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30th Anniversary of Molecules—Recent Advances in Chemical Biology

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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: 31 December 2026 | Viewed by 18338

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Special Issue Editors

Prof. Dr. Akinori Kuzuya

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Organization for Research and Development of Innovative Science and Technology (ORDIST), Kansai University, Suita 564-8680, Osaka, Japan
Interests: nucleic acid chemistry; DNA nanotechnology; supramolecular chemistry; molecular machines; molecular robotics; molecular technology
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Prof. Dr. Daisuke Miyoshi

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Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Interests: G-quadruplex; i-motif; molecular crowding; phase separation; thermodynamics; kinetics; aptamer; ligand
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Dr. Camila C. Portugal

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Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
Interests: neuroscience; microglia; oxidative stress; vitamin C; Alzheimer's disease
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Dr. Takuya Terai

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Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
Interests: chemical biology; fluorescence/luminescence probe; fluorescence imaging; high-throughput screening; directed molecular evolution; peptide aptamer
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Special Issue Information

Dear Colleagues,

In 2026, we will be celebrating the 30th anniversary of our journal Molecules. To date, the journal has published more than 50,000 papers. Molecules has carved out a notable space in the chemical literature, with an Impact Factor of 4.6 (2024) and a 5-Year Impact Factor of 5.0 (2024). Our sincerest thanks go to our readers, innumerable authors, anonymous peer reviewers, Editors, and all the people working for the journal in some capacity. Without your help, we would never have achieved this.

To mark this important milestone, a Special Issue entitled “30th Anniversary of Molecules—Recent Advances in Chemical Biology” is being launched. This Special Issue collects communications, full papers, and high-quality papers in the chemical biology fields. We kindly invite and encourage all research groups covering various areas of chemical biology to contribute to this Special Issue.

Prof. Dr. Akinori Kuzuya
Prof. Dr. Daisuke Miyoshi
Dr. Camila C. Portugal
Dr. Takuya Terai
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-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

bioorthogonal chemistry
peptides
nucleic acids
proteins
analytical methods
chemical inhibitors
chemical probe
ubiquitination
structure-activity relationship

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Published Papers (10 papers)

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Research

Jump to: Review

16 pages, 4879 KB

Open AccessArticle

Enhancement of Cytoskeletal Tension Promotes Amyloid-β Aggregation on the Neuronal Cell Surface

by Juri Nakayama, Yuna Fujiya, Kiyotaka Tokuraku and Masahiro Kuragano

Molecules 2026, 31(4), 718; https://doi.org/10.3390/molecules31040718 - 19 Feb 2026

Viewed by 254

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for the majority of dementia cases. The accumulation of amyloid-β (Aβ) aggregates on neuronal surfaces is a known important event that typifies AD. Although cell membrane architecture and cytoskeletal tension are thought to be involved in the process of Aβ aggregation, it remains unclear how cytoskeleton-derived tension alters the function of cell membranes, which serve as a scaffold for Aβ aggregation. In this study, we investigated whether cytoskeletal tension promotes Aβ aggregation on neuroblastoma, SH-SY5Y cells. Cytoskeletal tension was enhanced by jasplakinolide, an actin depolymerization inhibitor, and calyculin A, a serine/threonine phosphatase inhibitor that promotes myosin II activation. Real-time imaging with quantum-dot-labeled Aβ nanoprobes revealed that both pharmacological treatments significantly increased Aβ deposition on the surface of living cells. Our findings suggest that cytoskeletal tension promotes Aβ aggregation over the membrane barrier, providing new insights into the biophysical mechanisms underlying Aβ accumulation in AD pathogenesis. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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13 pages, 3421 KB

Open AccessArticle

A Whole-Cell Catalytic System for Equol Production Based on Daidzein Reductase Engineering

by Bing-Juan Li, Jiao-Jiao Zhuo, Meng-Ran Tian, Dan Meng and Hong-Yan Li

Molecules 2026, 31(4), 711; https://doi.org/10.3390/molecules31040711 - 18 Feb 2026

Viewed by 274

Abstract

As an isoflavone metabolite with diverse physiological activities, the development of efficient and sustainable manufacturing technologies for (S)-equol holds significant importance. This study focuses on the semi-rational design of daidzein reductase (DZNR), the first key enzyme in the (S)-equol biotransformation pathway. Through multiple sequence alignment and three-dimensional structural analysis, two critical residues, Gly30 and Ala105, were identified in DZNR. A library of single and combinatorial mutants was constructed and screened, yielding the double variant DZNR30S+105S with substantially enhanced catalytic performance. In a whole-cell biocatalytic system, the recombinant E. coli (Escherichia coli) strain harboring this combinatorial mutant achieved a yield of 238.3 mg/L (S)-equol at a substrate concentration of 1 mM daidzein, demonstrating markedly improved catalytic efficiency. Upon increasing the daidzein concentration to 2 mM, the reaction reached equilibrium within 5 h, producing 384.6 mg/L (S)-equol, which highlights the mutant’s excellent potential for high-substrate-concentration applications. This study not only provides novel mechanistic insights into DZNR catalysis but also successfully establishes a DZNR variant with enhanced activity, offering an efficient biocatalytic component for the industrial-scale biomanufacturing of (S)-equol and thereby advancing the development of green biosynthesis technologies for this valuable compound. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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17 pages, 2809 KB

