Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

carbohydrates, drug development,

There are multiple challenges in developing carbohydrate/cyclodextrin-based drugs that we also face at CarboHyde every day. One is to develop proper analytical techniques, which are especially difficult for biological samples and if the drug is not a single compound but a mixture of components (just like HP-b-CD used in Niemann-Pick C). While HP-b-CD has been promising in vitro and in vivo, a clear understanding of the mechanism(s) of action is lacking.
That being said, we particularly welcome the study disclosing method for a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. Investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. The following changes in the proteome suggest that HP-b-CD promotes exocytosis in this neuron-like model. Utilizing state-of-the-art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP-b-CD as a potential therapeutic.
Antony Cougnoux, (Karolinska Institutet), Melissa Pergande, Fidel Serna-Perez, and Stephanie Cologna (University of Illinois Chicago)

See the full article here: Investigation of 2-Hydroxypropyl-β-Cyclodextrin Treatment in a Neuronal-Like Cell Model of Niemann–Pick Type C Using Quantitative Proteomics

Thymoquinone: Hydroxypropyl-β-cyclodextrin Loaded Bacterial Cellulose for the Management of Wounds

carbohydrates

Yet another cool carbohydrate combination is now proposed for wound healing. Iza Radecka, Sam S., and their team at University of Wolverhampton incorporated thymoquinone within bacterial cellulose, utilizing cyclodextrin as a novel method of solubilizing hydrophobic compounds.

See the full article here: Thymoquinone: Hydroxypropyl-β-cyclodextrin Loaded Bacterial Cellulose for the Management of Wounds

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics

Today's cyclodextrin,

today’s cyclodextrin:
is a nice piece of research from a collaboration between Università di Pisa and CarboHyde‘s CSO, Milo Malanga investigating the use of silylated-acetylated cyclodextrins as #chiral #sensors for the enantiodiscrimination of fluorinated anesthetics

Alessandra Recchimurzo, Federica Balzano, Gloria Uccello Barretta, Luca Gherardi and Federica Aiello

See the full article here: Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics

An Engineered Nanosugar Enables Rapid and Sustained Glucose-Responsive Insulin Delivery in Diabetic Mice

carbohydrates, drug delivery

Glucose-responsive insulin-delivery platforms sensitive to dynamic glucose concentration fluctuations and providing both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. RMIT University and Monash University present biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release. The nanoparticles are “nanosugars” bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nano complexes. A single subcutaneous injection of nano complexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, this results in optimal blood glucose levels for up to 13 h. The nano complexes’ morphology is key to controlling rapid and extended glucose-regulated insulin delivery in vivo. These studies reveal that the injected nano complexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on natural and biodegradable nano sugar.
Rong XU, Sukhvir Kaur Bhangu, Karly Sourris, Domitilla Vanni, Marc-Antoine Sani, Karen Alt, Be’eri Niego, Dr. Quinn A. Besford, Brendan Dyett, Irena (Iśka) Carmichael, Mark Cooper, Christoph Hagemeyer, Francesca Cavalieri, et al

See the full article here: An Engineered Nanosugar Enables Rapid and Sustained Glucose-Responsive Insulin Delivery in Diabetic Mice

Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

carbohydrates, drug discovery,

This great research team recently presented a new series of 1,1-diarylthiogalactoside for targeting the Pseudomonas aeruginosa LecA. The highest affinity (Kd = 160 nM) was obtained for a divalent ligand containing two galactoside units. A monovalent ligand displayed high affinity toward LecA (Kd = 1 μM) and strong antibiofilm activity while others induced a significant antibiofilm activity with no associated bactericidal activity.
Alexandre Bruneau, Emilie Gillon, Aurélie Furiga, Etienne BRACHET, Mouad Alami, Christine Roques, Annabelle Varrot, Anne Imberty, Samir Messaoudi 

See the full article here: Discovery of potent 1,1-diarylthiogalactoside glycomimetic inhibitors of Pseudomonas aeruginosa LecA with antibiofilm properties

Chemistry, structure and function of approved oligonucleotide therapeutics

carbohydrates

Chemistry, structure and function of approved #oligonucleotide therapeutics by Martin Egli (Vanderbilt University) and Muthiah (Mano) Manoharan (Alnylam Pharmaceuticals).
Eighteen nucleic acid therapeutics have been approved for the treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. 
Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2′-fluoro-RNA, 2′-O-methyl RNA, and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2′-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability, and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.

See the full article here: Chemistry, structure and function of approved oligonucleotide therapeutics