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The synthesis of two protected tetrasaccharide pentenyl glycosides with diarabinan and digalactan branching related to the pectic polysaccharide rhamnogalacturonan I is reported. The strategy relies on the coupling of N-phenyl trifluoroacetimidate disaccharide donors to a common rhamnosyl acceptor. The resulting trisaccharide thioglycosides were finally coupled to an n-pentenyl galactoside acceptor to access the two protected branched tetrasaccharides.

Parkinson’s disease involves the accumulation of aggregates of ɑ-synuclein (ɑ-Syn), both as intracellular fibrils and as cytotoxic soluble oligomeric species (ɑSOs). No available nanobodies show exclusive preference for the oligomeric state of ɑ-Syn. Here, we describe two nanobodies NB1 and NB2, obtained by immunizing a llama with αSOs, which bind ɑSOs with nM affinity and do not show any measurable affinity for monomeric ɑ-Syn or ɑ-Syn fibrils. While the nanobodies were not useful for high-throughput screening for therapeutic compounds or high-resolution cryoEM, they retained their ability to discriminate against ɑ-Syn monomers in brain tissue and were able to detect ɑ-Syn aggregates in diseased tissue. In addition, αSO binding affinity was improved by DNA-scaffold-mediated NB1 dimerization compared to scaffolded monomeric NB1. The nanobodies promote the uptake of ɑSOs into HEK93 cells via the Sortilin receptor pathway. Their absolute specificity for oligomeric ɑ-Syn makes them promising reagents to detect oligomeric ɑ-Syn in patient samples.

In the past, development of tankyrase inhibitors has focused on the ADP-ribosyltransferase domain. Targeting tankyrases ability to interact with protein substrates through their ARC domains represents an alternative strategy to be explored as a therapeutic approach against specific protein-protein interactions. In this paper, we employed a FRET-based assay to identify ARC4-binding compounds by screening the EU-OPENSCREEN Pilot and Commercials Diversity libraries. We discovered an effective series of compounds with the same scaffold and through chemical synthesis we obtained the compound S8 (ARCher-142), which binds selectively to ARC4 with potency of 8 µM. NMR analysis and X-ray crystallography allowed us to identify the binding site in ARC4 and to rationalize the observed selectivity. Despite binding exclusively to ARC4, the inhibitor can attenuate the WNT/β-catenin signaling pathway in cells. Our work demonstrates that targeting single ARC domains is possible, offering an inhibition approach tailored to tankyrase ARC4 inhibition. Tankyrases impact a variety of cellular processes by binding proteins through their ARC domains and the inhibition of these scaffolding functions represents an alternative therapeutic approach to catalytic inhibitors. With a FRET-based high-throughput screening of the EU-OPENSCREEN Pilot and Commercials Diversity libraries we discovered a pyrrolone-based scaffold that is interestingly selective towards ARC4, despite the high conservation of the ARC binding site. Our synthesized compound S8 (ARCher-142) displays an 8 µM potency for TNKS2 ARC4. With NMR and X-ray crystallography we demonstrate that S8 (ARCher-142) competes with the peptide optimized for binding and extends to a unique hydrophobic sub-pocket of ARC4. The compound attenuates the WNT/β-catenin signaling pathway in cells and interestingly offers the possibility to target specific protein-protein interactions mediated by ARC4, paving the way for the development of a pyrrolone-based class of tankyrase scaffolding inhibitors.

Background Candida auris is an emerging multidrug-resistant yeast pathogen with several risk factors, including diabetes mellitus (DM). This study analyzed the epidemiological aspects of C. auris patients with DM (CaDM). We searched related databases without time and linguistic limitations for studies reporting DM among patients with proven C. auris infection (PCaI). Methods A meta-analysis was conducted using STATA (version 17) with the random-effects model based on DerSimonian and Laird methods, employing the metan and metaprop commands. Results A total of 43 studies were included. Our random effect model reached the pooled prevalence of 36% ( p value: < 0.001) for DM among patients with PCaI. The prevalence of DM among PCaI patients is almost 40% higher than non-auris patients (OR: 1.40; p value: < 0.001). Men with DM were 46% lower susceptibility to C. auris infection compared to women (OR: 0.54; p value: 0.905). However, this was not statistically significant. Our results showed that 57% of unadjusted all-cause mortality were recorded among CaDM patients ( p value: 0.03). Chronic kidney diseases (CKD), hypertension (HTN), and respiratory diseases (RD) were the most frequent comorbidities. Central venous catheter (CVC), ICU stay, and mechanical ventilation were the most frequent hospital-related factors. Conclusions We concluded that despite the significant advances in diagnosis and treatments, prevalence, risk, and mortality rates of C. auris infection and diabetes mellitus remained high.