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Chemical Biology in Europe
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Chemical Biology in Europe

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

Deadline for manuscript submissions: 30 September 2026 | Viewed by 4287

Editors

Prof. Dr. Steven Verhelst

E-Mail Website
Guest Editor
Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
Interests: activity-based probes; activity-based protein profiling; bioorthogonal chemistry; chemical proteomics; cleavable linkers; intramembrane proteases; photoaffinity labeling; proteases; protease inhibitors
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Alessio Peracchi

E-Mail Website
Guest Editor
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy
Interests: enzymes; enzyme evolution; kinetics; metabolism; functional proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you know, chemical biology is an interdisciplinary field whose scope encompasses both the fundamental understanding of biological processes at the molecular level and the development of new technologies in life sciences and in biomedicine. This Special Issue will collect communications, research articles, and high-quality reviews from chemical biology laboratories in Europe. The topics may include, but are not restricted to, novel chemical probe development, bioorthogonal chemistries, target identification of small molecules, small molecule-based detection of post-translational modifications (PTMs), and chemical probe-based imaging in situ or in vivo. Experimental studies at the interface with enzymology and biotechnology are also encouraged, such as approaches that may provide mechanistic insights and drive innovation in drug discovery, diagnostics, and synthetic biology. Other suitable topics for experimental articles and reviews may be the use of artificial intelligence (AI) in the design and interpretation of chemical biology studies.

Prof. Dr. Steven Verhelst 
Prof. Dr. Alessio Peracchi
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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 probes
  • bioorthogonal chemistry
  • chemical proteomics
  • target identification
  • probe-based visualization
  • PTM detection

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Published Papers (4 papers)

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Research

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19 pages, 2195 KB  
Article
The Differential Redox Resilience of Alvelestat and Sivelestat: A Mechanistic Hypothesis for Inhibitor Performance Under Oxidative Stress
by Maura D’Amato, Pasquale Linciano, Laurent R. Chiarelli, Giampiero Pietrocola, Paolo Iadarola, Simona Collina, Maria Antonietta Grignano, Marilena Gregorini, Teresa Rampino and Simona Viglio
Molecules 2026, 31(9), 1454; https://doi.org/10.3390/molecules31091454 - 28 Apr 2026
Viewed by 596
Abstract
Human neutrophil elastase (HNE) is a key driver of inflammatory lung disorders, promoting extracellular matrix degradation and tissue damage. Although inhibitors such as Sivelestat and Alvelestat are clinically relevant, their performance within the oxidative microenvironment of diseased lungs remains poorly understood. Here, we [...] Read more.
Human neutrophil elastase (HNE) is a key driver of inflammatory lung disorders, promoting extracellular matrix degradation and tissue damage. Although inhibitors such as Sivelestat and Alvelestat are clinically relevant, their performance within the oxidative microenvironment of diseased lungs remains poorly understood. Here, we employed an integrated in vitro and in silico approach to investigate their behavior under physiological and oxidative conditions and to provide a molecular-level interpretation. Under physiological conditions, enzymatic assays and steady-state kinetics confirmed that both compounds act as competitive inhibitors, with Sivelestat displaying higher baseline potency. Under oxidative stress, however, Sivelestat exhibited a marked reduction in inhibitory potency, whereas Alvelestat retained its efficacy. Molecular modeling and molecular dynamics simulations of native and oxidized HNE variants provided a structural rationale for this divergence. Alvelestat, as a non-covalent inhibitor, maintains stable binding despite increased flexibility of the active site, whereas Sivelestat, acting via a reversible covalent mechanism, requires a precise pre-acylation geometry. Oxidation-induced remodeling of the S1 pocket disrupts the near-attack configuration required for covalent bond formation, thereby impairing inhibition. Overall, these findings indicate that oxidative stress may selectively compromise covalent inhibition while preserving enzymatic activity, and suggest that context-dependent redox-related structural effects may represent a consideration for the design of next-generation HNE inhibitors. Full article
(This article belongs to the Special Issue Chemical Biology in Europe)
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25 pages, 6140 KB  
Article
Oxidized Phosphatidylcholines Regulate Secretory Phospholipase A2 Through Membrane Nanodomain Remodeling
by Vesela Yordanova, Rusina Hazarosova, Victoria Vitkova, Ralitsa Angelova, Biliana Nikolova, Atanaska Elenkova, Albena Momchilova and Galya Staneva
Molecules 2026, 31(8), 1298; https://doi.org/10.3390/molecules31081298 - 16 Apr 2026
Viewed by 642
Abstract
Oxidative stress generates oxidized phospholipids (OxPLs) that alter membrane structure and inflammatory lipid signaling, yet the underlying biophysical mechanisms remain poorly understood. Here, we examine how two structurally distinct truncated oxidized phosphatidylcholines (OxPCs), 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), remodel [...] Read more.
Oxidative stress generates oxidized phospholipids (OxPLs) that alter membrane structure and inflammatory lipid signaling, yet the underlying biophysical mechanisms remain poorly understood. Here, we examine how two structurally distinct truncated oxidized phosphatidylcholines (OxPCs), 1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), remodel membrane lateral organization and regulate secretory phospholipase A2 (sPLA2) activity. Large unilamellar vesicles composed of sphingomyelin, cholesterol, and either monounsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or polyunsaturated 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC) were used to reconstitute the liquid-ordered/liquid-disordered (Lo/Ld) phase coexistence characteristic of eukaryotic plasma membranes. Fluorescence spectroscopy revealed that OxPLs modulate lipid packing and nanodomain organization in a structure- and composition-dependent manner. POVPC promoted pronounced membrane ordering and Lo domain stabilization compared with PGPC, particularly in monounsaturated membranes with low cholesterol content. In contrast, PDPC-containing membranes, especially at elevated cholesterol, exhibited enhanced structural resilience to OxPL-induced perturbations. These biophysical changes were associated with distinct functional outcomes. Notably, the relationship between membrane structural parameters and sPLA2 activity was not linear, indicating a decoupling between bulk membrane properties and enzymatic response. sPLA2 activity was linked to membrane lateral organization: the size of Lo domains modulate hydrolysis by influencing the physicochemical properties of Lo/Ld interfaces, which may represent preferential sites for enzyme activation. Consistent with this, POVPC reduced sPLA2 activity through stabilization of ordered domains at both low and high cholesterol, while PGPC enhanced hydrolysis at high cholesterol. Importantly, PDPC-containing membranes attenuated sPLA2 activity and exhibited a protective effect against OxPC-induced enzymatic activation. Together, these findings identify membrane lateral organization as a key regulator of sPLA2 function and provide mechanistic insight into how oxidative stress can differentially modulate inflammatory lipid signaling depending on membrane composition. This work highlights membrane organization as an active determinant of enzyme activity and a potential target in pathologies associated with oxidative stress, including atherosclerosis, neuroinflammation, and metabolic disease. Full article
(This article belongs to the Special Issue Chemical Biology in Europe)
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23 pages, 2570 KB  
Article
The Substrate Versatility of Δ1-Pyrroline-5-carboxylate Reductase (ProC) from Escherichia coli
by Eugenia Polverini, Alessandro Vecchi, Giulia Capra, Alessia Pastori and Alessio Peracchi
Molecules 2026, 31(3), 501; https://doi.org/10.3390/molecules31030501 - 31 Jan 2026
Viewed by 881
Abstract
Δ1-Pyrroline-5-carboxylate reductase (EC 1.5.1.2; called ProC in most bacteria) is an enzyme of central metabolism that catalyzes the last step of the proline biosynthetic pathways, namely the NADPH-dependent reduction of pyrroline-5-carboxylate (P5C) to L-proline (L-Pro). The enzyme, however, is also active [...] Read more.
Δ1-Pyrroline-5-carboxylate reductase (EC 1.5.1.2; called ProC in most bacteria) is an enzyme of central metabolism that catalyzes the last step of the proline biosynthetic pathways, namely the NADPH-dependent reduction of pyrroline-5-carboxylate (P5C) to L-proline (L-Pro). The enzyme, however, is also active towards other substrates, and these reactions might have physiological relevance. Herein, the substrate versatility of ProC from Escherichia coli was explored as follows. We initially characterized the reverse reaction carried out by ProC, i.e., the formation of P5C from L-Pro. This reaction was easily measurable at pH 10, allowing the determination of the kinetic parameters. Under the same conditions, we then tested the ability of ProC to oxidize a number of L-Pro analogs, confirming that ProC reacts most effectively with analogs containing a simple five-membered ring such as L-thioproline (THP) and 3,4-dehydro-L-proline (DHP). Larger substrates such as L-pipecolate (PIP) reacted with lower efficiency, and the four-membered ring analog, L-azetidine-2-carboxylate (A2C) showed no detectable reactivity and behaved as a weak inhibitor of the ProC reaction. To interpret these results, we built a structural model of ProC and employed this model for a docking analysis of L-Pro and of its analogs. This approach highlighted the presence of a peculiar “three-point interaction”, in which the L-Pro carboxylate and amino groups form hydrogen bonds with conserved residues in the binding site, while the substrate ring stacks with the nicotinamide ring of NADP+. The L-Pro analogs tried to preserve as much as possible these critical interactions for a correct positioning and a favorable binding. The possibility of an inherent multifunctionality of ProC was further explored by examining the genomic context of the proC gene in a large number of bacterial species. Full article
(This article belongs to the Special Issue Chemical Biology in Europe)
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Review

