature
- Author
-
Evelia Rasolofonjatovo, Frédéric Taran, Alexandra Bouriaud, Manon Chaumontet, Sergii Kolodych, and Sewan Theeramunkong
- Subjects
Azides ,Cycloaddition Reaction ,Molecular Structure ,Dimer ,Organic Chemistry ,Temperature ,chemistry.chemical_element ,Triazoles ,Iridium ,Biochemistry ,Catalysis ,Cycloaddition ,Hydrocarbons, Brominated ,chemistry.chemical_compound ,Direct route ,chemistry ,Cyclization ,Alkynes ,Polymer chemistry ,Physical and Theoretical Chemistry - Abstract
Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.
- Published
- 2013
18. Ultrafast click chemistry with fluorosydnones
- Author
-
Hui Liu, Davide Audisio, Sarita Forsback, Alain Wagner, Lucie Plougastel, Mourad Elhabiri, Anna Krzyczmonik, David-Alexandre Buisson, Véronique Gouverneur, Frédéric Taran, Oleksandr Koniev, Olof Solin, Sergii Kolodych, and Elodie Decuypere
- Subjects
010405 organic chemistry ,Electrophilic fluorination ,Kinetics ,Mesoionic ,General Medicine ,General Chemistry ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,Cycloaddition ,0104 chemical sciences ,chemistry.chemical_compound ,Reaction rate constant ,chemistry ,Click chemistry ,Reactivity (chemistry) ,Selectfluor ,ta116 - Abstract
We report the synthesis and reactivity of 4-fluorosydnones, a unique class of mesoionic dipoles displaying exquisite reactivity towards both copper-catalyzed and strain-promoted cycloaddition reactions with alkynes. Synthetic access to these new mesoionic compounds was granted by electrophilic fluorination of σ-sydnone Pd(II) precursors in the presence of Selectfluor. Their reactions with terminal and cyclic alkynes were found to proceed very rapidly and selectively, affording 5-fluoro-1,4-pyrazoles with bimolecular rate constants up to 10(4) m(-1) s(-1) , surpassing those documented in the literature with cycloalkynes. Kinetic studies were carried out to unravel the mechanism of the reaction, and the value of 4-fluorosydnones was further highlighted by successful radiolabeling with [(18) F]Selectfluor.
- Published
- 2016
19. 2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation
- Author
-
Igor Dovgan, Alain Wagner, Sergii Kolodych, and Oleksandr Koniev
- Subjects
0301 basic medicine ,Multidisciplinary ,Aqueous solution ,010405 organic chemistry ,Chemistry ,Ring (chemistry) ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Förster resonance energy transfer ,Biochemistry ,Succinimide ,Reagent ,Maleimide ,Linker ,Conjugate - Abstract
The vast majority of antibody-drug conjugates (ADC) are prepared through amine-to-thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the preparation of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analogue of a SMCC reagent, i.e., sodium 4-(maleimidomethyl)-1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine-to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepared and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aqueous buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the preparation of serum stable antibody-dye conjugate.
- Published
- 2016
20. Reaction Discovery by Using a Sandwich Immunoassay
- Author
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Sandra Gabillet, Valentina Bevilacqua, Marie-Claire Nevers, Julia Quinton, Pierre Thuéry, Hervé Volland, Sergii Kolodych, Frédéric Taran, Manon Chaumonet, and Christophe Créminon
- Subjects
Azoles ,Immunoassay ,Chromatography ,Molecular Structure ,Chemistry ,High-throughput screening ,Analytical chemistry ,Hochdurchsatz screening ,General Medicine ,General Chemistry ,Catalysis ,Oxygen ,Aminobenzoates ,Sandwich immunoassay ,Copper - Published
- 2012
21. 4-Halogeno-sydnones for fast strain promoted cycloaddition with bicyclo-[6.1.0]-nonyne
- Author
-
Oleksandr Koniev, Lucie Plougastel, Christophe Créminon, Elodie Decuypere, Frédéric Taran, Alain Wagner, Sergii Kolodych, Simon Specklin, and David-Alexandre Buisson
- Subjects
Cycloaddition Reaction ,Strain (chemistry) ,Bicyclic molecule ,Stereochemistry ,Proton Magnetic Resonance Spectroscopy ,Metals and Alloys ,General Chemistry ,Medicinal chemistry ,Catalysis ,Cycloaddition ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Bridged Bicyclo Compounds ,chemistry.chemical_compound ,Halogens ,chemistry ,Materials Chemistry ,Ceramics and Composites ,Sydnone - Abstract
New sydnone derivatives have been synthesized and screened for their capacity to undergo fast copper-free cycloaddition reaction with bicyclo-[6.1.0]-nonyne. The influences of substitution in positions N-3 and C-4 of sydnones have been particularly studied leading to the identification of highly reactive partners for bio-orthogonal ligation reactions.
