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  1. Article ; Online: Glycosaminoglycan microarrays for studying glycosaminoglycan-protein systems.

    Chittum, John E / Thompson, Ally / Desai, Umesh R

    Carbohydrate polymers

    2024  Volume 335, Page(s) 122106

    Abstract: More than 3000 proteins are now known to bind to glycosaminoglycans (GAGs). Yet, GAG-protein systems are rather poorly understood in terms of selectivity of recognition, molecular mechanism of action, and translational promise. High-throughput screening ( ...

    Abstract More than 3000 proteins are now known to bind to glycosaminoglycans (GAGs). Yet, GAG-protein systems are rather poorly understood in terms of selectivity of recognition, molecular mechanism of action, and translational promise. High-throughput screening (HTS) technologies are critically needed for studying GAG biology and developing GAG-based therapeutics. Microarrays, developed within the past two decades, have now improved to the point of being the preferred tool in the HTS of biomolecules. GAG microarrays, in which GAG sequences are immobilized on slides, while similar to other microarrays, have their own sets of challenges and considerations. GAG microarrays are rapidly becoming the first choice in studying GAG-protein systems. Here, we review different modalities and applications of GAG microarrays presented to date. We discuss advantages and disadvantages of this technology, explain covalent and non-covalent immobilization strategies using different chemically reactive groups, and present various assay formats for qualitative and quantitative interpretations, including selectivity screening, binding affinity studies, competitive binding studies etc. We also highlight recent advances in implementing this technology, cataloging of data, and project its future promise. Overall, the technology of GAG microarray exhibits enormous potential of evolving into more than a mere screening tool for studying GAG - protein systems.
    MeSH term(s) Glycosaminoglycans ; Binding, Competitive ; Biological Assay ; Microarray Analysis ; Research
    Chemical Substances Glycosaminoglycans
    Language English
    Publishing date 2024-03-29
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1501516-6
    ISSN 1879-1344 ; 0144-8617
    ISSN (online) 1879-1344
    ISSN 0144-8617
    DOI 10.1016/j.carbpol.2024.122106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Computational studies on glycosaminoglycan recognition of sialyl transferases.

    Sankaranarayanan, Nehru Viji / Sistla, Srinivas / Nagarajan, Balaji / Chittum, John E / Lau, Joseph T Y / Desai, Umesh R

    Glycobiology

    2023  Volume 33, Issue 7, Page(s) 579–590

    Abstract: Despite decades of research, glycosaminoglycans (GAGs) have not been known to interact with sialyl transferases (STs). Using our in-house combinatorial virtual library screening (CVLS) technology, we studied seven human isoforms, including ST6GAL1, ... ...

    Abstract Despite decades of research, glycosaminoglycans (GAGs) have not been known to interact with sialyl transferases (STs). Using our in-house combinatorial virtual library screening (CVLS) technology, we studied seven human isoforms, including ST6GAL1, ST6GAL2, ST3GAL1, ST3GAL3, ST3GAL4, ST3GAL5, and ST3GAL6, and predicted that GAGs, especially heparan sulfate (HS), are likely to differentially bind to STs. Exhaustive CVLS and molecular dynamics studies suggested that the common hexasaccharide sequence of HS preferentially recognized ST6GAL1 in a site overlapping the binding site of the donor substrate CMP-Sia. Interestingly, CVLS did not ascribe any special role for the rare 3-O-sulfate modification of HS in ST6GAL1 recognition. The computational predictions were tested using spectrofluorimetric studies, which confirmed preferential recognition of HS over other GAGs. A classic chain length-dependent binding of GAGs to ST6GAL1 was observed with polymeric HS displaying a tight affinity of ~65 nM. Biophysical studies also confirmed a direct competition between CMP-Sia and an HS oligosaccharide and CS polysaccharide for binding to ST6GAL1. Overall, our novel observation that GAGs bind to ST6GAL1 with high affinity and compete with the donor substrate is likely to be important because modulation of sialylation of glycan substrates on cells has considerable physiological/pathological consequences. Our work also brings forth the possibility of developing GAG-based chemical probes of ST6GAL1.
    MeSH term(s) Humans ; Glycosaminoglycans/chemistry ; Transferases/metabolism ; Heparitin Sulfate/metabolism ; Binding Sites ; Molecular Dynamics Simulation
    Chemical Substances Glycosaminoglycans ; Transferases (EC 2.-) ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2023-05-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1067689-2
    ISSN 1460-2423 ; 0959-6658
    ISSN (online) 1460-2423
    ISSN 0959-6658
    DOI 10.1093/glycob/cwad040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein.

    Chittum, John E / Sankaranarayanan, Nehru Viji / O'Hara, Connor P / Desai, Umesh R

    ACS medicinal chemistry letters

    2021  Volume 12, Issue 11, Page(s) 1710–1717

    Abstract: SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early ...

    Abstract SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray of 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led to identification of only eight sequences as potent antagonists; results that were supported by detailed dual-filter computational studies. Competitive studies using the HS microarray suggested almost equivalent importance of IdoA2S-GlcNS6S and GlcNS3S structures, which were supported by affinity studies. Exhaustive virtual screening on a library of >93 000 sequences led to a novel pharmacophore with at least two 3-
    Language English
    Publishing date 2021-10-08
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.1c00343
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Glycan Modulation of Insulin-like Growth Factor-1 Receptor.

    Boothello, Rio S / Sankaranarayanan, Nehru Viji / Sistla, Jyothi C / Nagarajan, Balaji / Sharon, Chetna / Chittum, John E / Niyaz, Rabiya Y / Roy, Swarnali / Nandi, Aditi / O'Hara, Connor P / Gangji, Rahaman Navaz / Afosah, Daniel K / Ongolu, Ravikumar / Patel, Bhaumik B / Desai, Umesh R

    Angewandte Chemie (International ed. in English)

    2022  Volume 61, Issue 49, Page(s) e202211320

    Abstract: ... sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, a phenomenon directly ...

    Abstract The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal that activation of IGF-1R by its cognate ligand IGF1 is inhibited by shorter, soluble heparan sulfate (HS) sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, a phenomenon directly opposed to the traditional relationship known for GAG-protein systems. The inhibition arises from smaller oligosaccharides binding in a unique pocket in the IGF-1R ectodomain, which competes with the natural cognate ligand IGF1. This work presents a highly interesting observation on preferential and competing inhibition of IGF-1R by smaller sequences, whereas polysaccharides are devoid of this function. These insights will be of major value to glycobiologists and anti-cancer drug discoverers.
    MeSH term(s) Humans ; Ligands ; Neoplasms/metabolism ; Polysaccharides ; Signal Transduction ; Receptors, Somatomedin/metabolism
    Chemical Substances Ligands ; Polysaccharides ; Receptors, Somatomedin
    Language English
    Publishing date 2022-11-09
    Publishing country Germany
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202211320
    Database MEDical Literature Analysis and Retrieval System OnLINE

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