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32 pages, 15151 KB  
Review
Optimizing Lactoferrin Isolation for Functional and Structural Integrity: A Molecular Insight
by Ahmet Alperen Canbolat, Nur Hasret İstekli, Kadir Yılmaz, Mikhael Bechelany and Sercan Karav
Molecules 2026, 31(3), 454; https://doi.org/10.3390/molecules31030454 - 28 Jan 2026
Cited by 1 | Viewed by 1549
Abstract
Lactoferrin (Lf) occurs predominantly within milk, coexisting with measurable levels across different glandular products and body fluids. Lf exhibits variation in relative molecular mass, influenced by its biological source and glycosylation profile; nevertheless, it is a close to 80 kDa glycoprotein. Provided that [...] Read more.
Lactoferrin (Lf) occurs predominantly within milk, coexisting with measurable levels across different glandular products and body fluids. Lf exhibits variation in relative molecular mass, influenced by its biological source and glycosylation profile; nevertheless, it is a close to 80 kDa glycoprotein. Provided that its bioactive structure is preserved, Lf performs a spectrum of physiological roles, comprising antioxidant, antifungal, antiviral, antiapoptotic, and antimicrobial actions. To sustain its bioactivity after isolation and ensure its effectiveness in subsequent applications, optimal conditions must be established throughout the optimization protocol, since inadequate optimization of parameters such as pH, temperature, ion balance, and protease activity may lead to aggregation, denaturation, and deterioration in functional regions, including the iron-binding domains. This review offers a comprehensive framework that associates isolation methodologies with structural integrity, preservation of iron-binding domains, and antimicrobial performance. Ion-exchange, affinity-based, and membrane-based approaches are systematically evaluated from analytical and functional perspectives, thereby yielding a synthesis that facilitates procedure selection and optimization for Lf isolation. In addition, the objectives of analytical characterization techniques implemented following isolation and the broadening scope of biotechnological applications of Lf are outlined. Full article
(This article belongs to the Special Issue Chemical Biology in Europe)
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