bims-supasi 2024-09-08 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–09–08
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Thrombin-derived C-terminal peptides bind and form aggregates with sulfated glycosaminoglycans.
Semi-synthetic chondroitin sulfate CS-semi5 upregulates miR-122-5p, conferring a therapeutic effect on osteoarthritis via the p38/MMP13 pathway.
Novel simultaneous analysis of 18 types of glycosaminoglycan-derived disaccharides using 4-aminobenzoic acid ethyl ester derivatization by HPLC with fluorescence detection.
Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation.
Multifunctional natamycin modified chondroitin sulfate eye drops with anti-inflammatory, antifungal and tissue repair functions possess therapeutic effects on fungal keratitis in mice.
Extraction and characterization of valuable compounds from chicken sternal cartilage: Type II collagen and chondroitin sulfate.
Structure and anticoagulant activity of a galactoarabinan sulfate polysaccharide and its oligosaccharide from the green algae, Codium fragile.
Chemoenzymatic Synthesis of Sulfated N-Glycans Recognized by Siglecs and Other Glycan-Binding Proteins.
Sulfoglycodendron Antivirals with Scalable Architectures and Activities.
Chondroitin sulfate-based microneedles for transdermal delivery of stem cell-derived extracellular vesicles to treat rheumatoid arthritis.
A critical review on pharmacological properties of sulfated polysaccharides from marine macroalgae.
Anti-tumor and anti-metastasis of water-soluble sulfated β-glucan derivatives from Saccharomyces cerevisiae.
Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate.
In Situ Heparan Sulfate-Induced Peptide Self-Assembly to Overcome the Cell Surface Glycocalyx Barrier for Cancer Treatment.

Heliyon. 2024 Aug 30. 10(16): e35703

Thrombin-derived C-terminal peptides bind and form aggregates with sulfated glycosaminoglycans.

Ganna Petruk, Jitka Petrlova, Firdaus Samsudin, Peter J Bond, Artur Schmidtchen.

Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) play crucial roles in inflammation and wound healing, serving as regulators of growth factors and pro-inflammatory mediators. In this study, we investigated the influence of heparin/HS on thrombin proteolysis and its interaction with the generated 11 kDa thrombin-derived C-terminal peptides (TCPs). Employing various biochemical and biophysical methods, we demonstrated that 11 kDa TCPs aggregate in the presence of GAGs, including heparin, heparan sulfate, and chondroitin sulfate-B. Circular dichroism analysis demonstrated that 11 kDa TCPs, in the presence of GAGs, adopt a β-sheet structure, a finding supported by thioflavin T1 (ThT) fluorescence measurements and visualization of 11 kDa TCP-heparin complexes using transmission electron microscopy (TEM). Furthermore, our investigations revealed a stronger binding affinity between 11 kDa TCPs and GAGs with higher sulfate group contents. Congruently, in silico simulations showed that interactions between 11 kDa TCPs and heparin/HS are predominantly electrostatic in nature. Collectively, our study suggests that 11 kDa TCPs have the capacity to aggregate in the presence of GAGs, shedding light on their potential roles in inflammation and wound healing.

DOI: https://doi.org/10.1016/j.heliyon.2024.e35703
Acta Pharm Sin B. 2024 Aug;14(8): 3528-3542

Semi-synthetic chondroitin sulfate CS-semi5 upregulates miR-122-5p, conferring a therapeutic effect on osteoarthritis via the p38/MMP13 pathway.

Xiang Li, Ya Zhou, Xuefeng Chen, Hongjun Wang, Shuang Yang, Jun Yang, Yunfeng Song, Zhehui Zhao, Haijing Zhang, Lianqiu Wu.

  Osteoarthritis (OA) is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage. Traditional treatments for OA are limited to alleviating various OA symptoms. There is a lack of drugs available in clinical practice that can truly repair cartilage damage. Here, we developed the chondroitin sulfate analog CS-semi5, semi-synthesized from chondroitin sulfate A. In vivo, CS-semi5 alleviated inflammation, provided analgesic effects, and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model. A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats, revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment. Binding prediction revealed that miR-122-5p acted on the 3'-untranslated region of p38 mitogen-activated protein kinase, which was related to MMP13 regulation. Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis, which was further validated in the articular cartilage of OA rats. This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5, revealing its cartilage-protecting, anti-inflammatory, and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.

