bims-supasi 2025-07-06 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–07–06
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

FTIR characterisation of chondroitin sulfate E (CS-E) di-, tetra-, and hexasaccharide derivatives and their biotinylated or reducing conjugates.
Group A Streptococcus interacts with glycosaminoglycans via M proteins to modulate bacterial adherence in vitro.
A synthetic HS structure selectively impairs the morphology and function of excitatory synapse by disrupting neurexin1 interactions.
Engineering a novel adenine-sulfotransferase for efficient synthesis of PAPS and chondroitin sulfate in microbial cells.
Association of DHEAS levels with COVID19 severity, gender, age, comorbidities, and management strategies.
Synthesis of the endogenous non-reducing end heparan sulfate disaccharide for newborn screening and diagnosis of Mucopolysaccharidosis type IIIA.
Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease.
Evaluation of transduction efficiency in pancreatic beta and alpha cells utilizing various AAV serotypes.
Optimization and Hepatoprotective Potential of Sulfated Polysaccharide From Pleurotus ostreatus.
LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9.
Sulfated Lewis A from the oviduct reservoir selectively binds to camel (Camelus dromedarius) sperm and extends their lifespan in vitro.
Linear and nonlinear rheological properties of sulfated, phosphorylated and carboxymethylated Mesona chinensis polysaccharide - wheat starch systems.
From Docking and Molecular Dynamics to Experimental Discovery: Exploring the Hydrophobic Landscapes of Heparanase to Design Potent Inhibitors.

Analyst. 2025 Jun 30.

FTIR characterisation of chondroitin sulfate E (CS-E) di-, tetra-, and hexasaccharide derivatives and their biotinylated or reducing conjugates.

Elise Vincent, Valérie Untereiner, Florian Chabot, Aude Vibert, Marie Schuler, Jorgan Guard, Romain Rivet, Isabelle Proult, Chrystel Lopin-Bon, Stéphane Brézillon, Ganesh D Sockalingum.

Sulfated glycosaminoglycans (GAGs), namely, chondroitin sulfate (CS), dermatan sulfate, keratan sulfate, heparin, and heparan sulfate, are linear complex polysaccharides that are covalently attached to core proteins to form proteoglycans. They are present at the cell surface and in the extracellular matrix and play a key role in the regulation of cellular microenvironmental effectors. To better understand the biological functions of GAGs and particularly of CS-E (4,6-disulfated) at the molecular level, structurally well-defined oligosaccharides are necessary. Chemically synthesised biotinylated conjugates are useful to study the interactions with proteins at the intra- and extracellular levels. Herein, FTIR spectroscopy was used to characterise nine chondroitin oligosaccharides, including biotinylated or reducing CS-E di-, tetra- and hexasaccharides as well as their non-sulfated analogs. Spectral features characteristic of the vibrational modes of oligosaccharides (1640, 1626, 1565, 1418, 1375, and 1160 cm-1), CS-E (1280-1200, 1134, 1065, 1034, 1000, 927, and 866-860, 815 cm-1), and biotin (1681, 1460, 1425, and 792 cm-1) were identified. FTIR spectroscopy was sensitive enough to reveal structural microheterogeneity, allowing distinguishing C-4 from C-6 sulfated isoforms. CS-E- and biotin-specific signatures were obtained via difference spectra. PCA plots revealed three distinct groups: biotinylated oligosaccharides, CS-E biotinylated oligosaccharides and CS-E reducing oligosaccharides. Furthermore, the first component clearly distinguished sulfated from non-sulfated forms, while component two tended to discriminate according to the chain length, exclusively for non-sulfated oligosaccharides. Identifying the spectral signatures of these oligosaccharides is an important step for future research on the monitoring of the internalisation of oligosaccharide- and cell-penetrating peptide-bound forms in drug-delivery studies.

DOI: https://doi.org/10.1039/d5an00136f
FEBS J. 2025 Jul 03.

Group A Streptococcus interacts with glycosaminoglycans via M proteins to modulate bacterial adherence in vitro.

Tahnee B-D McEwan, David M P De Oliveira, Emily K Stares, Lauren E Hartley-Tassell, Christopher J Day, Mark J Walker, Michael P Jennings, Ronald Sluyter, Martina L Sanderson-Smith.

