Tweaking α -Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics.
AH10-7 α-galactosylceramide
Cancer immunotherapy
dual modification
immunotherapeutics
natural killer T-cells
Journal
Current pharmaceutical biotechnology
ISSN: 1873-4316
Titre abrégé: Curr Pharm Biotechnol
Pays: Netherlands
ID NLM: 100960530
Informations de publication
Date de publication:
2020
2020
Historique:
received:
23
04
2019
revised:
29
06
2019
accepted:
04
11
2019
pubmed:
19
11
2019
medline:
19
12
2020
entrez:
19
11
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 31738132
pii: CPB-EPUB-102424
doi: 10.2174/1389201020666191118103342
doi:
Substances chimiques
Adjuvants, Immunologic
0
Antigens, CD1d
0
CD1D protein, human
0
Galactosylceramides
0
Receptors, Antigen, T-Cell
0
KRN 7000
WX671898JF
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1354-1367Informations de copyright
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