- Published
- 2014
22. CBTF: new amine-to-thiol coupling reagent for preparation of antibody conjugates with increased plasma stability
- Author
-
Sergii Kolodych, François Debaene, Alain Wagner, Alain Van Dorsselaer, J.-Y. Bonnefoy, Oleksandr Koniev, Zoljargal Baatarkhuu, and Sarah Cianférani
- Subjects
Immunoconjugates ,Halogenation ,Sodium ,Biomedical Engineering ,Pharmaceutical Science ,chemistry.chemical_element ,Bioengineering ,Cell Line ,Maleimides ,chemistry.chemical_compound ,Benzene Derivatives ,Organic chemistry ,Humans ,Sulfhydryl Compounds ,Amines ,Maleimide ,Pharmacology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Coupling reagent ,Combinatorial chemistry ,Cross-Linking Reagents ,chemistry ,Reagent ,Thiol ,biology.protein ,Amine gas treating ,Antibody ,Biotechnology ,Conjugate - Abstract
Amine-to-thiol coupling is the most common route for the preparation of antibody–drug conjugates (ADC). It is usually achieved by using heterobifunctional reagents possessing an activated ester at one end and a maleimide group at the other. However, maleimide-based conjugates were recently revealed to have limited stability in blood circulation, which can compromise therapeutic efficacy of the conjugate. To address this issue, we have developed a heterobifunctional reagent, sodium 4-((4-(cyanoethynyl)benzoyl)oxy)-2,3,5,6-tetrafluorobenzenesulfonate (CBTF), for amine-to-thiol coupling. It comprises a recently described 3-arylpropionitrile (APN) function in replacement of maleimide and allows for the preparation of remarkably stable conjugates. A series of antibody–dye conjugates have been prepared using this reagent and shown superior stability in human blood plasma compared to maleimide-derived conjugates.
- Published
- 2015
23. Copper(I)-catalyzed cycloaddition of 4-bromosydnones and alkynes for the regioselective synthesis of 1,4,5-trisubstituted pyrazoles
- Author
-
Elodie Decuypere, Simon Specklin, Lucie Plougastel, Hui Liu, Frédéric Taran, Sergii Kolodych, Davide Audisio, and Sandra Gabillet
- Subjects
Cycloaddition Reaction ,Molecular Structure ,Chemistry ,Organic Chemistry ,Regioselectivity ,chemistry.chemical_element ,Stereoisomerism ,Biochemistry ,Copper ,Sydnones ,Cycloaddition ,Catalysis ,chemistry.chemical_compound ,Alkynes ,Functional group ,Organic chemistry ,Pyrazoles ,Physical and Theoretical Chemistry - Abstract
Copper-catalyzed cycloaddition of alkynes with 4-bromosydnones provides a convenient, mild, and regioselective method for the synthesis of a wide range of bromopyrazoles. The broad functional group tolerance of the cycloaddition reaction and further palladium-catalyzed cross-coupling reactions allowed the preparation of polyfunctionalized 1,4,5-pyrazoles that are otherwise difficult to obtain by conventional methods.
- Published
- 2014
24. ChemInform Abstract: Iridium-Catalyzed Cycloaddition of Azides and 1-Bromoalkynes at Room Temperature
- Author
-
Frédéric Taran, Evelia Rasolofonjatovo, Sergii Kolodych, Alexandra Bouriaud, Manon Chaumontet, and Sewan Theeramunkong
- Subjects
chemistry.chemical_compound ,Direct route ,chemistry ,Dimer ,Polymer chemistry ,Triazole derivatives ,chemistry.chemical_element ,Organic chemistry ,General Medicine ,Iridium ,Cycloaddition ,Catalysis - Abstract
Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.
- Published
- 2014
25. ChemInform Abstract: Reaction Discovery by Using a Sandwich Immunoassay
- Author
-
Pierre Thuéry, Hervé Volland, Valentina Bevilacqua, Christophe Créminon, Sandra Gabillet, Manon Chaumonet, Marie-Claire Nevers, Julia Quinton, Sergii Kolodych, and Frédéric Taran
- Subjects
Chromatography ,Chemistry ,General Medicine ,Sandwich immunoassay - Published
- 2012
26. Correction to Copper(I)-Catalyzed Cycloaddition of 4-Bromosydnones and Alkynes for the Regioselective Synthesis of 1,4,5-Trisubstituted Pyrazoles
- Author
-
Elodie Decuypere, Simon Specklin, Sandra Gabillet, Davide Audisio, Hui Liu, Lucie Plougastel, Sergii Kolodych, and Frédéric Taran
- Subjects
Organic Chemistry ,Physical and Theoretical Chemistry ,Biochemistry - Published
- 2015
27. MAPN: First-in-Class Reagent for Kinetically ResolvedThiol-to-Thiol Conjugation.
- Author
-
Oleksandr Koniev, Sergii Kolodych, Zoljargal Baatarkhuu, Johann Stojko, Jitka Eberova, Jean-Yves Bonnefoy, Sarah Cianférani, Alain Van Dorsselaer, and Alain Wagner
- Published
- 2015
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