Background: The last few decades have witnessed groundbreaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α -galactosylceramide derivative, KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T(iNKT) cells with notable potency against cancer cells in mouse models; a therapeutic success was not well replicated in human models. Dual structural modification of KRN7000 entailing the incorporation of hydrocinnamoyl ester on C6" and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells.

Objective/Methods: Therefore, to gain molecular insights into the structural dynamics and selective mechanisms of AH10-7 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the inhibitory activities of KRN7000 andAH10-7 on hTCR-CD1d towards activating iNKT.

Results: Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with ‘non-common’ binding site residues.

Conclusion: Findings extracted from this study further reveal important molecular and structural perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

背景：在过去的几十年中，目睹了针对免疫监视机制的开创性研究，并在癌症免疫治疗领域取得了重大进展。这种方法缩小了激活或增强免疫系统识别功能以促进恶性细胞破坏的治疗剂的开发范围。α-半乳糖基神经酰胺衍生物KRN7000是一种免疫治疗剂，由于其药理学能力可激活CD1d限制性不变的自然杀伤性T（iNKT）细胞而在小鼠模型中具有显着的效力，因此受到了关注。在人类模型中不能很好地复制治疗成功。KRN7000的双重结构修饰，使得在C6上引入了肉桂醛酸酯”

目的/方法：因此，为了深入了解AH10-7对人类变体的结构动力学和选择性机制的分子见解，我们采用了整合的分子动力学模拟和热力学计算来研究KRN7000和AH10-7对hTCR-CD1d激活的抑制作用iNKT。

结果：有趣的是，我们的发现表明AH10-7对hTCR-CD1d表现出更高的亲和力结合和结构效应，这是由于并入了氢肉桂酰基酯部分所介导的，这说明了与“非公共”结合位点残基之间更强的分子间相互作用。

结论：从这项研究中获得的发现进一步揭示了重要的分子和结构观点，这些观点可能有助于设计用于癌症免疫治疗的新型α-GalCer衍生物。