Keywords:  Cartilage; Chondroitin sulfate; Extracellular matrix; Inflammation; MMP13; Osteoarthritis; miRNA; p38

DOI:  https://doi.org/10.1016/j.apsb.2024.05.016
Anal Bioanal Chem. 2024 Aug 30.

Novel simultaneous analysis of 18 types of glycosaminoglycan-derived disaccharides using 4-aminobenzoic acid ethyl ester derivatization by HPLC with fluorescence detection.

Takamasa Ishii, Kengo Hirai, Kyohei Higashi, Ayaka Aijima, Nae Yokota, Toshihiko Toida, Yusuke Iwasaki, Rie Ito, Nobuaki Higashi, Hiroshi Akiyama.

  Glycosaminoglycans (GAGs), including hyaluronic acid (HA), chondroitin sulfate (CS)/dermatan sulfate (DS), heparan sulfate (HS)/heparin (HP), and keratan sulfate (KS), play pivotal roles in living organisms. Generally, GAGs are analyzed after enzymatic digestion into unsaturated or saturated disaccharides. Due to high structural similarity between disaccharides, however, separation during analysis is challenging. Additionally, little is known about the structures of GAGs and their functional relationships. Elucidating the function of GAGs requires highly sensitive quantitative analytical methods. We developed a method for the simultaneous analysis of 18 types of disaccharides derived from HA (1 type), CS/DS (7 types), HS/HP (8 types), and KS (2 types) potentially detectable in analyses of human urine. The simple method involves HPLC separation with fluorescence detection following derivatization of GAG-derived disaccharides using 4-aminobenzoic acid ethyl ester (ABEE) as a pre-labeling agent and 2-picoline borane as a reductant. The ABEE derivatization reaction can be performed under aqueous conditions, and excess derivatization reagents can be easily, rapidly, and safely removed. This method enables highly sensitive simultaneous analysis of the 18 abovementioned types of GAG-derived disaccharides using HPLC with fluorescence detection in small amounts of urine (1 mL) in a single run. The versatile method described here could be applied to the analysis of GAGs in other biological samples.

Keywords:  2-Picoline borane; 4-Aminobenzoic acid ethyl ester; Disaccharide GAG analysis; Glycosaminoglycans; HPLC; Human urinary GAG analysis

DOI:  https://doi.org/10.1007/s00216-024-05504-5
Nat Commun. 2024 Aug 31. 15(1): 7584

Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation.

Vaishali N Patel, Marit H Aure, Sophie H Choi, James R Ball, Ethan D Lane, Zhangjie Wang, Yongmei Xu, Changyu Zheng, Xibao Liu, Daniel Martin, Jillian Y Pailin, Michaela Prochazkova, Ashok B Kulkarni, Toin H van Kuppevelt, Indu S Ambudkar, Jian Liu, Matthew P Hoffman.

Heparan sulfate (HS) regulation of FGFR function, which is essential for salivary gland (SG) development, is determined by the immense structural diversity of sulfated HS domains. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS), and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs) that produce basement membrane (BM) and are a growth factor signaling hub. Hs3st3a1;Hs3st3b1 double-knockout (DKO) mice generated to investigate 3-O-HS regulation of MEC function and growth factor signaling show loss of specific highly 3-O-HS and increased FGF/FGFR complex binding to HS. During development, this increases FGFR-, BM- and MEC-related gene expression, while in adult, it reduces MECs, increases BM and disrupts acinar polarity, resulting in salivary hypofunction. Defined 3-O-HS added to FGFR pulldown assays and primary organ cultures modulates FGFR signaling to regulate MEC BM synthesis, which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.

DOI: https://doi.org/10.1038/s41467-024-51862-0
Int J Biol Macromol. 2024 Sep 02. pii: S0141-8130(24)06097-5. [Epub ahead of print]279(Pt 2): 135290

Multifunctional natamycin modified chondroitin sulfate eye drops with anti-inflammatory, antifungal and tissue repair functions possess therapeutic effects on fungal keratitis in mice.

