bims-supasi 2023-10-22 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–10–22
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Sulfated polysaccharides in sea cucumbers and their biological properties: A review.
Heparan Sulfate-Mimicking Glycopolymers Bind SARS-CoV-2 Spike Protein in a Length- and Sulfation Pattern-Dependent Manner.
Silkworm glycosaminoglycans bind to Bombyx mori nuclear polyhedrosis virus and facilitate its entry.
Complex sulfated galactans from hot water extracts of red seaweed Asparagopsis taxiformis comprise carrageenan and agaran structures.
Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice.
Tyrosine phosphorylation of recombinant hirudin increases affinity to thrombin and antithrombotic activity.
Comparative Study of Insulin Sensitivity and Resistance and Their Correlation with Androgens in Lean and Obese Women with Polycystic Ovary Syndrome.

Int J Biol Macromol. 2023 Oct 14. pii: S0141-8130(23)04226-5. [Epub ahead of print]253(Pt 7): 127329

Sulfated polysaccharides in sea cucumbers and their biological properties: A review.

Abul Hossain, Deepika Dave, Fereidoon Shahidi.

  Sea cucumbers contain a wide range of biomolecules, including sulfated polysaccharides (SPs), with immense therapeutic and nutraceutical potential. SPs in sea cucumbers are mainly fucosylated chondroitin sulfate (FCS) and fucan sulfate (FS) which exhibit a series of pharmacological effects, including anticoagulant activity, in several biological systems. FCS is a structurally distinct glycosaminoglycan in the sea cucumber body wall, and its biological properties mainly depend on the degree of sulfation, position of sulfate group, molecular weight, and distribution of branches along the backbone. So far, FCS and FS have been recognized for their antithrombotic, anti-inflammatory, anticancer, antidiabetic, anti-hyperlipidemic, anti-obesity, and antioxidant potential. However, the functions of these SPs are mainly dependent on the species, origins, harvesting season, and extraction methods applied. This review focuses on the SPs of sea cucumbers and how their structural diversities affect various biological activities. In addition, the mechanism of actions of SPs, chemical structures, factors affecting their bioactivities, and their extraction methods are also discussed.

Keywords:  Biological activity; Fucan sulfates; Fucosylated chondroitin sulfate; Sea cucumber; Structure; Sulfated polysaccharide

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127329
ACS Med Chem Lett. 2023 Oct 12. 14(10): 1411-1418

Heparan Sulfate-Mimicking Glycopolymers Bind SARS-CoV-2 Spike Protein in a Length- and Sulfation Pattern-Dependent Manner.

Hawau Abdulsalam, Jiayi Li, Ravi S Loka, Eric T Sletten, Hien M Nguyen.

Heparan sulfate-mimicking glycopolymers, composed of glucosamine (GlcN)-glucuronic acid (GlcA) repeating units, bind to the receptor-binding subunit (S1) and spike glycoprotein (S) domains of the SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent fashion. A glycopolymer composed of 12 repeating GlcNS6S-GlcA units exhibits a much higher affinity to the S1 protein (IC50 = 13 ± 1.1 nM) compared with the receptor-binding domain (RBD). This glycopolymer does not interfere in angiotensin-converting enzyme 2 binding of the RBD. Although this compound binds strongly to the S1/membrane-fusion subunit (S2) junction (KD = 29.7 ± 4.18 nM), it does not shield the S1/S2 site from cleavage by furin-a behavior contrary to natural heparin. This glycopolymer lacks iduronic acid, which accounts for 70% of heparin. Further, this compound, unlike natural heparin, is well defined in both sulfation pattern and length, which results in fewer off-target interactions with heparin-binding proteins. The results highlight the potential of using polymeric heparan sulfate (HS) mimetics for the therapeutic agent development.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00319
Int J Biol Macromol. 2023 Oct 12. pii: S0141-8130(23)04249-6. [Epub ahead of print]253(Pt 6): 127352

Silkworm glycosaminoglycans bind to Bombyx mori nuclear polyhedrosis virus and facilitate its entry.