Open AccessArticle

Synthesis of Arapaima gigas Growth Hormone (ag-GH) in HEK 293 Cells: Its Purification and Characterization via In Vivo Bioassay in Dwarf “Little” Mice

by Eliana Rosa Lima, Jeniffer Cristina Ribeiro Melo, Filipe Menezes Bezerra, Miriam Fussae Suzuki, Amanda Palermo Nunes, Thais Cristina dos Anjos Sevilhano, João Ezequiel Oliveira, Riviane Garcez, Lucas Simon Torati, Geraldo Santana Magalhães, Cibele Nunes Peroni and Paolo Bartolini

Molecules 2026, 31(3), 572; https://doi.org/10.3390/molecules31030572 - 6 Feb 2026

Viewed by 279

Abstract

Arapaima gigas growth hormone (ag-GH) cDNA was previously cloned from A. gigas pituitaries. In this work ag-GH has been synthesized using human embryonic kidney 293 cells (HEK293) transiently transfected with the 3.4-TOPO^® vector carrying ag-GH cDNA. The 4th day after transfection, the presence of putative ag-GH was detected via SDS-PAGE and Western blotting in comparison with human GH. Ion exchange purification exhibited a clearly symmetric peak, absent in the control medium. The purified fraction, submitted to high-performance size-exclusion chromatography (HPSEC), SDS-PAGE, and Western blotting, contained an immunoreactive molecule, slightly smaller than hGH as expected. MALDI-TOF-MS determined a high-resolution molecular mass of 21,220 Da versus a theoretical value of 21,150. A phylogenetic analysis positioned ag-GH within basal teleost lineages, consistent with earlier analyses of A. gigas gonadotrophic hormones, reinforcing the structural and functional conservation relevant for its biologic activity. An in vivo bioassay based on the body weight increase of dwarf “little” mice demonstrated a biological activity for ag-GH comparable to that of the international reference preparation of rec-hGH. For two species (H. sapiens and A. gigas) separated by an evolutionary period of >100 million years, such a positive biological correlation is remarkable. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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20 pages, 2766 KB

Open AccessArticle

Liquid Chromatography-Tandem Mass Spectrometry Method Development and Validation for the Determination of a New Mitochondrial Antioxidant in Mouse Liver and Cerebellum, Employing Advanced Chemometrics

by Anthi Panara, Dimitra Biliraki, Markus Nussbaumer, Michaela D. Filiou, Nikolaos S. Thomaidis, Ioannis K. Kostakis and Evagelos Gikas

Molecules 2025, 30(9), 1900; https://doi.org/10.3390/molecules30091900 - 24 Apr 2025

Cited by 1 | Viewed by 1273

Abstract

Anxiety and stress-related disorders affect all ages in all geographical areas. As high anxiety and chronic stress result in the modulation of mitochondrial pathways, intensive research is being carried out on pharmaceutical interventions that alleviate pertinent symptomatology. Therefore, innovative approaches being currently pursued include substances that target mitochondria bearing an antioxidant moiety. In this study, a newly synthesized antioxidant consisting of triphenylphosphine (TPP), a six-carbon alkyl spacer, and hydroxytyrosol (HT) was administered orally to mice via drinking water. Cerebellum and liver samples were collected and analyzed using ultra-high-performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-MS/MS) to assess the levels of TPP-HT in the respective tissues to evaluate in vivo administration efficacy. Sample preparation included extraction with appropriate solvents and a preconcentration step to achieve the required sensitivity. Both methods were validated in terms of selectivity, linearity, accuracy, and limits of detection and quantification. Additionally, a workflow for evaluating and statistically summarizing multiple fortified calibration curves was devised. TPP-HT penetrates the blood–brain barrier (BBB), with a level of 11.5 ng g⁻¹ quantified in the cerebellum, whereas a level of 4.8 ng g⁻¹ was detected in the liver, highlighting the plausibility of orally administering TPP-HT to achieve mitochondrial targeting. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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28 pages, 4465 KB

