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Biomolecules
Special Issues
The Role of Glycosaminoglycans and Proteoglycans in Human Disease
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The Role of Glycosaminoglycans and Proteoglycans in Human Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2026) | Viewed by 9672

Editor

Prof. Dr. Umesh Desai

E-Mail Website
Guest Editor
1. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
2. Drug Discovery and Development, Institute for Structural Biology, Virginia Commonwealth University, Richmond, VA 23219, USA
Interests: drug discovery; chemical biology; biological macromolecules; glycosaminoglycans; coagulation factors; cancer; viral infection; bio-mimetic design; enzyme mechanisms; computational biology; high throughput screening
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are arguably the most structurally complex and diverse naturally occurring molecules. Their structural diversity arises from their template-less, spatiotemporal biosynthesis, as well as the enzymatic fine tuning of their mature forms, which appear to play an essential role in their involvement in various diseases. GAGs and PGs have been implicated in thrombosis, cancer (tumor growth, metastasis, angiogenesis, cancer stem cell modulation), inflammation, atherosclerosis, wound healing, Alzheimer’s and other neurological diseases, and many others. In terms of discrete molecular processes, GAGs and PGs modulate a host of proteins such as growth factors, chemokines, serpins, coagulation factors, inflammation-related proteases, receptor tyrosine kinases, integrins, etc. Their fundamental mechanisms of modulation range from causing conformational change in the target protein and linking two proteins to facilitate interaction, to promoting translational motion at a molecular level. GAGs and PGs are present on cell surfaces as well as in the extracellular matrix and intracellular compartments. GAGs and PGs are also present on exosomes, which have been implicated in pathogenesis. Likewise, GAGs are also present in biological milieu, e.g., blood. Despite this wealth of knowledge, it is clear that we have revealed only the tip of the iceberg. Much remains to be understood at a fundamental level in order to impact patients at the clinic level. In this context, elucidating the role of GAGs and PGs in diseases is crucial. This Special Issue is dedicated to highlighting the myriad ways in which GAGs and PGs are implicated in nature. Special emphasis will be placed on the targets and mechanisms of GAGs and PGs, which will enable the translation of this research to the clinic.

Prof. Dr. Umesh Desai
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 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. 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

  • glycosaminoglycans (GAGs)
  • proteoglycans (PGs)
  • diseases
  • mechanisms
  • molecules

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Published Papers (4 papers)

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Research

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18 pages, 4452 KB  
Article
Structural Basis of Chemokine CXCL8 Monomer and Dimer Binding to Chondroitin Sulfate: Insights into Specificity and Plasticity
by Bryon P. Mahler, Balaji Nagarajan, Nehru Viji Sankaranarayanan, Prem Raj B. Joseph, Umesh R. Desai and Krishna Rajarathnam
Biomolecules 2026, 16(1), 124; https://doi.org/10.3390/biom16010124 - 12 Jan 2026
Viewed by 802
Abstract
Chemokines play a central role in orchestrating neutrophil recruitment from the bloodstream and determining their effector functions at sites of infection. Chemokine activity is determined by three key properties: reversible monomer–dimer equilibrium, binding to glycosaminoglycans (GAGs), and signaling through the GPCR class of [...] Read more.
Chemokines play a central role in orchestrating neutrophil recruitment from the bloodstream and determining their effector functions at sites of infection. Chemokine activity is determined by three key properties: reversible monomer–dimer equilibrium, binding to glycosaminoglycans (GAGs), and signaling through the GPCR class of receptors CXCR1 and CXCR2. In this study, we investigated the structural basis of CXCL8 monomer and dimer binding to GAG chondroitin sulfate (CS) using nuclear magnetic resonance (NMR) spectroscopy, docking, and molecular dynamics (MD) measurements. Our studies reveal that both the monomer and dimer use essentially the same set of basic residues for binding, that the interface is extensive, that the dimer is the high-affinity CS ligand, and that the CS-binding residues form a contiguous surface within a monomer. Several of these residues also participate in receptor interactions, suggesting that CS-bound CXCL8 is likely impaired in its ability to bind receptors. Notably, we observe that the same basic residues are involved in binding CS and heparin/heparan sulfate, even though these GAGs differ in backbone structures and sulfation patterns. We conclude that the strategic distribution and topology of basic residues on the CXCL8 scaffold enable engagement with diverse GAG structures, which likely allows fine-tuning receptor signaling to regulate neutrophil trafficking and effector functions. Full article
(This article belongs to the Special Issue The Role of Glycosaminoglycans and Proteoglycans in Human Disease)
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Review

