Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators

Kishi, Junichiro; Inuki, Shinsuke; Hirata, Natsumi; Kashiwabara, Emi; Yoshidome, Daisuke; Ichihara, Osamu; Fujimoto, Yukari

doi:10.1016/j.bmcl.2019.02.018

Cited by 13 publications

(10 citation statements)

References 20 publications

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“…After synthesis and treatment with a series of diether-containing α-GalCer analogues, Th17 selectivity with IL-17 secretion was improved . Fujimoto and others synthesized αGalCer analogues with modified Bz amide groups, which further showed Th2 type-biased immune responses . Other works have achieved diverse modifications of the ceramide and the glycosidic bond to achieve unequivocal immune responses in the last five years. − …”

Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

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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Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

114

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“…11,12 We have also developed α-GalCer derivatives with a Bz amide group (Figure 1b, α-GalCer-p-MeOPh-amide) that can interact with not only polar amino acid residues (Glu14 or Ser28) but also an aromatic amino acid residue (Phe70). 13 Furthermore, in order to develop Th2-biasing glycolipid ligands with short acyl groups (m + 14 ≈ 20, Figure 1c), we have used the amide group as an anchor moiety to enhance the interaction and activity. 12 We then introduced an additional functional group capable of forming a covalent linkage to glycolipid ligands having shorter acyl groups (m + 14 < 20) for the purpose of increasing the cytokine response.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The α-GalCer derivatives containing an amide group in the fatty acid chain (Figure b, α-GalCer-C26-amide) exhibited increases in cytokine production. We revealed that the positions of the amides in the acyl chain were particularly important for improving its activities, and this could be the result of the formation of shielded hydrogen bonds between the amide group and Glu14 or Ser28 within the hydrophobic environment of the A′ pocket. , We have also developed α-GalCer derivatives with a Bz amide group (Figure b, α-GalCer- p -MeOPh-amide) that can interact with not only polar amino acid residues (Glu14 or Ser28) but also an aromatic amino acid residue (Phe70) . Furthermore, in order to develop Th2-biasing glycolipid ligands with short acyl groups ( m + 14 ≈ 20, Figure c), we have used the amide group as an anchor moiety to enhance the interaction and activity .…”

Section: Introductionmentioning

confidence: 99%

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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“…Recently p-MeOBz amide-containing a-GalCer analogs have been reported that contain aromatic groups within the acyl chain but also carry an amide linker, as well as an additional oxygen following the aromatic group. The polar amide was designed to interact with a region in the A´ pocket of CD1d that for a slightly polar side pocket (Ser28 and Gln14) (36). Surprisingly, the incorporation of polar groups within the acyl chain results in a Th2 polarized NKT cell response characterized by a reduced production of IFN-g and increased levels of IL-4.…”

Section: Discussionmentioning

confidence: 99%