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Chemical Probe Synthesis and Applications in Chemical Biology

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Special Issue Information
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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 23886

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Special Issue Editor

Dr. James T. Hodgkinson

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Guest Editor

University of Leicester, Leicester, UK
Interests: chemical biology; chemical probe; chemical tool; small molecules; affinity probe; photoaffinity probe; activity-based probe; fluorescent probe; heterobifunctional molecule; targeted protein degradation; protein-protein interaction; stapled peptide; cell-penetrating peptide; cyclic peptide; peptidomimetic; structure-based drug design; ligand-based drug design; chemical space; structure-activity relationship (SAR); synthesis

Special Issue Information

Dear Colleagues,

A chemical probe can be considered a cell permeable small-molecule modulator, typically an inhibitor, with defined selectivity and affinity for a specific biological macromolecule, most commonly a protein. Chemical probes with high affinity and selectivity allow the study of phenotypes associated with a specific protein. Such probes can be aids in drug target validation and complementary tools to genetic approaches. The perception of chemical probes, as mainly small-molecule inhibitors, could perhaps broaden with an increase in prevalence of selective protein–protein interaction modulators, heterobifunctional protein degraders, and cell permeable and stapled peptides. Chemical probes can be further functionalised with fluorophores, photoreactive groups, biotin, or bio-orthogonal functional groups for in cell labelling. This facilitates not only the study of phenotypes associated with the protein, but also in-cell imaging, quantifying enzymatic activity, and identifying other potential protein binding partners via protein–protein complexes and potential ‘off-target’ protein interactions. Despite these advances, not one approach to the development of chemical probes is amenable for all proteins or biological macromolecules. High affinity, selectivity, and cell permeability still remain significant hurdles to the development of high quality chemical probes. This is an exciting and rapidly developing field of research to which synthetic chemists and chemical biologists can contribute through the design and synthesis of new chemical probes. We invite original research articles or review contributions to this Special Issue on chemical probes, in all aspects of chemical probes including design, synthesis, optimisation studies, methodologies of use, and applications in all areas of chemical biology.

Dr. James T. Hodgkinson
Guest Editor

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. Molecules is an international peer-reviewed open access semimonthly 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

Chemical biology
Chemical probe
Chemical tool
Small molecules
Affinity probe
Photoaffinity probe
Activity-based probe
Fluorescent probe
Heterobifunctional molecule
Targeted protein degradation
Protein–protein interaction
Stapled peptide
Cell-penetrating peptide
Cyclic peptide
Peptidomimetic
Structure-based drug design
Ligand-based drug design
Chemical space
Structure–activity relationship (SAR)
Synthesis

Published Papers (6 papers)

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Research

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11 pages, 1162 KiB

Open AccessArticle

Improved Cathepsin Probes for Sensitive Molecular Imaging

by Yonit Yitzhak, Hanmant Gaikwad, Tommy Weiss-Sadan, Emmanuelle Merquiol, Boris Turk and Galia Blum

Molecules 2022, 27(3), 842; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030842 - 27 Jan 2022

Viewed by 2551

Abstract

Cysteine cathepsin proteases are found under normal conditions in the lysosomal compartments of cells, where they play pivotal roles in a variety of cellular processes such as protein and lipid metabolism, autophagy, antigen presentation, and cell growth and proliferation. As a consequence, aberrant localization and activity contribute to several pathologic conditions such as a variety of malignancies, cardiovascular diseases, osteoporosis, and other diseases. Hence, there is a resurgence of interest to expand the toolkit to monitor intracellular cathepsin activity and better ascertain their functions under these circumstances. Previous fluorescent activity-based probes (ABPs) that target cathepsins B, L, and S enabled detection of their activity in intact cells as well as non-invasive detection in animal disease models. However, their binding potency is suboptimal compared to the cathepsin inhibitor on which they were based, as the P1 positive charge was capped by a reporter tag. Here, we show the development of an improved cathepsin ABP that has a P1 positive charge by linking the tag on an additional amino acid at the end of the probe. While enhancing potency towards recombinant cathepsins, the new probe had reduced cell permeability due to additional peptide bonds. At a second phase, the probe was trimmed; the fluorophore was linked to an extended carbobenzoxy moiety, leading to enhanced cell permeability and superb detection of cathepsin activity in intact cells. In conclusion, this work introduces a prototype design for the next generation of highly sensitive ABPs that have excellent detection of cellular cathepsin activity. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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17 pages, 32018 KiB

Open AccessArticle

Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog–Thalidomide PROTACs

by Ga Yeong Kim, Chae Won Song, Yo-Sep Yang, Na-Rae Lee, Hyung-Seok Yoo, Seung Hwan Son, Soo Jin Lee, Jong Seon Park, Jong Kil Lee, Kyung-Soo Inn and Nam-Jung Kim

Molecules 2021, 26(9), 2525; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092525 - 26 Apr 2021

Cited by 22 | Viewed by 4259

Abstract

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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12 pages, 2341 KiB

Open AccessArticle

Solid-Phase Synthesis of Fluorescent Probes for Plasma Membrane Labelling

by Shuo Zhang, Annamaria Lilienkampf and Mark Bradley

Molecules 2021, 26(2), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020354 - 12 Jan 2021

Cited by 1 | Viewed by 3261

Abstract

The cellular plasma membrane plays a fundamental role in biological processes, including cell growth, signaling and transport. The labelling of the plasma membrane with targeted fluorescent probes offers a convenient and non-invasive way to image the morphological changes and dynamics of a membrane in real-time and, despite many examples of fluorescent plasma membrane probes, a “universal targeting/anchoring moiety” is still required. In this study, a small number of stearic acid-based probes labelled with 6-carboxyfluorescein was designed and fabricated via solid-phase synthesis in which variations in both charge and hydrophobicity were explored. To ease the synthesis process, a gram-scale synthesis of the Fmoc-Lys(6-carboxyfluoresein diacetate)-OH building block was developed, allowing the discovery of optimal probes that carried a positively charged amino group and a stearic acid tail that exhibited intense plasma membrane brightness and robust retention. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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Graphical abstract

13 pages, 3327 KiB

Open AccessArticle

A Photoalkylative Fluorogenic Probe of Guttiferone A for Live Cell Imaging and Proteome Labeling in Plasmodium falciparum

by Romain Duval, Kevin Cottet, Magali Blaud, Anaïs Merckx, Sandrine Houzé, Philippe Grellier, Marie-Christine Lallemand and Sylvie Michel

Molecules 2020, 25(21), 5139; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25215139 - 04 Nov 2020

Cited by 4 | Viewed by 2213

Abstract

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose–response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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Review

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24 pages, 14396 KiB

Open AccessReview

Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study

by Eleanor L. Atkinson, Jessica Iegre, Paul D. Brear, Elizabeth A. Zhabina, Marko Hyvönen and David R. Spring

Molecules 2021, 26(7), 1977; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26071977 - 31 Mar 2021

Cited by 15 | Viewed by 3269

Abstract

Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase’s biology, with wide-reaching implications for drug development. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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30 pages, 2631 KiB

Open AccessReview

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

by Joshua P. Smalley, Shaun M. Cowley and James T. Hodgkinson

Molecules 2020, 25(19), 4394; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194394 - 24 Sep 2020

Cited by 30 | Viewed by 7283

Abstract

Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics—single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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