Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti‐inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation‐related diseases.

Five N-methyl-N-R-N,N-bis(2-hydroxyethyl) ammonium bromides (R = -benzyl (chloride, BNQAS), -dodecyl (C12QAS), -tetradecyl (C14QAS), -hexadecyl (C16QAS), -octadecyl (C18QAS)) were prepared based on N-methyldiethanolamine (MDEA) and halohydrocarbon. Five QAS were characterized by FTIR, NMR, and MS. BNQAS, C12QAS, C14QAS, and C16QAS were confirmed by X-ray single-crystal diffraction. Their antibacterial properties indicated good antibacterial abilities against E. coli, S. aureus, B. subtilis, especially C12QAS with the best antibacterial ability (100% to E. coli, 95.65% to S. aureus, and 91.41% to B. subtilis). In addition, C12QAS also displayed the best antifungal activities than BNQAS and C18QAS against Cytospora mandshurica, Botryosphaeria ribis, Physalospora piricola, and Glomerella cingulata with the ratio of full marks. The strategy provides a facile way to design and develop new types of antibacterial drugs for application in preventing the fruit rot, especially apple.

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Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a-d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, α-H-tococcus, β-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2). TEM and SEM images of E. coli and S. aureus morphologies treated with 7d showed that the antibacterial mechanism might be the QAS fixing on cell wall surfaces and puncturing to result in the release of bacterial cytoplasm. This study provides new information of QAS, which could be used to design novel antimicrobial agents applied in clinic or agriculture.

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