Xue Tian, Lu Zhan, Xiaojing Long, Jing Lin, Yingxue Zhang, Junjie Luan, Xudong Peng, Guiqiu Zhao.

  Fungal keratitis (FK) is recognized as a stubborn ocular condition, caused by intense fungal invasiveness and heightened immune reaction. The glycosaminoglycan chondroitin sulfate exhibits properties of immunomodulation and tissue regeneration. In prior investigations, oxidized chondroitin sulfate (OCS) ameliorated the prognosis of FK in murine models. To further improve the curative efficacy, we used the antifungal drug natamycin to functionalize OCS and prepared oxidized chondroitin sulfate-natamycin (ON) eye drops. The structure of ON was characterized by FTIR, UV-vis, and XPS, revealing that the amino group of natamycin combined with the aldehyde group in OCS through Schiff base reaction. Antifungal experiments revealed that ON inhibited fungal growth and disrupted the mycelium structure. ON exhibited exceptional biocompatibility and promoted the proliferation of corneal epithelial cells. Pharmacokinetic analysis indicated that ON enhanced drug utilization by extending the mean residence time in tears. In murine FK, ON treatment reduced the clinical score and corneal fungal load, restored corneal stroma conformation, and facilitated epithelial repair. ON effectively inhibited neutrophil infiltration and decreased the expression of TLR-4, LOX-1, IL-1β, and TNF-α. Our research demonstrated that ON eye drops achieved multifunctional treatment for FK, including inhibiting fungal growth, promoting corneal repair, enhancing drug bioavailability, and controlling inflammatory reactions.

Keywords:  Anti-inflammatory; Antifungal; Chondroitin sulfate; Fungal keratitis; Natamycin; Tissue regeneration

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135290
Food Chem. 2024 Aug 30. pii: S0308-8146(24)02673-6. [Epub ahead of print]462 141023

Extraction and characterization of valuable compounds from chicken sternal cartilage: Type II collagen and chondroitin sulfate.

Ozge Ata, Neslihan Bozdogan, Ceren Evrim Mataraci, Seher Kumcuoglu, Sibel Kaya Bayram, Sebnem Tavman.

  Type II collagen (Col II) and chondroitin sulfate (CS) are the main macromolecules in the extracellular matrix. This study investigated the characteristics of Col II and CS obtained from chicken sternal cartilage (CSC) via enzymatic hydrolysis for various treatment times. For Col II and CS, the highest efficiency of enzymatic hydrolysis was achieved after 24 and 6 h of treatment, respectively. The average molecular weights were α1 chain-130 kDa, β chain-270 kDa for Col II, and 80.27 kDa for CS. Fourier transform infrared spectroscopy revealed that the Col II samples maintained their triple-helical structure and that the predominant type of CS was chondroitin-4-sulfate. Scanning electron microscopy revealed that the Col II and CS samples possessed fibrillar and clustered structures, respectively. This study suggests that collagen and CS obtained from CSC can be used as promising molecules for application in food and pharmaceutical industries.

Keywords:  Characterization; Chicken sternal cartilage; Chondroitin sulfate; Enzymatic extraction; Type II collagen

DOI:  https://doi.org/10.1016/j.foodchem.2024.141023
Int J Biol Macromol. 2024 Sep 03. pii: S0141-8130(24)06061-6. [Epub ahead of print] 135255

Structure and anticoagulant activity of a galactoarabinan sulfate polysaccharide and its oligosaccharide from the green algae, Codium fragile.

Li Peipei, Zhang Qinghong, Chen Yin, He Pengfei, Zeng Junjie.

