Stereoselective Synthesis of α- and β-<scp>l</scp>-Ara4N Glycosyl H-Phosphonates and a Neoglycoconjugate Comprising Glycosyl Phosphodiester Linked β-<scp>l</scp>-Ara4N

Hollaus, Ralph; Kosma, Paul; Zamyatina, Alla

doi:10.1021/acs.orglett.6b03358

“…To clarify the biological outcome of the Ara4N modification, a reliable synthetic approach toward β-L-Ara4N-containing LPS partial structures was developed [ 151 ]. To facilitate the assessment of an immunogenic potential of the unique β-L-Ara4N substitution at the glycosidically linked 1-phosphate group, a neoglycoconjugate 103 entailing an epitope βGlcN(1→6)-αGlcN(1→P←1)-β-L-Ara4N 102 was synthesised in a stereoselective manner [ 152 ] ( Scheme 12 ).…”

Section: Reviewmentioning

confidence: 99%

Aminosugar-based immunomodulator lipid A: synthetic approaches

Zamyatina

¹

2018

Beilstein J. Org. Chem.

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The immediate immune response to infection by Gram-negative bacteria depends on the structure of a lipopolysaccharide (LPS, also known as endotoxin), a complex glycolipid constituting the outer leaflet of the bacterial outer membrane. Recognition of picomolar quantities of pathogenic LPS by the germ-line encoded Toll-like Receptor 4 (TLR4) complex triggers the intracellular pro-inflammatory signaling cascade leading to the expression of cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The “endotoxic principle” of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A content of LPS comprises a complex mixture of structural homologs varying in the acylation pattern, the length of the (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl long-chain residues and in the phosphorylation status of the β(1→6)-linked diglucosamine backbone. The structural heterogeneity of the lipid A isolates obtained from bacterial cultures as well as possible contamination with other pro-inflammatory bacterial components makes it difficult to obtain unambiguous immunobiological data correlating specific structural features of lipid A with its endotoxic activity. Advanced understanding of the therapeutic significance of the TLR4-mediated modulation of the innate immune signaling and the central role of lipid A in the recognition of LPS by the innate immune system has led to a demand for well-defined materials for biological studies. Since effective synthetic chemistry is a prerequisite for the availability of homogeneous structurally distinct lipid A, the development of divergent and reproducible approaches for the synthesis of various types of lipid A has become a subject of considerable importance. This review focuses on recent advances in synthetic methodologies toward LPS substructures comprising lipid A and describes the synthesis and immunobiological properties of representative lipid A variants corresponding to different bacterial species. The main criteria for the choice of orthogonal protecting groups for hydroxyl and amino functions of synthetically assembled β(1→6)-linked diglucosamine backbone of lipid A which allows for a stepwise introduction of multiple functional groups into the molecule are discussed. Thorough consideration is also given to the synthesis of 1,1′-glycosyl phosphodiesters comprising partial structures of 4-amino-4-deoxy-β-L-arabinose modified Burkholderia lipid A and galactosamine-modified Francisella lipid A. Particular emphasis is put on the stereoselective construction of binary glycosyl phosphodiester fragments connecting the anomeric centers of two aminosugars as well as on the advanced P(III)-phosphorus chemistry behind the assembly of zwitterionic double glycosyl phosphodiesters.

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Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Strobl,

Zucchetta,

Vašíček

et al. 2024

Angewandte Chemie

0

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Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, toll‐like receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of Lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1'‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1')βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation.

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Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Strobl,

Zucchetta,

Vašíček

et al. 2024

Angew Chem Int Ed

0

View full text Add to dashboard Cite

Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, toll‐like receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of Lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1'‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1')βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation.

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Stereoselective Synthesis of α- and β-l-Ara4N Glycosyl H-Phosphonates and a Neoglycoconjugate Comprising Glycosyl Phosphodiester Linked β-l-Ara4N

Cited by 7 publications

References 30 publications

Aminosugar-based immunomodulator lipid A: synthetic approaches

Aminosugar-based immunomodulator lipid A: synthetic approaches

Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

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