In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.
IDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors.
The effect of Mitracarpus scaber on carbon tetrachloride-induced acute liver damage in the rat has been evaluated. Results showed that treatment with Mitracarpus scaber decoction resulted in significant hepatoprotection against CCl4-induced liver injury both in-vivo and in-vitro. In-vivo, Mitracarpus scaber pretreatment reduced levels of serum glutamate-oxalate-transaminase (P < 0.01 for 250, 500 and 1000 mg kg(-1)) and serum glutamate-pyruvate-transaminase (P < 0.05 for 250 mg kg(-1) and P < 0.01 for 1000 mg kg(-1)) previously increased by administration of CCl4. In-vitro results indicated that addition to the culture medium of Mitracarpus scaber extracts significantly reduced glutamate-oxalate-transaminase (P < 0.05 for 100 microg mL(-1) and P < 0.01 for 10 and 1000 microg mL(-1)) and lactate dehydrogenase activity (P < 0.05 for 10 microg mL(-1)). Mitracarpus treatment also resulted in a good ( > 93%) survival rate for the CCl4-intoxicated hepatocytes as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Moreover, as in the in-vitro assay, Mitracarpus scaber had radical-scavenging properties, shown by its reaction with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (EC50, the extract concentration resulting in a 50% reduction in the absorbance of DPPH blank solution, = 41.64+/-1.5 microg mL(-1)). The results of this study showed that Mitracarpus scaber had antihepatotoxic potential, a finding which supports the validity of traditional usage of this drug in Mali for the treatment of liver diseases.
<b><i>Background:</i></b> Specific drugs and/or immunotherapies are widely used to treat allergies, but drug-induced adverse effects recently led to explore new additional strategies. We studied whether a probiotic preparation (iPROB®; Anallergo SpA, Florence, Italy) is effective in allergic patients and the mechanisms underlying clinical outcomes. <b><i>Methods:</i></b> Eligible patients (<i>n</i> = 28), all suffering from allergic rhinitis with/without bronchial asthma, were consecutively recruited at the Allergology Medical Unit (Novara, Italy) and treated with this probiotic. From each patient, we collected blood and stool samples at the baseline, after 60 days of probiotic supplementation, and after 60 days from probiotic discontinuation. In each blood sample, the percentage of hematopoietic stem cells, eosinophils, and basophils was measured by FACS. To analyze stool microbiota composition, genomic DNA was extracted, bacterial 16S DNA libraries sequenced by Illumina platform (Miseq), and raw sequences processed. Generated data were statistically analyzed. <b><i>Results:</i></b> Probiotic-treated patients showed a significant decrease in Average Rhinitis Total Symptom Score (<i>d</i> = −10.5714), and Visual Analog Scale (<i>d</i> = −2.00) clinical indices, as well as important improvements in quality of life. In whole blood, a significant reduction in the percentage of activated eosinophils and basophils was determined, and this effect persisted after specific cell stimulation. Consistently, the serum levels of IL-4 and IL-5 decreased after probiotic treatment, suggesting a reduction in the Th2 cytokine profile. In addition, microbiome genomic analysis (<i>n</i> = 6) showed an increase in microbiome biodiversity, which positively correlates with clinical and cellular data. <b><i>Conclusion:</i></b> Present study suggests that iPROB® preparation has clinical/biological properties to be a valid add-on supplementation in allergic patients with asthma and rhinitis.
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