  A polysaccharide, CZS-0-1, was obtained from the marine green algae Codium fragile using ion-exchange and size-exclusion chromatography. Composition and characteristics analyses showed CZS-0-1 was a sulfated galactoarabinan consisting of arabinose, galactose and a small amount of glucose in a ratio of 9:2:1 with 21% sulfate content and a molecular weight of 810 kDa. Structural properties were determined using desulfation and methylation analyses combined with instrument analysis. The results showed that the backbone of CZS-0-1 was (1 → 3)-β-L-Arap. Its O-4 and/or O-2 positions showed sulfate modification; additionally, it had 10% of (1 → 3)-β-D-Galp branches at the O-4 position of the (1 → 3)-β-L-Arap. The galactose side chains also had sulfate modification at the O-4 or O-6 position. The structure of CZS-0-1 was further confirmed by Top-down analysis of the oligosaccharides after oxidated hydrolysis by mass spectrometry. CZS-0-1 exhibited significant heparin-like anticoagulant activity. It exerted anticoagulant effects by inhibiting FIIa and FXa activities with the presence of heparin cofactors. The anticoagulant activity of CSZ-0-1 was closely related to the molecular weight, and the reduction of molecular weight may lead to a significant decrease in the anticoagulant activity. This study demonstrated that the green algae, Codium fragile can be considered as a useful resource for bioactive polysaccharides.

Keywords:  Anticoagulant activity; Marine green algae; Polysaccharide

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135255
JACS Au. 2024 Aug 26. 4(8): 2966-2978

Chemoenzymatic Synthesis of Sulfated N-Glycans Recognized by Siglecs and Other Glycan-Binding Proteins.

Kun Huang, Eleanor E Bashian, Guanghui Zong, Corwin M Nycholat, Ryan McBride, Margaryta Gomozkova, Shengyang Wang, Chin Huang, Digantkumar G Chapla, Edward N Schmidt, Matthew Macauley, Kelley W Moremen, James C Paulson, Lai-Xi Wang.

Sulfated N-glycans are present in many glycoproteins, which are implicated in playing important roles in biological recognition processes. Here, we report the systematic chemoenzymatic synthesis of a library of sulfated and sialylated biantennary N-glycans and assess their binding to Siglecs and glycan-specific antibodies that recognize them as glycan ligands. The combined use of three human sulfotransferases, GlcNAc-6-O-sulfotransferase (CHST2), Gal-3-O-sulfotransferase (Gal3ST1), and keratan sulfate Gal-6-O-sulfotransferase (CHST1), resulted in asymmetric and symmetric branch-selective sulfation of the GlcNAc and/or Gal moieties of N-glycans. The extension of the sugar chain using α-2,3- and α-2,6-sialyltransferases afforded the sulfated and sialylated N-glycans. These synthetic glycans with different patterns of sulfation and sialylation were evaluated for binding to selected Siglecs and sulfoglycan-specific antibodies using glycan microarrays. The results confirm previously documented glycan-recognizing properties and further reveal novel specificities for these glycan-binding proteins, demonstrating the utility of the library for assessing the specificity of glycan-binding proteins recognizing sulfated and sialylated glycans.

DOI: https://doi.org/10.1021/jacsau.4c00307
J Chem Inf Model. 2024 Sep 04.

Sulfoglycodendron Antivirals with Scalable Architectures and Activities.

Francesco Coppola, Roya Jafari, Katherine D McReynolds, Petr Král.

Many viruses initiate their cell-entry by binding their multisubunit receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglycodendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multiprotein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed the detailed nature of binding between these antivirals and viral protein receptors and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

DOI: https://doi.org/10.1021/acs.jcim.4c00541
J Control Release. 2024 Sep 05. pii: S0168-3659(24)00600-X. [Epub ahead of print]375 105-115

Chondroitin sulfate-based microneedles for transdermal delivery of stem cell-derived extracellular vesicles to treat rheumatoid arthritis.

Van Dat Bui, Jueun Jeon, Van Hieu Duong, Sol Shin, Jungmi Lee, Farrokhroo Ghahari, Chan Ho Kim, Yu Jin Jo, Won-Kyo Jung, Wooram Um, Jae Hyung Park.