  Glycosaminoglycans (GAGs) are enriched in the cutaneous extracellular matrix and have important roles in bacterial colonisation. Group A Streptococcus (GAS) can be categorised by emm patterning and M-family protein expression. M proteins of GAS are major adhesins with lectin-binding properties. This study aimed to provide a comprehensive specificity and affinity profile of phylogenetically diverse M proteins to a range of sulfated host GAGs and to investigate the physiological relevance of these interactions. Chondroitin sulfate preferentially associated with M proteins of A-C pattern strains, with binding localised to the central variable region of M1 protein. Dermatan sulfate was shown to associate with M proteins of all pattern type strains, with recognition involving multiple sites on M proteins. Heparin and heparan sulfate exclusively interacted with M proteins of A-C and D pattern strains. Multiple sites of M proteins were involved in heparin recognition, as indicated by surface plasmon resonance and site-directed mutagenesis of the heparin-binding XBXBX motif in the hypervariable-central region of M53 protein. In contrast, binding of heparan sulfate was localised to the non-repeat region between the B2 repeat and C1 repeat of M53 proteins. 5448 (M1-expressing GAS, A-C pattern) was shown to bind chondroitin sulfate, dermatan sulfate and heparin in an M protein-dependent manner. Furthermore, recruitment of chondroitin sulfate or dermatan sulfate by M1 proteins, but not heparin, was shown to increase GAS adherence to human HaCaT keratinocytes. This study increases our understanding of the molecular mechanisms underlying GAS adhesion, with key implications for bacterial colonisation and persistence of infection.

Keywords:  Streptococcus pyogenes; epithelial cells; flow cytometry; glycan microarray; polysaccharides

DOI:  https://doi.org/10.1111/febs.70167
Glycobiology. 2025 Jul 03. pii: cwaf039. [Epub ahead of print]

A synthetic HS structure selectively impairs the morphology and function of excitatory synapse by disrupting neurexin1 interactions.

Qin Xu, Leanne Auyeung, Zhangjie Wang, Yongmei Xu, Jian Liu, Peng Zhang.

  Excitatory and inhibitory synapses are the two major fundamental units of neuronal communication in the brain. The imbalance between excitatory and inhibitory synapses (E/I imbalance) is a leading mechanism underlying mental illness. Heparan sulfate (HS), a complex polysaccharide frequently implicated in mental disorders, is an emergent player in synaptic function. Yet, it remains unclear whether and how HS plays a preferential role in excitatory versus inhibitory synapses. This question is further complicated by the structural complexity of HS and the combined effects of both HS glycans and their attached proteoglycans. To address this challenge, we developed a platform that combines synthetic chemistry and synaptic biology to dissect the role of pure HS glycans in synapse development. As proof of principle, we assessed the effects of a synthetic dodecasaccharide (12-mer-19) and its non-sulfated counterpart (12-mer-NAc) on excitatory and inhibitory synapses in primary rat hippocampal neuron cultures. Unexpectedly, we found that 12-mer-19 selectively impaired the morphology and function of excitatory but not inhibitory synapses. Mechanistically, 12-mer-19 interferes with the interaction between neurexin1 and its partners at excitatory synapses, but has little effect on neurexin1's partner at inhibitory synapses. Moreover, 12-mer-NAc didn't have such effects, highlighting the importance of sulfated groups. Our results suggest that extracellular complex glycans may have a selective yet underappreciated role in excitatory synapses, perhaps contributing to the E/I imbalance. Moreover, current studies lay a foundation for future work to dissect the contribution of specific heparan sulfate structures to synaptic morphology and function.

Keywords:  Heparan sulfate oligosaccharide; primary hippocampal neuron culture; synapse formation; synaptic transmission

DOI:  https://doi.org/10.1093/glycob/cwaf039
Trends Biotechnol. 2025 Jul 02. pii: S0167-7799(25)00220-3. [Epub ahead of print]

Engineering a novel adenine-sulfotransferase for efficient synthesis of PAPS and chondroitin sulfate in microbial cells.

Simin Gu, Fan Zhang, Ziyao Li, Hejia Qi, Lingxin Huang, Kaifang Liu, Wei Song, Wanqing Wei, Cong Gao, Guipeng Hu, Xiaomin Li, Liming Liu.

