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Biomolecules
Special Issues
Novel Approaches in Biomolecule Labeling
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Novel Approaches in Biomolecule Labeling

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 26942

Special Issue Editors

Dr. Cyrille Sabot

E-Mail Website
Guest Editor
UMR 6014-CNRS COBRA, INSA, Université de Rouen1 rue Tesnière, 76821 Mont-Saint-Aignan CEDEX, France
Interests: current research interests focus on the development of biocompatible ligation tools (bioconjugation, click chemistry and bioorthogonal reactions), which find applications in target-guided synthesis strategy for drug discovery, and in the preparation of biomolecular systems suitable for bioimaging applications
Dr. Péter Kele

E-Mail Website
Guest Editor
Chemical Biology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary
Interests: fluorescent probes; fluorogenic probes; bioorthogonal chemistry; non-natural amino acids; photocage

Special Issue Information

Dear Colleagues,

Bioconjugates have found a wide range of applications in chemical biology, from the probing of biological processes in living systems, through developing modern biotherapeutics for medical chemistry applications, to designing surfaces with advanced properties for the material sciences. These conjugates mostly correspond to biomolecules or biopolymers linked covalently to a marker (fluorophore, radioisotope, MRI contrast agents etc.) or drugs. The resulting bioconjugates combine e.g. molecular recognition features or other biological activity of the biomolecule and the specific properties of the given marker. This combination of features is then harvested in the development of diagnostic tests, medical multimodal diagnostic imaging as well as in the fabrication of constructs enabling, e.g., targeted drug delivery.

Site-specific, selective covalent modification of biomolecules can be achieved by several means. Besides targeting rare natural functional groups (e.g. sulfhydryl of cysteines), modification methods relying on synthetic species carrying unnatural functions with unique and biocompatible reactivity (i.e. biorthogonal) have lately received considerable attention. The tremendous efforts that have been made in recent years to design reliable bioconjugation tools led to the emergence of effective chemoselective ligation techniques with reasonable kinetics. However, the construction of multivalent conjugation platforms e.g. for multicolor or multimodal labelling of biomolecules is increasingly required, and thus the development of new conjugation schemes with orthogonal reactivities are still in high demand. With contributions from experts in the field, this Special Issue of Biomolecules is dedicated to presenting chemical strategies for the modification of biomolecules. Not only do these contributions provide the readers with recent developments, but we also hope that this collection triggers new ideas, approaches and concepts.

Dr. Cyrille Sabot
Dr. Péter Kele
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Protein
  • Nucleic acid
  • Labeling
  • Fluorophore
  • Biorthogonal chemistry
  • Click chemistry
  • Bioconjugate reaction
  • Conjugation platform

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 196 KiB  
Editorial
Novel Approaches in Biomolecule Labeling
by Cyrille Sabot and Péter Kele
Biomolecules 2021, 11(12), 1809; https://doi.org/10.3390/biom11121809 - 02 Dec 2021
Viewed by 1285
Abstract
The selective functionalization of biomolecules such as proteins, nucleic acids, lipids or carbohydrates is a focus of persistent interest due to their widespread use, ranging from basic chemical biology research to gain insight into biological processes to the most promising biomedical applications, including [...] Read more.
The selective functionalization of biomolecules such as proteins, nucleic acids, lipids or carbohydrates is a focus of persistent interest due to their widespread use, ranging from basic chemical biology research to gain insight into biological processes to the most promising biomedical applications, including the development of diagnostics or targeted therapies [...] Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)

