Highlights d Purified cADPR directly activates the human TRPM2 channel (hTRPM2) d Docking and simulation dynamics predict the binding pocket of cADPR in hTRPM2 d The binding affinity of cADPR with TRPM2 is higher than that of ADPR by SPR assay d The binding pattern of ADPR is different from that of cADPR with hTRPM2

No abstract

CD38 is a multi‐functional signaling enzyme that catalyzes the biosynthesis of two calcium‐mobilizing second messengers: cyclic ADP‐ribose and nicotinic acid adenine dinucleotide phosphate. It also regulates intracellular nicotinamide adenine dinucleotide (NAD) contents, associated with multiple pathophysiological processes such as aging and cancer. As such, enzymatic inhibitors of CD38 offer great potential in drug development. Here, through virtual screening and enzymatic assays, we discovered compound LX‐102, which targets CD38 on the side opposite its enzymatic pocket with a binding affinity of 7.7 μm. It inhibits the NADase activity of CD38 with an IC50 of 14.9 μm. Surface plasmon resonance (SPR) and hydrogen/deuterium exchange and mass spectrometry experiments verified that LX‐102 competitively binds to the epitope of the therapeutic SAR 650984 antibody in an allosteric manner. Molecular dynamics simulation was performed to demonstrate the binding dynamics of CD38 with the allosteric ligand. In summary, we established that the cavity to which SAR 650984 binds was an allosteric site and was accessible for the rational design of small chemical modulators of CD38. The lead compound LX‐102 that we identified in this study could also be a useful tool for probing CD38 functions and promoting drug discovery.

No abstract

Pyroptosis is accompanied by immunogenic mediators’ release and serves as an innovative strategy to reprogram tumor microenvironments. However, damaged mitochondria, the origin of pyroptosis, are frequently eliminated by mitophagy, which will severely impair pyroptosis-elicited immune activation. Herein, black phosphorus nanosheets (BP) are employed as a pyroptosis inducer delivery and mitophagy flux blocking system since the degradation of BP could impair lysosomal function by altering the pH within lysosomes. The pyroptosis inducer of lonidamine (LND) was precoupled with the mitochondrial target moiety of triphenylphosphonium to facilitate the occurrence of pyroptosis. The mitochondria-targeting LND-modified BP (BPTLD) were further encapsulated into the macrophage membrane to endow the BPTLD with blood-brain barrier penetration and tumor-targeting capability. The antitumor activities of membrane-encapsulated BPTLD (M@BPTLD) were investigated using a murine orthotopic glioblastoma model. The results demonstrated that the engineered nanosystem of M@BPTLD could target the mitochondria, and induce as well as reinforce pyroptosis via mitophagy flux blocking, thereby boosting the release of immune-activated factors to promote the maturation of dendritic cells. Furthermore, upon near-infrared (NIR) irradiation, M@BPTLD induced stronger mitochondrial oxidative stress, which further advanced robust immunogenic pyroptosis in glioblastoma cells. Thus, this study utilized the autophagy flux inhibition and phototherapy performance of BP to amplify LND-mediated pyroptosis, which might greatly contribute to the development of pyroptosis nanomodulators.