  For the non-invasive treatment of rheumatoid arthritis (RA), a chondroitin sulfate C (CSC)-based dissolving microneedles (cMN) was prepared to deliver human adipose stem cell-derived extracellular vesicles (hASC-EV) into inflamed joints. Owing to their anti-inflammatory function, the hASC-EV-bearing cMN (EV@cMN) significantly suppressed activated fibroblast-like synoviocytes (aFLS) and M1 macrophages (M1), which are responsible for the progression of RA. In addition, EV@cMN facilitated the chondrogenic differentiation of bone marrow-derived stem cells. In mice with collagen-induced arthritis, EV@cMN efficiently delivered both hASC-EV and CSC to inflamed joints. Interestingly, pro-inflammatory cytokines in the inflamed joints were remarkably downregulated by the synergistic effect of CSC and hASC-EV. Consequently, as judged from the overall clinical score and joint swelling, EV@cMN showed an outstanding therapeutic effect, even comparable to the wild-type mice, without significant adverse effects. Overall, EV@cMN might have therapeutic potential for RA by efficiently delivering CSC and hASC-EV into the inflamed joints in a non-invasive manner.

Keywords:  Chondroitin sulfate; Dissolving microneedles; Extracellular vesicles; Fibroblast-like Synoviocytes; Macrophages; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.jconrel.2024.08.050
Carbohydr Polym. 2024 Nov 15. pii: S0144-8617(24)00714-8. [Epub ahead of print]344 122488

A critical review on pharmacological properties of sulfated polysaccharides from marine macroalgae.

Jegadeshwari B, Rajaram R.

  The marine ecosystem contains an assorted range of organisms, among which macroalgae stands out marine resources as an invaluable reservoir of structurally diverse bioactive compounds. Marine macroalgae are considered as primary consumers have gained more attention for their bioactive components. Sulfated polysaccharides (SPs) are complex polymers found in macroalgae that play a crucial role in their cell wall composition. This review consolidates high-tech methodologies employed in the extraction of macroalgal SPs, offering a valuable resource for researchers focuses in the pharmacological relevance of marine macromolecules. The pharmacological activities of SPs, focusing on their therapeutic action by encompassing diverse study models are summarized. Furthermore, in silico docking studies facilitates a comprehensive understanding of SPs interactions with their binding sites providing a valuable insight for future endeavors. The biological properties of algal SPs, along with a brief reference to mode of action based on different targets are presented. This review utilizes up-to-date research discoveries across various study models to elucidate the biological functions of SPs, focusing on their molecular-level mechanisms and offering insights for prospective investigations. Besides, the significance of SPs from seaweeds is highlighted, showcasing their potential beneficial applications in promoting human health. With promising biomedical prospects, this review explores the extensive uses and experimental evidence supporting the important roles of SPs in various fields.

Keywords:  Applications; In silico docking; Mechanisms of action; Pharmacological activities; Seaweeds; Sulfated polysaccharides

DOI:  https://doi.org/10.1016/j.carbpol.2024.122488
Carbohydr Polym. 2024 Nov 15. pii: S0144-8617(24)00692-1. [Epub ahead of print]344 122466

Anti-tumor and anti-metastasis of water-soluble sulfated β-glucan derivatives from Saccharomyces cerevisiae.

Jia Li, Mengmeng Zheng, Zhe Wang, Yang Liu, Qingfeng Niu, Han Zhou, Depeng Wang, Jike Song, Hongsheng Bi, Bin Guo, Guangli Yu, Chao Cai.

  Traditional fungi β-glucan commonly possesses high molecular weight with poor water solubility, which remains significant challenge in the drug development and medical application. Water-soluble β-glucan with high molecular weight (dHSCG) of 560 kDa, low molecular weight (dLSCG) of 60 kDa, and sulfated derivative (SCGS) with a molecular weight of 146 kDa and sulfate degree at 2.04 were obtained through well-controlled degradation and sulfated modification from Saccharomyces cerevisiae in this study. The structural characteristics were confirmed as β-1,3/6-glucan by FT-IR and NMR spectroscopy. Carbohydrate microarrays and surface plasmon resonance revealed distinct and contrasting binding affinities between the natural β-glucans and sulfated derivatives. SCGS exhibited strong binding to FGF and VEGF, while natural β-glucan showed no response, suggesting its potential as a novel antitumor agent. Moreover, SCGS significantly inhibited the migration rate of the highly metastatic melanoma (B16F10) cells. The lung metastasis mouse model also demonstrated that SCGS significantly reduced and eliminated the nodules, achieving an inhibition rate of 86.7% in vivo, with a dramatic improvement in IFN-α, TNF-α, and IL-1β levels. Through analysis of protein content and distribution in lung tissues, the anti-tumor and anti-metastasis mechanism of SCGS involves the regulation of degrading enzymes to protect extracellular matrix (ECM), as well as the reduction of angiogenic factor release. These findings provide a foundation for exploring the potential of SCGS in the development of new anti-tumor and anti-metastasis drugs and open up a new field in cancer research.

