RESUMO
Chimeric antigen receptor (CAR)-T-based therapeutics are a breakthrough in cancer treatment; however, they are hampered by constitutive activation, which leads to worrisome side effects. Engineering CAR-T cells to be as tightly controllable as possible remains a topic of ongoing investigation. Here, we report a photoswitchable approach that uses a mediator for the at-will regulation of CAR-T cells. This mediator carries dual folate and fluorescein isothiocyanate moieties tethered by an ortho-nitrobenzyl ester photocleavable linker. CAR-T cells were shown to be highly cytotoxic to targeted cells only in the presence of the mediator and acted in a dose-dependent manner. The toxicity of CAR-T cells can be rapidly terminated by cleavage of the mediator, and the effects of CAR-T cells can be activated again by resupplementation with the mediator without compromising tumor therapy. The approach described here provides a direction for enhancing the controllability of CAR-T cells and can likely be applied in other immunotherapies.
Assuntos
Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/terapia , Processos FotoquímicosRESUMO
A novel ligand (6) for copper-catalyzed azide-alkyne cycloaddition (CuAAC) in bioconjugation has been developed. Both in vitro and in vivo experiments indicate that 6 is more efficient and less cytotoxic than the canonical CuAAC ligands. Besides, 6 is easily accessible and can be prepared at gram scale. Our study reveals that 6 might be an ideal CuAAC ligand for bioconjugations.
RESUMO
Benefiting from their unique properties, the development of structurally novel and easily accessible medium rings is of significant interest in the pharmaceutical industry and academic research. However, synthetic access to medium-ring scaffolds is very difficult due to their rigid skeleton and large-angle strains. In this paper, a new class of medium rings bearing bitriazolyls (MRBTs) was designed, synthesized, identified as a promising new skeleton ligand for the Cu(I)-catalyzed click reaction, and used in site-special modification of protein. One of the MRBTs, 3aa, exhibited a turnover number (TON) as high as 55â¯000 and dramatic accelerating effects ( kobs = 1.95 M-1 s-1) and ranked among the most efficient ligands for copper-catalyzed alkyne and azide cycloaddition. Unlike the difficult access to other known medium rings, these 7-12-membered MRBTs can be prepared in straightforward, one-step manner from structurally diverse linear terminal diynes and azides. The unique accessibility and intriguing properties therefore imply their broad application perspectives.
RESUMO
Adenosine diphosphate-ribose (ADP-ribose) and its derivatives play important roles in a series of complex physiological procedures. The design and synthesis of artificial ADP-ribosylated compounds is an efficient way to develop valuable chemical biology tools and discover new drug candidates. However, the synthesis of ADP-ribosylated compounds is currently difficult due to structural complexity, easily broken pyrophosphate bond and high hydrophilicity. In this paper, ADP-ribosyl-N3 was designed and synthesized for the first time. With ADP-ribosyl-N3 as the key precursor, a divergent post-modification strategy was developed to prepare structurally diverse ADP-ribosylated compounds including novel nucleotides and peptides bearing ADP-ribosyl moieties.