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40 pages, 851 KB  
Review
Proteoglycans in Breast Cancer: Friends and Foes
by Noelia Vigo-Díaz, Rubén López-Cortés, Isabel Velo-Heleno, Laura Rodríguez-Silva and Cristina Núñez
Biomolecules 2025, 15(12), 1688; https://doi.org/10.3390/biom15121688 - 3 Dec 2025
Cited by 1 | Viewed by 1721
Abstract
Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting [...] Read more.
Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting adhesion, migration, angiogenesis, immune evasion, and metastasis. Their structural heterogeneity supports either subtype- or context-dependent functions. This review combines current studies of PGs in BC according to their classification into intracellular, cell-surface, pericellular, extracellular, and small leucine-rich PGs and a range of non-classical PGs. A literature-driven approach to focus on molecular mechanisms and clinical correlations will demonstrate how PGs respond with collagens, growth factors, cytokines, and proteolytic enzymes in order to modulate the ECM and affect therapy resistance. Indeed, PGs including syndecans, glypicans, perlecan, versican, biglycan and decorin showed the potential to be promoters or suppressors of cancer, with local effects on invasion, and have a significant modulating effect on BC subtypes or the prognosis and therapeutic response and may potentially serve as new biomarkers for stratification and liquid biopsy candidates. Furthermore, PGs appear to modulate the tumour immune landscape, are involved in the development of metastatic niches, and underlie signalling pathways like Wnt or TGFβ in a subtype-dependent manner, extending their translational prospects and therapeutic utility. PGs, taken together, seem to be major modulators of BC, with particular relevance for precision medicine. Full article
(This article belongs to the Special Issue The Role of Glycosaminoglycans and Proteoglycans in Human Disease)
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23 pages, 1820 KB  
Review
Heparan Sulfate Proteoglycans (HSPGs) and Their Degradation in Health and Disease
by Nicola Greco, Valentina Masola and Maurizio Onisto
Biomolecules 2025, 15(11), 1597; https://doi.org/10.3390/biom15111597 - 14 Nov 2025
Cited by 9 | Viewed by 2906
Abstract
Heparan sulfate proteoglycans (HSPGs) are essential constituents of the extracellular matrix (ECM) and cell surface, orchestrating a wide range of biological processes, such as cell adhesion, migration, proliferation, and intercellular communication. Through their highly sulfated glycosaminoglycan chains, HSPGs serve as crucial modulators of [...] Read more.
Heparan sulfate proteoglycans (HSPGs) are essential constituents of the extracellular matrix (ECM) and cell surface, orchestrating a wide range of biological processes, such as cell adhesion, migration, proliferation, and intercellular communication. Through their highly sulfated glycosaminoglycan chains, HSPGs serve as crucial modulators of bioavailability and signaling of growth factors, cytokines, and chemokines, thereby influencing tissue homeostasis. Their dynamic remodeling is mediated by numerous enzymes, with heparanase (HPSE) playing a predominant role as the only known human endo-β-D-glucuronidase that specifically cleaves heparan sulfate chains. Beyond its well-documented enzymatic activity in ECM degradation and the release of HS-bound molecules, HPSE also exerts non-enzymatic functions that regulate intracellular signaling cascades, transcriptional programs, and immune cell behavior. Dysregulated HPSE expression or activity has been implicated in various pathological conditions, including fibrosis, chronic inflammation, cancer progression, angiogenesis, metastasis, and immune evasion, positioning this enzyme as a pivotal driver of ECM plasticity in both health and disease. This review provides an updated overview of HSPG biosynthesis, structure, localization, and functional roles, emphasizing the activity of HPSE and its impact on tissue remodeling and disease pathogenesis. We further explored its involvement in the hallmark processes of cancer, the inflammatory tumor microenvironment, and its contribution to fibrosis. Finally, we summarize current therapeutic strategies targeting HPSE, outlining their potential to restore ECM homeostasis and counteract HPSE-driven pathological mechanisms. A deeper understanding of the HSPG/HPSE axis may pave the way for innovative therapeutic interventions in cancer, inflammatory disorders, and fibrotic diseases. Full article
(This article belongs to the Special Issue The Role of Glycosaminoglycans and Proteoglycans in Human Disease)
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22 pages, 1029 KB  
Review
Dermatan Sulfate: Structure, Biosynthesis, and Biological Roles
by Congcong Chen, Xuyang Zhang, Weiting Zhang, Dahai Ding, Ravi Sankar Loka, Kun Zhao, Peixue Ling and Shuaishuai Wang
Biomolecules 2025, 15(8), 1158; https://doi.org/10.3390/biom15081158 - 12 Aug 2025
Cited by 8 | Viewed by 3585
Abstract
Dermatan sulfate (DS) is a remarkably versatile glycosaminoglycan that plays critical roles across a wide array of biological processes. Its unique structure, characterized by repeating disaccharide units of N-acetyl-D-galactosamine (GalNAc) and Iduronic acid (IdoA) with variable sulfation patterns, enables it to interact [...] Read more.
Dermatan sulfate (DS) is a remarkably versatile glycosaminoglycan that plays critical roles across a wide array of biological processes. Its unique structure, characterized by repeating disaccharide units of N-acetyl-D-galactosamine (GalNAc) and Iduronic acid (IdoA) with variable sulfation patterns, enables it to interact with numerous biomolecules. These interactions mediate diverse functions, including the organization of the extracellular matrix, promotion of wound healing, and modulation of cancer progression. Despite its broad biological relevance, deciphering DS function remains challenging due to its pronounced structural complexity and heterogeneity. Variations in chain length, disaccharide composition, and sulfation patterns make it difficult to fully characterize DS’s intricate structure–function relationships. In this review, recent developments in biosynthesis, preparation, and applications of DS are summarized. Full article
(This article belongs to the Special Issue The Role of Glycosaminoglycans and Proteoglycans in Human Disease)
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