In this work, we present a bottom-up approach for the synthesis of lactose-functionalized glycomacromolecules and glycofunctionalized liposomes and apply these compounds to investigate their effects of multivalent presentation on binding to galectin-3.Step-wise assembly of tailor-made building blocks on solid supports was used to synthesize a series of oligo(amidoamine) scaffolds that were further conjugated to lactose via copper catalyzed 1,3-dipolar cycloaddition. Binding studies with galectin-3 revealed affinities in the micromolar range that increased with increasing carbohydrate valency, and decreased with increasing size and linker flexibility. To further explore their multivalency, selected glycomacromolecules were conjugated to lipids and used in liposomal formulations. Binding studies show a further increase in binding in nanomolar ranges in dependence of both ligand structure and liposomal presentation, demonstrating the power of combining the two approaches.
Glycomacromolecules show significant potential as antimicrobials. We highlight recent studies on their performance in hindering host cell entry and biofilm formation, and their potential as drug delivery and diagnostic agents.
Heparin (HP) and heparan sulfate (HS) are linear, anionically charged polysaccharides well-known for their diverse biological activities. While HP is generally localized in mast cells and in connective tissues, HS is part of the glycocalyx and involved in the attachment of viruses to host cells, constituting the first step of an infection. HP and HS also exhibit antiviral activity by blocking viral receptors, thereby inhibiting viruses from engaging with host cells. Inspired by their structural features, such as their high molecular weight and polyanionic character, various synthetic polymers mimicking HP/HS have been developed and used as model systems to study bioactivity, as well as for therapeutic applications. This Perspective provides an overview of the roles of HP/HS in viral engagement, and examines historical and recent approaches toward oligo-/polysaccharide, glycopolymer, and anionic polymer HP/HS mimetics. An overview of current applications and future prospects of these molecules is provided, demonstrating their potential in addressing current and future epidemics and pandemics.
Sulfated glycosaminoglycans (sGAGs) such as heparan sulfate (HS) are structurally diverse linear polysaccharides that are involved in many biological processes and have gained interest as antiviral compounds. Their recognition is driven by a complex orchestra of structural parameters that are still under intense investigation. One distinct characteristic is the incorporation of sulfation patterns including highly sulfated and non-sulfated sequences that provide variations in flexibility and conformation, which in turn impact the biological function of sGAGs. However, these distinct features have not yet been fully realized in the synthetic preparation of sGAG mimetics. Here, we present the synthesis of three groups of sulfated glycomacromolecules as sGAG mimetics: (i) globally sulfated glycooligomers, (ii) glycooligomers with sequence-defined sulfation patterns, and (iii) a globally sulfated glycooligomer-oligo-L-proline hybrid structure. The complete synthesis, including chemical sulfation, was conducted on solid support, enabled by the introduction of a commercially available photocleavable linker allowing for the preservation of sensitive sulfates during cleavage of the products. Structures were obtained in good purity and with high degrees of sulfation demonstrating the wide applicability of this methodology to prepare tailor-made sulfated glycomacromolecules and similar sGAG mimetics. Structures were tested for their anticoagulant properties showing activity similar to their natural HS counterpart and significantly lower than HP.
A 9-year-old boy was referred at night by the emergency physician with unstoppable continuous bleeding from a tumor on the upper lip that had grown over the preceding 2 weeks. The bleeding was brought under control by local application of epinephrine together with local and systemic administration of tranexamic acid (Hb min 9.7 g/dL). After excision under local anesthesia, histological analysis showed the growth to be a lobular capillary hemangioma. At 5-month follow-up the patient had no scarring and there had been no recurrence. According to the International Society for the Study of Vascular Anomalies, lobular capillary hemangiomas are fast-growing benign neoplasms. They occur mostly in the second or third decade of life or in children up to 7 years of age, and are usually located in the head and neck region. Lobular capillary hemangiomas are prone to ulceration and bleeding. The treatments of choice are complete excision, cryotherapy, or laser ablation; local application of propranolol may be appropriate in some cases. In 15 % of cases there is local recurrence or multiple satellite foci arise. The synonym "pyogenic granuloma" is misleading, because neither a pyogenic disease nor a granuloma is concerned. However, lobular capillary hemangiomas frequently occur in children after infection or injury. They are often misinterpreted and therefore left untreated. The etiologies of lobular capillary hemangioma and infantile hemangiomas have nothing in common.