Open AccessArticle

The Absence of a Very Long Chain Fatty Acid (VLCFA) in Lipid A Impairs Agrobacterium fabrum Plant Infection and Biofilm Formation and Increases Susceptibility to Environmental Stressors

by Iwona Komaniecka, Kamil Żebracki, Andrzej Mazur, Katarzyna Suśniak, Anna Sroka-Bartnicka, Anita Swatek and Adam Choma

Molecules 2025, 30(5), 1080; https://doi.org/10.3390/molecules30051080 - 26 Feb 2025

Cited by 1 | Viewed by 1301

Abstract

The Agrobacterium fabrum C58 is a phytopathogen able to infect numerous species of cultivated and ornamental plants. During infection, bacteria genetically transform plant cells and induce the formation of tumours at the site of invasion. Bacterial cell wall components play a crucial role in the infection process. Lipopolysaccharide is the main component of Gram-negative bacteria’s outer leaflet of outer membrane. Its lipophilic part, called lipid A, is built of di-glucosamine backbone substituted with a specific set of 3-hydroxyl fatty acids. A. fabrum incorporates a very long chain hydroxylated fatty acid (VLCFA), namely 27-hydroxyoctacosanoic acid (28:0-(27OH)), into its lipid A. A. fabrum C58 mutants deprived of this component due to mutation in the VLCFA’s genomic region, have been characterised. High-resolution mass spectrometry was used to establish acylation patterns in the mutant’s lipid A preparations. The physiological properties of mutants, as well as their motility, ability to biofilm formation and plant infectivity, were tested. The results obtained showed that the investigated mutants were more sensitive to environmental stress conditions, formed a weakened biofilm, exhibited impaired swimming motility and were less effective in infecting tomato seedlings compared to the wild strain. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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Review

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28 pages, 2835 KB

Open AccessReview

The Molecular Network of Neutrophil Extracellular Traps in Hepatocellular Carcinoma: Biogenesis, Function, and Therapeutic Implications

by Chang Liu, Jienan Lu, Yang Tian, Sinan Lu, Weili Wang, Jun Jiang, Xiang Zheng and Sheng Yan

Molecules 2026, 31(4), 749; https://doi.org/10.3390/molecules31040749 - 23 Feb 2026

Viewed by 284

Abstract

Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death worldwide. Its high aggressiveness and resistance to therapy arise, in large part, from an immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are web-like assemblies of chromatin and granular proteins released during NETosis, and they have emerged as major inflammatory drivers within the HCC TME. NETs actively promote tumor progression by physically trapping circulating tumor cells, remodeling the extracellular matrix, stimulating angiogenesis, and facilitating immune evasion. In this review, we systematically dissect the molecular networks that link NETs to HCC. We summarize the signaling pathways that regulate NETs formation, detail the multifaceted roles of NETs in hepatocarcinogenesis, metastasis, and therapy resistance, and assess the translational potential of NETs as diagnostic biomarkers and therapeutic targets. Together, these analyses offer theoretical guidance for developing the next generation of precision-medicine strategies for HCC. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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36 pages, 1705 KB

Open AccessFeature PaperReview

Caloric Restriction Mimetics as Priming Agents of Mesenchymal Stem Cells Secretome to Enhance Regenerative Responses to Parkinson’s Disease

by Bárbara Carneiro-Pereira, Filipa Ferreira-Antunes, Jonas Campos, António J. Salgado and Belém Sampaio-Marques

Molecules 2025, 30(11), 2260; https://doi.org/10.3390/molecules30112260 - 22 May 2025

Cited by 1 | Viewed by 2523

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder primarily defined by the deterioration of motor function and characterized by the loss of dopaminergic neurons in the nigrostriatal system. Although it is the second most prevalent disorder of the central nervous system, current treatments primarily focus on symptom management and modestly slowing disease progression, ultimately failing to preserve the long-term quality of life of a substantial proportion of affected individuals. Innovative therapies that can restore neuronal function have emerged, such as the use of the secretome of Mesenchymal Stem Cells (MSCs) due to their rich composition of bioactive molecules. This therapy exhibits robust paracrine activity that drives most of the self-renewal capacity, differentiation potential, and immune regulation of MSCs without presenting compatibility issues often associated with stem cell-based therapies. While conceptually appealing, the clinical application of this approach is still limited by the availability and proliferation capacity of MSCs, as it impacts not only secretome production but also its quality. Various protocols have been developed to enhance secretome action by adding various compounds to cell culture media, given the high environmental plasticity of MSCs. Some of the compounds already used are Caloric Restriction Mimetics (CRMs), molecules that mimic Caloric Restriction (CR) conditions, which have been demonstrated to extend lifespan and reduce age-related diseases in various organisms. While not sufficient to cure neurodegenerative disorders, these compounds may potentiate secretome efficiency by enhancing autophagy pathways and relieving oxidative stress burden from MSCs. Therefore, in this article, we aim to explore the effects of CRMs priming on MSCs and how it may help bridge existing gaps in regenerative therapies for PD. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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52 pages, 5132 KB

