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Rational design of red AIEgens with a new core structure from non-emissive heteroaromatics.

ABSTRACT: The development of new aggregation-induced emission (AIE) systems is a hot research topic, from which functional materials with diversified structures and properties are derived. Here, based on rare, non-emissive and highly electron-withdrawing heteroaromatics of 1,4,5,8-tetraazaanthracene (TAA), experimental and theoretical studies reveal that attaching phenyl rotors to TAA is crucial to creating a new N-type AIE core structure. Furthermore, by covalent attachment of electron-donating aromatic amines to the peripheries of the AIE core, red AIEgens could be obtained readily, which exhibit excellent photostability for long-term lysosome tracking. This work not only provides a new strategy to design heterocycle-containing AIEgens from non-emissive heteroaromatics but also stimulates more their applications as bio-imaging materials.

SUBMITTER: Chen M

PROVIDER: S-EPMC6194487 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Rational design of red AIEgens with a new core structure from non-emissive heteroaromatics.

Chen Ming M Hu Xianglong X Liu Junkai J Li Baixue B Leung Nelson L C NLC Viglianti Lucia L Cheung Tsz Shing TS Sung Herman H Y HHY Kwok Ryan T K RTK Williams Ian D ID Qin Anjun A Lam Jacky W Y JWY Tang Ben Zhong BZ

Chemical science 20180821 40

The development of new aggregation-induced emission (AIE) systems is a hot research topic, from which functional materials with diversified structures and properties are derived. Here, based on rare, non-emissive and highly electron-withdrawing heteroaromatics of 1,4,5,8-tetraazaanthracene (TAA), experimental and theoretical studies reveal that attaching phenyl rotors to TAA is crucial to creating a new N-type AIE core structure. Furthermore, by covalent attachment of electron-donating aromatic ...[more]

PMID: 30429992

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Project description:Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D?=??1?-?5??M. Beyond the affinity threshold at K D?<?1??M we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma.

Dataset Information

Rational design of red AIEgens with a new core structure from non-emissive heteroaromatics.

Publications

Rational design of red AIEgens with a new core structure from non-emissive heteroaromatics.

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