  Sulfonated compounds are widely utilized in feed additives, daily commodities, industrial manufacturing, and healthcare applications. Their production relies on the sulfonate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS). This study identified a novel adenine-sulfotransferase with sulfotransferase activity toward adenosine monophosphate for adenosine phosphosulfate formation. The identified enzyme was rationally engineered, yielding the mutant BtaAPSSTH8M/L117D, which exhibited a 0.93-fold increase in sulfotransfer efficiency. The mutant BtaAPSSTH8M/L117D was subsequently combined with additional enzymes to reconstruct what we term the RPA pathway, enabling the synthesis of PAPS at titers of 7.6 g/l and 5.03 g/l in Escherichia coli and Bacillus subtilis, respectively, using adenine and ribose as substrates. The RPA pathway was further integrated into the chondroitin producing strain E. coli GZ17, to construct E. coli CSA-02, which produced 1.89 g/l chondroitin sulfate A (CSA) with a sulfation rate of 76%. These results offer a promising way to enhance the biosynthesis of sulfonated compounds in microbial cell factories.

Keywords:  3′-phosphoadenosine-5′-phosphosulfate; adenine-sulfotransferase; chondroitin sulfate A; protein engineering

DOI:  https://doi.org/10.1016/j.tibtech.2025.06.005
Sci Rep. 2025 Jul 01. 15(1): 21348

Association of DHEAS levels with COVID19 severity, gender, age, comorbidities, and management strategies.

Tahereh Jamali, Sussan Kaboudanian Ardestani, Mohammad-Reza Vaez-Mahdavi, Arezou Rezaei, Mohammad Mehdi Naghizadeh, Fatemeh Tuserkani, HosseinAli Khazaei, Ali Khodadadi, Bahman Khazaei, Keivan Latifi, Tooba Ghazanfari.

  COVID-19 has globally impacted millions. This study investigates DHEAS (dehydroepiandrosterone sulfate) as a factor for COVID-19 progression, analyzing its relationship with disease status, temporal patterns, age, gender, and comorbidities to improve outcomes. DHEAS was quantified with a competitive chemiluminescent immunoassay. We conducted DHEAS analysis across different days. COVID-19 patients, particularly inpatients, have lower DHEAS levels compared to controls. DHEAS levels in COVID-19 patients showed a dynamic pattern, with an initial decline followed by recovery. The scatter plot analysis suggested COVID-19 could increase the age-related decline in DHEAS among males. Comorbidities, including hypertension, heart disease, and diabetes mellitus, were prevalent among COVID-19 patients and correlated with disease severity. Hypertension moderated the relationship between hospitalization and DHEAS, especially in females. Our findings showed a significant association between lower DHEAS and COVID-19 severity, along with temporal dynamics. COVID-19's potential to increase the age-related decline in DHEAS, especially in males, underscores its intricate relationship with age. Hypertension's influence on DHEAS suggests a gender-specific effect, emphasizing tailored management approaches. These findings offer valuable insights into the interaction between COVID-19, hormonal dynamics, and demographic factors, suggesting that DHEAS levels may play a role in the pathophysiology of the disease and could be considered alongside other markers.

Keywords:  COVID-19; Comorbidity diseases; DHEAS; Inpatients; Outpatients

DOI:  https://doi.org/10.1038/s41598-025-05919-9
Carbohydr Res. 2025 Jun 19. pii: S0008-6215(25)00210-1. [Epub ahead of print]555 109584

Synthesis of the endogenous non-reducing end heparan sulfate disaccharide for newborn screening and diagnosis of Mucopolysaccharidosis type IIIA.

Sachin Popat Gholap, Zackary Herbst, Rajan K Paranji, Michael H Gelb.

  Mucopolysaccharidosis IIIA (MPS IIIA) is caused by deficiency of the lysosomal enzyme heparan N-sulfatase. Newborn screening of MPS IIIA is carried out by first-tier measurement of enzyme activity followed by measurement of accumulated heparan sulfate-derived biomarker, both by tandem mass spectrometry. Here we described the synthesis of the endogenous non-reducing end disaccharide (in unlabeled and heavy isotopic form) that can be used for quantification of this biomarker in patient samples.

Keywords:  Diagnosis; Inborn errors of metabolism; Lysosomal storage disease; Mucopolysaccharidosis-III; Newborn screening; Sanfilippo syndrome type A

DOI:  https://doi.org/10.1016/j.carres.2025.109584
Sci Rep. 2025 Jul 02. 15(1): 23406

Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease.