Weiwei Zhou, Jindie Hong, Jinying Han, Fuchuan Cai, Qi Tang, Qian Yu, Guohui Li, Shangshang Ma, Xiaoyong Liu, Shuhao Huo, Keping Chen, Feifei Zhu.

  Interacting with cell surface attachment factors or receptors is the first step for virus infection. Glycans cover a thick layer on eukaryotic cells and are potential targets of various viruses. Bombyx mori nuclear polyhedrosis viruses (BmNPV) is a baculovirus that causes huge economic loss to the sericulture industry but the mechanism of infection is unclear. Looking for potential host receptors for the virus is an important task. In this study, we investigated the role of glycosaminoglycan (GAG) modifications, including heparan sulfate (HS) and chondroitin sulfate (CS), during BmNPV infection. Enzymatic removal of cell surface HS and CS effectively inhibited BmNPV infection and replication. Exogenous HS and CS can directly bind to BmNPV virion in solution and act as neutralizers for viral infection. Furthermore, the expression of enzymes involved in GAG biosynthesis was upregulated in the BmNPV susceptible silkworm after virus administration, but down-regulated in the resistant strain after virus treatment, suggesting that BmNPV was able to utilize host cell machinery to promote the biosynthesis of GAGs. This study demonstrated HS and CS as important attachment factors that facilitate the viral entry process, and targeting HS and CS can be an effective means of inhibiting BmNPV infection.

Keywords:  BmNPV; Glycosaminoglycan; Silkworm

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127352
Carbohydr Polym. 2023 Dec 15. pii: S0144-8617(23)00779-8. [Epub ahead of print]322 121314

Complex sulfated galactans from hot water extracts of red seaweed Asparagopsis taxiformis comprise carrageenan and agaran structures.

Rodrigo A Rodríguez Sánchez, Kadri Saluri, Rando Tuvikene, María C Matulewicz, Marina Ciancia.

  Hot water extraction from the red seaweed Asparagopsis taxiformis yielded three extracts which showed sulfated galactans with a D:L-galactose ratio non consistent with carrageenan or agaran backbones. The major extract was fractionated by cetrimide precipitation and redissolution with increasing sodium chloride concentrations due to their low solubility. Seven fractions were obtained, and studied by methylation analysis, desulfation-methylation, and NMR spectroscopy of the partially hydrolyzed and the native samples. Fractions with the highest yield were those obtained at high concentrations of NaCl. They comprised both agaran and crageenan structures in considerable amounts. The main agaran structures were β-D-galactose 4-sulfate and β-D-galactose 2-sulfate units linked to α-L-galactose 2,3-disulfate residues, and β-D-galactose linked to α-L-galactose 3-sulfate or 6-sulfate, or substituted with single stubs of β-D-xylose on C3, while the carrageenan structures comprised β-D-galactose (2-sulfate) linked to α-D-galactose 3-sulfate or 2,3-disulfate, and β-D-galactose 2,4-disulfate linked to α-D-galactose 2,3-disulfate. Between the less sulfated fractions, the one obtained by solubilization in 0.5 M NaCl was mainly constituted by agarans, which included 3,6-anhydro-α-L-galactose units. Anticoagulant activity was assayed by general coagulation tests (aPTT and TT), showing a moderate action compared with heparin. This is the first detailed study of the sulfated galactans from the order Bonnemaisoniales.

Keywords:  Agaran; Anticoagulant activity; Asparagopsis taxiformis; Carrageenan; DL-Hybrid galactan; Red seaweed

DOI:  https://doi.org/10.1016/j.carbpol.2023.121314
Mol Pharm. 2023 Oct 20.

Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice.

Atsushi Imakiire, Hideto Morimoto, Hidehiko Suzuki, Tomomi Masuda, Eiji Yoden, Asuka Inoue, Hiroki Morioka, Takashi Konaka, Ayaka Mori, Ryoji Shirasaka, Ryo Kato, Tohru Hirato, Hiroyuki Sonoda, Kohtaro Minami.

  Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.