Background: Graft-versus-host disease (GVHD) is a major cause of mortality after unrelated hematopoietic stem cell transplantations (HSCT). Despite the development of modern immunosuppressive strategies, a nearly perfectly controlled compatibility of the classical HLA genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and availability of numerous so-called minor histocompatibility antigens (e.g. HY or HA-1), its incidence remains largely unexplained to date. MIC genes (MHC class I chain-related) - a distinct lineage of MHC class I genes – are promising candidates to explain, at least partially, the incidence of GVHD in HLA-matched transplantations. MICA and MICB are highly polymorphic (100 alleles for MICA and 40 for MICB) and encode functional cell-surface glycoproteins up-regulated by cell stress. They interact with NKG2D, an activating receptor expressed on the surface of cytotoxic αβ CD8+ and γδ T lymphocytes and natural killer cells. MIC genes are already known to have a HLA-independent effect on solid graft outcomes and may play a similar role in HSCT by triggering GVHD. Objective: The objective of the present study was to determine the impact of donor/patient matching at the MICA and MICB loci on the incidence of GVHD in patients undergoing unrelated HSCT. Methods: We retrospectively analyzed a multicenter cohort of 1072 unrelated transplantations performed between 1996 and 2013. All donor-recipient pairs were fully typed at high resolution for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 and were matched for ten of ten HLA alleles (HLA 10/10 matched). High resolution genotyping of MICA and MICB was performed by sequenced-based typing in order to define matching grades between donors and patients. The endpoints of the study were acute and chronic GVHD. Apart from HLA-DPB1 matching, statistical models were adjusted for major clinical variables which have been shown to be associated with outcome (patient’s age, patient’s and donor’s sex, patient’s and donor’s serological status for cytomegalovirus, year of transplantation, time to transplantation, transplantation center, source of stem cells, conditioning regimen, GVHD prophylaxis, treatment with anti-thymocyte globulin, disease category and severity at transplantation). Results: Of the 1072 transplantations, 134 (12.5 %) and 380 (35.4 %) were mismatched at the MICA and MICB locus, respectively. Both MICA and MICB mismatches were significantly associated with an increased incidence of severe acute GVHD (grades III-IV) in univariate and multivariate models (multivariate model: HR = 2.32, 95 % CI = 1.84-2.92; p=0.0003 for MICA and HR = 1.49, 95 % CI = 1.24-1.79; p=0.03 for MICB). At day 100 post-HSCT severe acute GVHD incidences in mismatched vs. matched transplantations were 19.62 % vs. 15.08 % and 20.00 % vs. 14.84 % for MICA and MICB, respectively (Figure 1). Chronic GVHD was associated with MICA and MICB mismatches in univariate analysis (HR = 1.55, 95 % CI = 1.27-1.89; p=0.029 for MICA and HR=1.38, 95 % CI = 1.19-1.62; p=0.03 for MICB), but showed only a trend for association in multivariate models. Figure 1 Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Figure 1. Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Conclusion: To date this is the largest reported MICA and MICB sequence analysis whether in HSCT or solid organ transplantation. Inclusion of MICA and MICB typing in the donor selection process may be a practical clinical strategy for lowering the risks of severe acute GVHD after unrelated HSCT. Disclosures No relevant conflicts of interest to declare.
Lectin–glycan interactions are at the heart of a multitude of biological events. Glycans are usually presented in a multivalent manner on the cell surface as part of the so-called glycocalyx, where they interact with other entities. This multivalent presentation allows us to overcome the typical low affinities found for individual glycan–lectin interactions. Indeed, the presentation of glycans may drastically impact their binding by lectins, highly affecting the corresponding binding affinity and even selectivity. In this context, we herein present the study of the interaction of a variety of homo- and heteromultivalent lactose-functionalized glycomacromolecules and their lipid conjugates with two human galectins. We have employed as ligands the glycomacromolecules, as well as liposomes decorated with those structures, to evaluate their interactions in a cell-mimicking environment. Key details of the interaction have been unravelled by NMR experiments, both from the ligand and receptor perspectives, complemented by cryo-electron microscopy methods and molecular dynamics simulations.
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