Sabbir Ahmed, Rolf W Sparidans, Robin W M Vernooij, Silvia M Mihaila, Roel Broekhuizen, Roel Goldschmeding, Tri Q Nguyen, Rosalinde Masereeuw, Karin G F Gerritsen.

  Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p-cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD.

Keywords:  Diabetic kidney disease; Hippuric acid; Indoxyl sulfate; Protein-bound uremic toxins; Tubular function marker

DOI:  https://doi.org/10.1038/s41598-025-07248-3
Sci Rep. 2025 Jul 01. 15(1): 20927

Evaluation of transduction efficiency in pancreatic beta and alpha cells utilizing various AAV serotypes.

Vishal Ahuja, Sanjeev Jeyabalan, Emmanuel S Tzanakakis.

  Adeno-associated viruses (AAVs) have emerged as powerful tools for delivering genes to various cell types, including pancreatic endocrine cells. Currently, AAV serotype 8 (AAV8) is the primary AAV vector employed for transducing pancreatic cells for transgene expression. We aimed to determine whether alternative serotypes, specifically AAV2, AAV6, and AAV9, commonly used for gene transfer, can efficiently transduce pancreatic cells in vitro. Murine pancreatic β-cells, α-cells, and fibroblasts were transduced with AAV serotypes 2, 6, and 9 carrying the transgene for enhanced green fluorescent protein (eGFP). To understand further the interaction between the foregoing AAV types and the cells for optimal transduction, the additives heparin and neuraminidase were screened. AAV2 outperformed AAV9 in transducing pancreatic cells, while AAV6 induced cytotoxicity. Recombinant AAV2 was also utilized to deliver a blue-light photoactivatable adenylyl cyclase (bPAC) to β-cells, resulting in the efficient modulation of insulin secretion upon illumination. Both AAV2 and AAV9 displayed slightly higher tropism for α-cells than for β-cells, potentially mirroring differences in the expression of heparan sulfate proteoglycan (HSPG)-processing enzymes. The fraction of GFP-expressing cells at various multiplicities of infection was consistently lower for fibroblasts than for the pancreatic cells. Incubation of AAV2 with heparin before transduction failed to induce transgene expression in β-cells, indicating that HSPGs are the primary interaction sites with pancreatic cells. Treating β-cells with neuraminidase before exposure to AAV9 did not significantly improve the transduction efficiency. These findings expand the repertoire of available serotypes for AAV-mediated delivery of transgenes to pancreatic endocrine cells in vitro and may contribute to designing efficacious gene therapy strategies for pancreas pathologies.

Keywords:  Adeno-associated virus; Alpha-cells; Beta-cells; Gene delivery; Pancreas; Transduction

DOI:  https://doi.org/10.1038/s41598-025-05518-8
Chem Biodivers. 2025 Jun 29. e00031

Optimization and Hepatoprotective Potential of Sulfated Polysaccharide From Pleurotus ostreatus.

Wen-Xin Xu, Xu-Hang Guo, Xin-Yu Li, Shu-Ting Bao, Jian-Jun Zhang.

  In this study, we explored an efficient method for synthesizing sulfated Pleurotus ostreatus polysaccharides (SPOP) with a higher degree of substitution. The structure conformation was characterized and confirmed by the Fourier transform infrared (FT-IR) spectroscopy analysis. A three-factor-three-level Box-Behnken design (BBD) was successfully applied to optimize the SPOP synthesis process. Under the optimal conditions, including a ratio of pyridine to chlorosulfonic acid of 5.10:1, a reaction temperature of 59.92°C, and a reaction time of 3.05 h, the predicted maximum degree of sulfate substitution (DS) reached 0.423 ± 0.006. Furthermore, we evaluated the in vitro radical scavenging abilities and in vivo anti-acute liver injury (anti-ALI) effects of SPOP. The results showed that SPOP demonstrated significantly superior hepatoprotective effects against CCl4-induced liver damage, specifically by enhancing antioxidant activities both in vitro and in vivo, as well as improving hepatic functions. Our findings suggested that SPOP exhibited significant potential as a natural therapeutic agent for ALI and its associated complications, and contributed to the potential antioxidant capacities.

Keywords:  hepatoprotection; in vitro antioxidant; optimization; sulfated Pleurotus ostreatus polysaccharides

DOI:  https://doi.org/10.1002/cbdv.202500031
Arterioscler Thromb Vasc Biol. 2025 Jul 03.

LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9.

Silvia Cecilia Pacheco-Velázquez, Carlota Oleaga, Bastian Ramms, Joshua Hay, Paul A Mueller, Ester López-Aguilar, Joshua Miles, Ryan N Porell, Chelsea Nora, Kamil Godula, Hagai Tavori, Philip L S M Gordts, Sergio Fazio, Nathalie Pamir.

   BACKGROUND: Hepatic heparan sulfate proteoglycans (HSPGs) accelerate the clearance of PCSK9 (proprotein convertase subtilisin/kexin type 9). We tested the hypothesis that free- and LDL (low-density lipoprotein)-bound PCSK9 forms have different HSPG-mediated clearance kinetics.
METHODS: Metabolic and turnover studies were performed after administration of free- and LDL-bound PCSK9 to 2 HSPG knockout mouse models: (1) Global knockout of syndecan-1 (Sdc1-/-), an HSPG involved in hepatic triglyceride clearance; and (2) hepatocyte-specific knockout of heparan sulfate N-deacetylase/N-sulfotransferase (AlbCre+Ndst1f/f).
RESULTS: The clearance of both free- and LDL-bound PCSK9 followed a 2-phase decay behavior comprising a fast and a slow phase. The more notorious effect of HSPG deletion was on the slow phase: the clearance of free-PCSK9 was faster in Sdc1-/- mice (t1/2,slow 13.5±1.5 minutes; P=0.0305) than in wild-type (t1/2,slow 28.8±4.2 minutes) and AlbCre+Ndst1f/f mice (t1/2,slow 32.7±4.9 minutes). The clearance of LDL-bound PCSK9 was slower yet not statistically significant in Sdc1-/- mice (t1/2,slow 111.2±21.6 minutes) than in wild-type (t1/2,slow 52±6.4 minutes) and AlbCre+Ndst1f/f mice (t1/2,slow 39.55±2.96 minutes). However, the area under the curve showed a delayed clearance of LDL-bound PCSK9 in Sdc1-/- mice (44 576±2435 min×ng, P=0.004) but not in AlbCre+Ndst1f/f (34 738±3721 min×ng, P=0.578) mice compared with wild-type (30 865±1907 min×ng). Hepatic Ndst1-deficiency did not alter hepatic PCSK9 or LDLR (LDL receptor) expression.
CONCLUSIONS: The clearance rate of plasma LDL-bound PCSK9 is slower than the clearance rate of its free form. The HSPG syndecan-1 modestly contributes to PCSK9 clearance through an LDLR-independent pathway.

Keywords:  cholesterol; homeostasis; lipoproteins; proteoglycans; syndecan-1

DOI:  https://doi.org/10.1161/ATVBAHA.124.322334
Vet World. 2025 May;18(5): 1147-1155

Sulfated Lewis A from the oviduct reservoir selectively binds to camel (Camelus dromedarius) sperm and extends their lifespan in vitro.

Mohamed M M El-Sokary, Hamad A Albreiki, Salem Belal, Latifa R Alshamsi.

   Background and Aim: Camel reproduction faces significant challenges, including poor semen preservation and a limited understanding of gamete interactions, particularly within the oviduct. Glycan-mediated sperm binding in the oviduct is pivotal for sperm storage and longevity in various species. This study aimed to evaluate the binding affinity of camel epididymal sperm to sulfated Lewis A (SuLeA) - a trisaccharide from the oviductal isthmus - and investigate its effect on sperm lifespan and viability in vitro.
Materials and Methods: Fluorescent-labeled SuLeA was used to localize glycan-binding sites on camel sperm. An in vitro model involving biotinylated SuLeA conjugated to streptavidin-sepharose beads was developed to mimic oviductal interactions. Sperm-oviduct binding specificity was assessed by pre-incubating sperm with SuLeA before their exposure to epithelial cell aggregates. Sperm viability was evaluated over 48 h using SYBR-14 and propidium iodide staining.
Results: Fluorescent SuLeA showed preferential binding to the post-acrosomal region of camel sperm (53%, p < 0.05). Pre-incubation with SuLeA significantly inhibited sperm adhesion to oviductal aggregates (82% vs. 25%, p < 0.05), confirming binding specificity. Sperm demonstrated a high affinity to immobilized SuLeA (5 sperm/bead), which was reduced to 1 sperm/bead following glycan pre-incubation. Notably, sperm bound to immobilized SuLeA exhibited significantly higher viability (59%) after 48 h compared to unbound sperm (5%, p < 0.05).
Conclusion: This study establishes that SuLeA selectively binds to camel sperm at the post-acrosomal region, mimicking physiological sperm-oviduct adhesion. The interaction not only confirms glycan specificity but also significantly prolongs sperm viability. These findings provide a promising foundation for developing freeze-free preservation techniques and improving artificial insemination protocols in camelids.