Keywords:  blood-retinal barrier; electroretinography; mucopolysaccharidosis II; pabinafusp alfa; retinopathy; transferrin receptor

DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00736
Proteins. 2023 Oct 20.

Tyrosine phosphorylation of recombinant hirudin increases affinity to thrombin and antithrombotic activity.

Alina Volkova, Pavel Semenyuk.

  Thrombin is one of the key enzymes of the blood coagulation system and a promising target for the development of anticoagulants. One of the most specific natural thrombin inhibitors is hirudin, contained in the salivary glands of medicinal leeches. The medicinal use of recombinant hirudin is limited because of the lack of sulfation on Tyr63, resulting in a 10-fold decrease in activity compared to native (sulfated) hirudin. In the present work, a set of hirudin derivatives was tested for affinity to thrombin: phospho-Tyr63, Tyr63(carboxymethyl)Phe, and Tyr63Glu mutants, which mimic Tyr63 sulfation and Gln65Glu mutant and lysine-succinylated hirudin, which enhance the overall negative charge of hirudin, as well as sulfo-hirudin and desulfo-hirudin as references. Using steered molecular dynamics simulations with subsequent umbrella sampling, phospho-hirudin was shown to exhibit the highest affinity to thrombin among all hirudin analogs, including native sulfo-hirudin; succinylated hirudin was also prospective. Phospho-hirudin exhibited the highest antithrombotic activity in in vitro assay in human plasma. Taking into account the modern methods for obtaining phospho-hirudin and succinylated hirudin, they are prospective as anticoagulants in clinical practice.

Keywords:  antithrombotic activity; hirudin; hirudin derivative; phosphotyrosine; steered molecular dynamics simulation; thrombin affinity

DOI:  https://doi.org/10.1002/prot.26616
Reprod Sci. 2023 Oct 17.

Comparative Study of Insulin Sensitivity and Resistance and Their Correlation with Androgens in Lean and Obese Women with Polycystic Ovary Syndrome.

Sukirti Misra, Jugal Gada, Charushila Dhole, Premlata Varthakavi, Nikhil Bhagwat.

  There is a lack of consensus on the optimal screening strategy for insulin resistance (IR), particularly in lean women with polycystic ovary syndrome (PCOS). Therefore, we conducted a cross-sectional study in 80 women with PCOS (28 lean/52 obese) and 80 age- and body mass index (BMI)-matched controls. Using a 5-point 75-g oral glucose tolerance test (OGTT) (0, 30, 60, 90, 120 min), we examined glucose and insulin excursions, IR, insulin sensitivity, beta-cell function (ßF), and the effect of androgens on IR. Lean and obese women with PCOS had similar glucose but higher insulin (except fasting in lean women) and insulin AUC as compared to their respective controls (p < 0.05). Lean women with PCOS were equally insulin-resistant but more hyperinsulinemic than the obese controls (p < 0.05). Although ßF ([1st phase: 481.71 ± 263.53 vs. 430.56 ± 232.37], [2nd phase: 815.16 ± 447.12 vs. 752.66 ± 428.95]) was comparable in lean and obese women with PCOS, lean women had better insulin sensitivity (112.78 ± 66.26 vs. 75.49 ± 55.6) (p < 0.05). Dehydroepiandrosterone sulfate (DHEAS) and androstenedione decreased with increasing BMI in lean women, and this correlated with deteriorating insulin sensitivity and exaggerated hyperinsulinemia. In obese women with PCOS, sex hormone-binding globulin (SHBG) correlated negatively with BMI and hyperinsulinemia, and positively with insulin sensitivity. This data suggests that estimating only fasting insulin may miss IR in lean women with PCOS; hence, additional time points in OGTT will add value to screening for IR. DHEAS and androstenedione may have a beneficial effect on insulin sensitivity and may be used to screen IR in lean women, while SHBG can be used as a predictive marker for IR in obese women with PCOS.

Keywords:  Androgens; Insulin resistance; Insulin sensitivity; Lean women with PCOS

DOI:  https://doi.org/10.1007/s43032-023-01374-x