Research

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13 pages, 2098 KiB  
Article
Fluorophore-Assisted Click Chemistry through Copper(I) Complexation
by Victor Flon, Magalie Bénard, Damien Schapman, Ludovic Galas, Pierre-Yves Renard and Cyrille Sabot
Biomolecules 2020, 10(4), 619; https://doi.org/10.3390/biom10040619 - 16 Apr 2020
Cited by 8 | Viewed by 3731
Abstract
The copper-catalyzed alkyne-azide cycloaddition (CuAAC) is one of the most powerful chemical strategies for selective fluorescent labeling of biomolecules in in vitro or biological systems. In order to accelerate the ligation process and ensure efficient formation of conjugates under diluted conditions, external copper(I) [...] Read more.
The copper-catalyzed alkyne-azide cycloaddition (CuAAC) is one of the most powerful chemical strategies for selective fluorescent labeling of biomolecules in in vitro or biological systems. In order to accelerate the ligation process and ensure efficient formation of conjugates under diluted conditions, external copper(I) ligands or sophisticated copper(I)-chelating azides are used. This latter strategy, however, increases the bulkiness of the triazole linkage, thus perturbing the biological function or dynamic behavior of the conjugates. In a proof-of-concept study, we investigated the use of an extremely compact fluorophore-based copper(I) chelating azide in order to accelerate the CuAAC with concomitant fluorescence labeling; in our strategy, the fluorophore is able to complex copper(I) species while retaining its photophysical properties. It is believed that this unprecedented approach which was applied for the labeling of a short peptide molecule and the fluorescent labeling of live cells, could be extended to other families of nitrogen-based fluorophores in order to tune both the reaction rate and photophysical characteristics. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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11 pages, 873 KiB  
Communication
Fluorogenic and Bioorthogonal Modification of RNA Using Photoclick Chemistry
by Katja Krell and Hans-Achim Wagenknecht
Biomolecules 2020, 10(3), 480; https://doi.org/10.3390/biom10030480 - 21 Mar 2020
Cited by 6 | Viewed by 3348
Abstract
A bromoaryltetrazole-modified uridine was synthesized as a new RNA building block for bioorthogonal, light-activated and postsynthetic modification with commercially available fluorescent dyes. It allows “photoclick”-type modifications by irradiation with light (300 nm LED) at internal and terminal positions of presynthesized RNA with maleimide-conjugated [...] Read more.
A bromoaryltetrazole-modified uridine was synthesized as a new RNA building block for bioorthogonal, light-activated and postsynthetic modification with commercially available fluorescent dyes. It allows “photoclick”-type modifications by irradiation with light (300 nm LED) at internal and terminal positions of presynthesized RNA with maleimide-conjugated fluorophores in good yields. The reaction was evidenced for three different dyes. During irradiation, the emission increases due to the formation of an intrinsically fluorescent pyrazoline moiety as photoclick product. The fluorogenecity of the photoclick reaction was significantly enhanced by energy transfer between the pyrazoline as the reaction product (poor emitter) and the photoclicked dye as the strong emitter. The RNA-dye conjugates show remarkable fluorescent properties, in particular an up to 9.4 fold increase of fluorescence, which are important for chemical biology and fluorescent imaging of RNA in cells. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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21 pages, 4375 KiB  
Article
Development of Novel 111-In-Labelled DOTA Urotensin II Analogues for Targeting the UT Receptor Overexpressed in Solid Tumours
by Benjamin Poret, Laurence Desrues, Marc-André Bonin, Martin Pedard, Martine Dubois, Richard Leduc, Romain Modzelewski, Pierre Decazes, Fabrice Morin, Pierre Vera, Hélène Castel, Pierre Bohn and Pierrick Gandolfo
Biomolecules 2020, 10(3), 471; https://doi.org/10.3390/biom10030471 - 19 Mar 2020
Cited by 3 | Viewed by 3297
Abstract
Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a [...] Read more.
Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111In-DOTA-hUII or 111In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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13 pages, 4638 KiB  
Article
A Bioorthogonally Applicable, Fluorogenic, Large Stokes-Shift Probe for Intracellular Super-Resolution Imaging of Proteins
by Evelin Németh, Gergely Knorr, Krisztina Németh and Péter Kele
Biomolecules 2020, 10(3), 397; https://doi.org/10.3390/biom10030397 - 04 Mar 2020
Cited by 16 | Viewed by 6078
Abstract
Herein, we present the synthesis and application of a fluorogenic, large Stokes-shift (>100 nm), bioorthogonally conjugatable, membrane-permeable tetrazine probe, which can be excited at common laser line 488 nm and detected at around 600 nm. The applied design enabled improved fluorogenicity in the [...] Read more.