Keywords:  camel; glycan binding; oviduct; reproductive biotechnology; sperm; sperm viability; sulfated Lewis A

DOI:  https://doi.org/10.14202/vetworld.2025.1147-1155
Int J Biol Macromol. 2025 Jun 26. pii: S0141-8130(25)06110-0. [Epub ahead of print]319(Pt 3): 145555

Linear and nonlinear rheological properties of sulfated, phosphorylated and carboxymethylated Mesona chinensis polysaccharide - wheat starch systems.

Xiangwen Pan, Xianxiang Chen, Jianhua Xie.

  Mesona chinensis polysaccharide (MCP) was subjected to chemical modifications by sulfation, phosphorylation and carboxylation, resulting in S-MCP, P-MCP and C-MCP, respectively. The small and large amplitude oscillatory shear (SAOS, LAOS) techniques indicate that these modifications can improve the rheological properties of wheat starch (WS) systems. In FT-IR spectra, typical absorption peaks of polysaccharides and absorption peaks of characteristic groups were represented in MCP and chemical modifications. SAOS analysis demonstrated that the chemically modified MCPs increased the critical strain (γL), short-term regrowth, gel structural strength, rigidity and reorganization of WS systems. Notably, sulfation (S-MCP) resulted in the most significant enhancement in viscoelastic properties (e.g. γL = 61.66 %). LAOS tests were analyzed using Chebyshev coefficients, Fourier transform method and Lissajous curves. The improved dispersion of chemically modified MCPs led to more pronounced strain hardening and shear thickening effects, as indicated by the parameters (e3 > 0, v3 < 0, G'L > 0, η'L > 0, S > 0 and T < 0). Among the modifications, S-MCP showed the greatest enhancement in rheological properties, followed by P-MCP, while C-MCP exhibited relatively minor improvements. Our findings suggest the chemical modification of MCP significantly influences its rheological properties.

Keywords:  Chemical modification; Mesona chinensis polysaccharide; Nonlinear rheology; Wheat starch

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145555
J Chem Inf Model. 2025 Jun 30.

From Docking and Molecular Dynamics to Experimental Discovery: Exploring the Hydrophobic Landscapes of Heparanase to Design Potent Inhibitors.

Hawau Abdulsalam, Mark A Hix, Livia Philip, Kartikey Singh, Alice R Walker, Hien M Nguyen.

Heparanase (HPSE), a glycoside hydrolase that cleaves heparan sulfate chains, plays a crucial role in cancer progression by remodeling the extracellular matrix and facilitating tumor metastasis. This study employed a computational design approach to develop novel HPSE inhibitors using aminoglycoside paromomycin and neomycin analogs. These analogs feature a defined N-sulfation sequence combined with either charged or hydrophobic groups. Initial docking screenings indicated that hydrophobic-capped ligands exhibit binding energies comparable to the free hydroxyl ligands, despite displaying lower overall binding efficiencies. Molecular dynamics simulations revealed that these hydrophobic-capped ligands adopt a folded conformation, with the saccharide moiety anchored in the enzyme's active site and the hydrophobic aromatic groups stabilizing the interaction. This conformation exposes the hydrophobic groups to the solvent, potentially enhancing inhibitory potency by increasing ligand retention within the active site. Further analysis revealed that the hydrophobic capped ligands exhibited a higher ligand binding stability as shown by a lower RMSD during the MD simulation. Experimental validation corroborated the computational findings, demonstrating that the introduction of hydrophobic aromatic groups led to a >100-fold increase in inhibitory potency, with IC50 values in the low nanomolar range. These results suggest that simultaneously targeting the charged and hydrophobic pockets of HPSE could yield more potent inhibitors, offering a promising strategy for future cancer therapeutics.

DOI: https://doi.org/10.1021/acs.jcim.5c00371