Keywords:  Anti-tumor and anti-metastasis; Extracellular matrix; Matrix metalloproteinases; Saccharomyces cerevisiae; Sulfated polysaccharides; β-Glucan

DOI:  https://doi.org/10.1016/j.carbpol.2024.122466
Nat Commun. 2024 Aug 30. 15(1): 7553

Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate.

Elena Ethel Vidal-Calvo, Anne Martin-Salazar, Swati Choudhary, Robert Dagil, Sai Sundar Rajan Raghavan, Lara Duvnjak, Mie Anemone Nordmaj, Thomas Mandel Clausen, Ann Skafte, Jan Oberkofler, Kaituo Wang, Mette Ø Agerbæk, Caroline Løppke, Amalie Mundt Jørgensen, Daria Ropac, Joana Mujollari, Shona Willis, Agnès Garcias López, Rebecca Louise Miller, Richard Torbjörn Gustav Karlsson, Felix Goerdeler, Yen-Hsi Chen, Ana R Colaço, Yong Wang, Thomas Lavstsen, Agnieszka Martowicz, Irina Nelepcu, Mona Marzban, Htoo Zarni Oo, Maj Sofie Ørum-Madsen, Yuzhuo Wang, Morten A Nielsen, Henrik Clausen, Michael Wierer, Dominik Wolf, Ismail Gögenur, Thor G Theander, Nader Al-Nakouzi, Tobias Gustavsson, Mads Daugaard, Ali Salanti.

Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

DOI: https://doi.org/10.1038/s41467-024-51781-0
ACS Appl Mater Interfaces. 2024 Sep 04.

In Situ Heparan Sulfate-Induced Peptide Self-Assembly to Overcome the Cell Surface Glycocalyx Barrier for Cancer Treatment.

Pengfei Pei, Long Chen, Xinyao Guan, Peng Wei, Xiaoxu Kang, Lili Gong, Lihong Liu, Wenxu Guo, Renji Gu, Lixin Wang, Chuanke Zhao, Jun F Liang, Shi-Zhong Luo.

  Heparan sulfate (HS) is a major component of cell surface glycocalyx with extensive negative charges and plays a protective role by preventing toxins, including small molecule drugs and anticancer cationic lytic peptides (ACLPs), from cells. However, this effect may compromise the treatment efficiency of anticancer drugs. To overcome the impedance of cancer cell glycocalyx, an HS-targeting ACLP PTP-7z was designed by fusion of an ACLP and a Zn2+-binding HS-targeting peptide. Upon Zn2+ ion binding, PTP-7z could self-assemble into uniform nanoparticles and show improved serum stability and reduced hemolysis, which enable it to self-deliver to tumor sites. The peptide PTP-7z showed a pH- and Zn2+ ion-dependent HS-binding ability, which triggers the HS-induced in situ self-assembling on the cancer cell surface in the acidic tumor microenvironment (TME). The self-assembled PTP-7z can overcome the impedance of cell glycocalyx by either disrupting cell membranes or translocating into cells through endocytosis and inducing cell apoptosis. Moreover, PTP-7z can also inhibit cancer cell migration. These results proved that HS-responsive in situ self-assembling is a practical strategy to overcome the cancer cell glycocalyx barrier for ACLPs and could be extended to the design of other peptide drugs to promote their in vivo application.

Keywords:  ACLP; HS targeting; charge conversion; glycocalyx barrier; in situ self-assembling

DOI:  https://doi.org/10.1021/acsami.4c09243