Effect of Probiotic Bacteria on the Gut Microbiome of Mice with Lipopolysaccharide-Induced Inflammation.

The role of lipopolysaccharide (LPS) in the development of diseases is clear, but the specific mechanisms remain poorly understood. This study aimed to investigate the microbiome aberrations in the guts of mice against the background of LPS, as well as the anti-inflammatory effect of probiotic supplementation with Lactobacillus plantarum from the gut, a mix of commercial probiotic lactic acid bacteria, and Weissella confusa isolated from milk using next-generation sequencing. LPS injections were found to induce inflammatory changes in the intestinal mucosa. These morphological changes were accompanied by a shift in the microbiota. We found no significant changes in the microbiome with probiotic supplementation compared to the LPS group. However, when Lactobacillus plantarum and a mix of commercial probiotic lactic acid bacteria were used, the intestinal mucosa was restored. Weissella confusa did not contribute to the morphological changes of the intestinal wall or the microbiome. Changes in the microbiome were observed with probiotic supplementation of Lactobacillus plantarum and a mix of commercial probiotic lactic acid bacteria compared to the control group. In addition, when Lactobacillus plantarum was used, we observed a decrease in the enrichment of the homocysteine and cysteine interconversion pathways with an increase in the L-histidine degradation pathway.

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines.

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Bifunctional small molecules that mediate the degradation of extracellular proteins.

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

Neutralization of Pathogenic Fungi with Small-Molecule Immunotherapeutics.

Systemic fungal infections represent an important public health concern, and new antifungal agents are highly desirable. Herein, we describe the design, synthesis, and biological evaluation of a novel class of antifungal compounds called antibody-recruiting molecules targeting fungi (ARM-Fs). Our approach relies on the use of non-peptidic small molecules, which selectively bind fungal cells and recruit endogenous antibodies to their surfaces, resulting in immune-mediated clearance. Using the opportunistic fungal pathogen Candida albicans as a model, we identified a highly specific bifunctional molecule able to mediate the engulfment and phagocytosis of C. albicans cells by human immune cells in biologically relevant functional assays. This work represents a novel therapeutic approach to treating fungal illness with significant potential to complement and/or combine with existing treatment strategies.