Tweaking α -Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics

Author(s): Houda Washah, Clement Agoni, Fisayo A. Olotu, Geraldene Munsamy, Mahmoud E.S. Soliman*

Journal Name: Current Pharmaceutical Biotechnology

Volume 21 , Issue 13 , 2020


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Abstract:

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.

Keywords: Cancer immunotherapy, natural killer T-cells, dual modification, immunotherapeutics, AH10-7 α-galactosylceramide.

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VOLUME: 21
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Year: 2020
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DOI: 10.2174/1389201020666191118103342
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