NAD(P)H: quinone oxidoreductase 1 activatable toll-like receptor 7/8 agonist designed for precise immunotherapy

Guo, Li; Xu, Yongxiao; Kong, Xiaojie; Gu, Liuwei; Qin, Yuling; Li, Wu

doi:10.1039/d3cc00663h

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Design and Working Principles Of Small Molecule-based Tlr-7/...1

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2024

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Cited by 2 publications

(1 citation statement)

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“…5). 71 The caged R848-QPA can achieve innate immune activation through intracellular overexpression of NQO1, while exhibiting reduced activity under conditions of NQO1-deprivation. After internalizing tumour cells, NQO1 induces the two-electron reduction of R848-QPA by forming an intramolecular cyclization lactone, resulting in the cleavage of the quinone trimethyl lock unit and subsequent release of R848 agonists.…”

Section: Design and Working Principles Of Small Molecule-based Tlr-7/...mentioning

confidence: 99%

Molecule engineering strategy of toll-like receptor 7/8 agonists designed for potentiating immune stimuli activation

Gu,

Kong,

et al. 2024

Chem. Commun.

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Section: Design and Working Principles Of Small Molecule-based Tlr-7/...mentioning

confidence: 99%

Molecule engineering strategy of toll-like receptor 7/8 agonists designed for potentiating immune stimuli activation

Gu,

Kong,

et al. 2024

Chem. Commun.

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Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis

Xu,

Chau,

Lee

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin ( MLu ) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of MLu as a photodynamic therapy sensitizer in cells. Two analogs of MLu , bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin ( MGd ), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin ( MMn ), is ineffective as both a photocatalyst and a ROS generator. Neither MGd nor MMn was found to trigger pyroptosis under the conditions where MLu was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with MLu at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.

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NAD(P)H: quinone oxidoreductase 1 activatable toll-like receptor 7/8 agonist designed for precise immunotherapy

Abstract: A NQO1-responsive precursor, named R848-QPA, has been developed for evoking anti-tumor immune response. This strategy can provide a new opinion for the development of tumor microenvironment-responsive prodrugs for antitumor immunotherapy.

Cited by 2 publications

References 22 publications

Molecule engineering strategy of toll-like receptor 7/8 agonists designed for potentiating immune stimuli activation

Molecule engineering strategy of toll-like receptor 7/8 agonists designed for potentiating immune stimuli activation

Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis

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