Open AccessReview

Early-Stage Pancreatic Cancer Diagnosis: Serum Biomarkers and the Potential for Aptamer-Based Biosensors

by Weisi He, Jingyu Cui, Xue-Yan Wang, Ryan H. P. Siu and Julian A. Tanner

Molecules 2025, 30(9), 2012; https://doi.org/10.3390/molecules30092012 - 30 Apr 2025

Cited by 4 | Viewed by 5640

Abstract

Pancreatic cancer has a high mortality rate, and both the incidence and mortality are continuing to increase in many countries globally. The poor prognosis of pancreatic cancer is in part due to the challenges in early diagnosis. Improving early-stage pancreatic cancer diagnosis would improve survival outcomes. Aptamer-based biosensors provide an alternative technological approach for the analysis of serum biomarkers with several potential advantages. This review summarizes the major pancreatic cancer serum biomarkers, as well as discusses recent progress in biomarker exploration and aptasensor development. Here, we review both established and novel serum biomarkers identified recently, emphasizing their potential for early-stage pancreatic cancer diagnosis. We also propose strategies for further expanding multiplex biomarker panels beyond the established CA19-9 biomarker to enhance diagnostic performance. We discuss technological advancements in aptamer-based sensors for pancreatic cancer-related biomarkers over the last decade. Optical and electrochemical sensors are highlighted as two primary modalities in aptasensor design, each offering unique advantages. Finally, we propose steps towards clinical application using aptamer-based sensors with multiplexed biomarker detection for improved pancreatic cancer diagnostics. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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23 pages, 2234 KB

Open AccessReview

Recent Progress and Potential of G4 Ligands in Cancer Immunotherapy

by Jiahui Lin, Zhu Gong, Yingyue Lu, Jiongheng Cai, Junjie Zhang, Jiaheng Tan, Zhishu Huang and Shuobin Chen

Molecules 2025, 30(8), 1805; https://doi.org/10.3390/molecules30081805 - 17 Apr 2025

Cited by 6 | Viewed by 3647

Abstract

G-quadruplex (G4) structures are non-canonical nucleic acid conformations that play crucial roles in gene regulation, DNA replication, and telomere maintenance. Recent studies have highlighted G4 ligands as promising anticancer agents due to their ability to modulate oncogene expression and induce DNA damage. By stabilizing G4 structures, these ligands affect tumor progression. Additionally, they have been implicated in tumor immunity modulation, particularly through the activation and immunogenic cell death induction of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. Moreover, their disruption of telomere maintenance and regulation of key oncogenes, such as c-MYC and KRAS, position them as candidates for immune-based therapeutic interventions. Despite their therapeutic potential, challenges remain in optimizing their clinical applications, particularly in patient stratification and elucidating their immunomodulatory effects. This review provides a comprehensive overview of the mechanisms through which G4 ligands influence tumor progression and immune regulation, highlighting their potential role in future cancer immunotherapy strategies. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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13 pages, 1772 KB

Open AccessReview

Chemical Conversations

by Jana Michailidu, Olga Maťátková, Alena Čejková and Jan Masák

Molecules 2025, 30(3), 431; https://doi.org/10.3390/molecules30030431 - 21 Jan 2025

Cited by 3 | Viewed by 1735

Abstract

Among living organisms, higher animals primarily use a combination of vocal and non-verbal cues for communication. In other species, however, chemical signaling holds a central role. The chemical and biological activity of the molecules produced by the organisms themselves and the existence of receptors/targeting sites that allow recognition of such molecules leads to various forms of responses by the producer and recipient organisms and is a fundamental principle of such communication. Chemical language can be used to coordinate processes within one species or between species. Chemical signals are thus information for other organisms, potentially inducing modification of their behavior. Additionally, this conversation is influenced by the external environment in which organisms are found. This review presents examples of chemical communication among microorganisms, between microorganisms and plants, and between microorganisms and animals. The mechanisms and physiological importance of this communication are described. Chemical interactions can be both cooperative and antagonistic. Microbial chemical signals usually ensure the formation of the most advantageous population phenotype or the disadvantage of a competitive species in the environment. Between microorganisms and plants, we find symbiotic (e.g., in the root system) and parasitic relationships. Similarly, mutually beneficial relationships are established between microorganisms and animals (e.g., gastrointestinal tract), but microorganisms also invade and disrupt the immune and nervous systems of animals. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Chemical Biology)

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