Entropy-driven binding of gut bacterial ß-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.

Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of ß-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial ß-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 µM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.

Dissecting the Structure-Activity Relationship of Galectin-Ligand Interactions.

Galectins are ß-galactoside-binding proteins. As carbohydrate-binding proteins, they participate in intracellular trafficking, cell adhesion, and cell-cell signaling. Accumulating evidence indicates that they play a pivotal role in numerous physiological and pathological activities, such as the regulation on cancer progression, inflammation, immune response, and bacterial and viral infections. Galectins have drawn much attention as targets for therapeutic interventions. Several molecules have been developed as galectin inhibitors. In particular, TD139, a thiodigalactoside derivative, is currently examined in clinical trials for the treatment of idiopathic pulmonary fibrosis. Herein, we provide an in-depth review on the development of galectin inhibitors, aiming at the dissection of the structure-activity relationship to demonstrate how inhibitors interact with galectin(s). We especially integrate the structural information established by X-ray crystallography with several biophysical methods to offer, not only in-depth understanding at the molecular level, but also insights to tackle the existing challenges.

Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice.

Parkinson's disease (PD) is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra. Intranasal drug administration may be useful for Parkinson's treatment because this route avoids first-pass metabolism and increases bioavailability in the brain. In this study, we investigated the neuroprotection/neurorestoration effect of dopamine D3 receptor (D3R) agonists administered via both intranasal and subcutaneous routes in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD mouse model. Furthermore, we employed D3R knock-out mice to validate the dependence on D3R signaling. We found that in wild-type mice, but not D3 receptor knockout mice, both intranasal and subcutaneous administration of D3R agonists rescue dopamine (DA) depletion in the striatum as well as DA neuronal death in the substantia nigra after MPTP treatment. Moreover, subcutaneous 7-OH-DPAT administration significantly improved gait performance (stride length and overall running speed) of MPTP-lesioned mice after 7 and 14 days of recovery. In addition, the distribution of D3 agonist 7-OH-DPAT was measured in designated brain areas by mass spectrometry analysis after subcutaneous and intranasal administration. Our data suggest that intranasal administration of D3R agonist would be a practical approach to treat PD.