Herein, we present the synthesis and application of a fluorogenic, large Stokes-shift (>100 nm), bioorthogonally conjugatable, membrane-permeable tetrazine probe, which can be excited at common laser line 488 nm and detected at around 600 nm. The applied design enabled improved fluorogenicity in the orange/red emission range, thus efficient suppression of background and autofluorescence upon imaging biological samples. Moreover, unlike our previous advanced probes, it does not require the presence of special target platforms or microenvironments to achieve similar fluorogenicity and can be generally applied, e.g., on translationally bioorthogonalized proteins. Live-cell labeling schemes revealed that the fluorogenic probe is suitable for specific labeling of intracellular proteins, site-specifically modified with a cyclooctynylated, non-canonical amino acid, even under no-wash conditions. Furthermore, the probe was found to be applicable in stimulated emission depletion (STED) super-resolution microscopy imaging using a 660 nm depletion laser. Probably the most salient feature of this new probe is that the large Stokes-shift allows dual-color labeling schemes of cellular structures using distinct excitation and the same detection wavelengths for the combined probes, which circumvents chromatic aberration related problems. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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16 pages, 2412 KiB  
Article
Site-Specific Fluorogenic Protein Labelling Agent for Bioconjugation
by Kelvin K. Tsao, Ann C. Lee, Karl É. Racine and Jeffrey W. Keillor
Biomolecules 2020, 10(3), 369; https://doi.org/10.3390/biom10030369 - 28 Feb 2020
Cited by 5 | Viewed by 2894
Abstract
Many clinically relevant therapeutic agents are formed from the conjugation of small molecules to biomolecules through conjugating linkers. In this study, two novel conjugating linkers were prepared, comprising a central coumarin core, functionalized with a dimaleimide moiety at one end and a terminal [...] Read more.
Many clinically relevant therapeutic agents are formed from the conjugation of small molecules to biomolecules through conjugating linkers. In this study, two novel conjugating linkers were prepared, comprising a central coumarin core, functionalized with a dimaleimide moiety at one end and a terminal alkyne at the other. In our first design, we developed a protein labelling method that site-specifically introduces an alkyne functional group to a dicysteine target peptide tag that was genetically fused to a protein of interest. This method allows for the subsequent attachment of azide-functionalized cargo in the facile synthesis of novel protein-cargo conjugates. However, the fluorogenic aspect of the reaction between the linker and the target peptide was less than we desired. To address this shortcoming, a second linker reagent was prepared. This new design also allowed for the site-specific introduction of an alkyne functional group onto the target peptide, but in a highly fluorogenic and rapid manner. The site-specific addition of an alkyne group to a protein of interest was thus monitored in situ by fluorescence increase, prior to the attachment of azide-functionalized cargo. Finally, we also demonstrated that the cargo can also be attached first, in an azide/alkyne cycloaddition reaction, prior to fluorogenic conjugation with the target peptide-fused protein. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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Review

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8 pages, 782 KiB  
Review
Bifunctional Non-Canonical Amino Acids: Combining Photo-Crosslinking with Click Chemistry
by Jan-Erik Hoffmann
Biomolecules 2020, 10(4), 578; https://doi.org/10.3390/biom10040578 - 10 Apr 2020
Cited by 11 | Viewed by 5199
Abstract
Genetic code expansion is a powerful tool for the study of protein interactions, as it allows for the site-specific incorporation of a photoreactive group via non-canonical amino acids. Recently, several groups have published bifunctional amino acids that carry a handle for click chemistry [...] Read more.
Genetic code expansion is a powerful tool for the study of protein interactions, as it allows for the site-specific incorporation of a photoreactive group via non-canonical amino acids. Recently, several groups have published bifunctional amino acids that carry a handle for click chemistry in addition to the photo-crosslinker. This allows for the specific labeling of crosslinked proteins and therefore the pulldown of peptides for further analysis. This review describes the properties and advantages of different bifunctional amino acids, and gives an overview about current and future applications. Full article
(This article belongs to the Special Issue Novel Approaches in Biomolecule Labeling)
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