Development of α-GalCer Analogues with an α-Fluorocarbonyl Moiety as Th2-Selective Ligands of CD1d

Kim, Hyunsoo; Song, Huacan; Park, June; Lee, Dong Sup; Park, Seung Bum

doi:10.1021/acsmedchemlett.9b00026

Cited by 8 publications

(8 citation statements)

References 41 publications

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“…2b ) and α-GalCerC20:2 analogues, respectively 88 . Additional acyl chain modifications that yielded strong T H 2-biased cytokine responses included (1) bioisosteric replacement of the acyl chain amide with a triazole, especially in long-chain analogues 89 , (2) incorporation of an amide in short fatty acid chain derivatives for hydrogen bonding with polar residues in the CD1d pocket (‘anchoring effect’) 90 , 91 , (3) incorporation of α-fluorocarbonyl moiety at the acyl chain terminus 92 and (4) introduction of a polar chloroacetylamide terminal group in short acyl chain analogues for covalent linkage with CD1d pocket residues 93 (Fig. 2a ).…”

Section: α-Galactosylceramide-derived Adjuvantsmentioning

confidence: 99%

Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action

2021

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Section: α-Galactosylceramide-derived Adjuvantsmentioning

confidence: 99%

Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action

2021

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“…Porcelli and co-workers designed photoactivable α-GalCer analogues, which could generate CD1d–ligand conjugates covalently attached to V257 of CD1d under UV irradiation . Park and co-workers developed α-GalCer analogues with an α-fluorocarbonyl moiety that was expected to bind to Cys12; however, they were not able to detect any evidence of covalent bonds between CD1d and their ligands . We herein report the development of a glycolipid ligand that can form a covalent bond to CD1d under physiological conditions.…”

Section: Introductionmentioning

confidence: 89%

“…17 Park and co-workers developed α-GalCer analogues with an αfluorocarbonyl moiety that was expected to bind to Cys12; however, they were not able to detect any evidence of covalent bonds between CD1d and their ligands. 18 We herein report the development of a glycolipid ligand that can form a covalent bond to CD1d under physiological conditions.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This result might imply that the chlorine atom has some positive effects on the interaction with the CD1d protein rather than being involved in covalent bond formation. Park et al 18 reported α-GalCer analogues having an α-fluorocarbonyl moiety, which was expected to form covalent bonds. Their analogues have much longer acyl chains than our covalent derivative 3a, and they were not able to identify the covalent adducts of CD1d with their analogues, suggesting that the position of functional groups (acyl chain length) is crucial for the formation of a covalent bond to Cys12.…”

Section: ■ Introductionmentioning

confidence: 99%

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Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands

et al. 2020

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CD1d is a nonpolymorphic antigen-presenting protein responsible for the regulation of natural killer T (NKT) cell activation. α-Galactosyl ceramide (α-GalCer, KRN7000) is the representative CD1d ligand that can bind to the CD1d protein. The resulting complex is recognized by the T cell receptors of the NKT cell, inducing various immune responses. Previous structure–activity relationship studies of α-GalCer have revealed that the ability of NKT cells to induce cytokines depends on the ligand structure, and in particular, ligands that form more stable complexes with CD1d display potent activity. We focused on the Cys residue of the large hydrophobic pockets of CD1d (A′ pocket) and developed α-GalCer derivatives containing groups that can form covalent bonds. The assay results revealed that these ligands displayed higher levels of cytokine production and Th2 cell-type cytokine polarization response. Furthermore, the LC-MS/MS analysis indicated that the chloroacetylamide-containing ligand was covalently bound to Cys12 of CD1d, which suggests that the enhanced activities result from the formation of a stable CD1d–ligand complex. To our knowledge, this is the first ligand that allows covalent bond formation to CD1d under physiological conditions.

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“…Calenbergh’s team modified αGalCer analogues with C4″-, C5′′-, C6′′, and phytosphingosine modification, that improved the iNKT cell stimulating ability in vitro and in vivo. − Park’s group recently synthesized α-fluorocarbonyl-modified αGalCer analogues through an alkyne–alkyne cross coupling strategy. In contrast, the screened molecule showed high Th2 type preference in the iNKT cell test . After synthesis and treatment with a series of diether-containing α-GalCer analogues, Th17 selectivity with IL-17 secretion was improved .…”

Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 94%

Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

114

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Personalized cancer vaccines (PCVs) are reinvigorating vaccine strategies in cancer immunotherapy. In contrast to adoptive T-cell therapy and checkpoint blockade, the PCV strategy modulates the innate and adaptive immune systems with broader activation to redeploy antitumor immunity with individualized tumor-specific antigens (neoantigens). Following a sequential scheme of tumor biopsy, mutation analysis, and epitope prediction, the administration of neoantigens with synthetic long peptide (SLP) or mRNA formulations dramatically improves the population and activity of antigen-specific CD4+ and CD8+ T cells. Despite the promising prospect of PCVs, there is still great potential for optimizing prevaccination procedures and vaccine potency. In particular, the arduous development of tumor-associated antigen (TAA)-based vaccines provides valuable experience and rational principles for augmenting vaccine potency which is expected to advance PCV through the design of adjuvants, delivery systems, and immunosuppressive tumor microenvironment (TME) reversion since current personalized vaccination simply admixes antigens with adjuvants. Considering the broader application of TAA-based vaccine design, these two strategies complement each other and can lead to both personalized and universal therapeutic methods. Chemical strategies provide vast opportunities for (1) exploring novel adjuvants, including synthetic molecules and materials with optimizable activity, (2) constructing efficient and precise delivery systems to avoid systemic diffusion, improve biosafety, target secondary lymphoid organs, and enhance antigen presentation, and (3) combining bioengineering methods to innovate improvements in conventional vaccination, "smartly" re-educate the TME, and modulate antitumor immunity. As chemical strategies have proven versatility, reliability, and universality in the design of T cell-and B cell-based antitumor vaccines, the union of such numerous chemical methods in vaccine construction is expected to provide new vigor and vitality in cancer treatment.

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Development of α-GalCer Analogues with an α-Fluorocarbonyl Moiety as Th2-Selective Ligands of CD1d

Cited by 8 publications

References 41 publications

Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action

Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action

Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands

Chemical Strategies to Boost Cancer Vaccines

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