Plicera (afegostat tartrate) / Amicus - LARVOL DELTA

Isofagomine-coumarin hybrids: bridging cancer and Alzheimer's disease. (PubMed, Chem Biol Interact) - "3D Holotomographic microscopy, through continuous live-cell imaging, proved mitotic arrest followed by apoptotic events to be involved in their mode of action. Azasugar-coumarin hybrids constitute promising multifaceted molecules in terms of therapeutics or prevention of neurodegeneration and cancer."

Journal • Alzheimer's Disease • CNS Disorders • Oncology • Pain

Stereoselective ring contractions in glycopyranosides as key-step en route to isoiminosugars. (PubMed, Carbohydr Res) - "A LiAlH4 induced stereoselective 1,2-shift of C-4 to C-2 in O-2 tosylated d-glucopyranosides leading to ring-contracted C-2 branched d-ribofuranosides allows for convenient access to either C-2- or C-5a-elongated analogues of powerful β-galactosidase inhibitor 4-epi-isofagomine. Mechanistic insights into the synthetic key-step, as well as its broader application targeting d-gluco mimicking isoiminosugars are provided."

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An isofagomine analogue with an amidine group in the 1,6-position. (PubMed, R Soc Open Sci) - "Density functional theory calculations showed that this compound has a remarkably different charge distribution compared with isofagomine. This may explain why the amidine is a poor glycosidase inhibitor (IC50 > 50 µM against all tested enzymes) compared with isofagomine."

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Copper(II) complexes of 2-hydroxy-1-naphthaldehyde Schiff bases: synthesis, in vitro activity and computational studies. (PubMed, Future Med Chem) - "The work recognizes latent active compounds for novel β-glucoronidase inhibitors, by further support these may be harnessed for the development of potent drugs."

Journal • Preclinical

A concise synthetic approach for isoiminosugars. (PubMed, Carbohydr Res) - "The key step relies on a stereospecific 1,2-hydride shift in O-2 tosylated glycopyranosides leading to C-2 branched glycofuranosides. This approach enables a 4-step synthesis of powerful β-galactosidase inhibitor 4-epi-isofagomine starting from a simple d-glucopyranoside."

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Microplate enzyme assay for hydrolase activity of TcdB glycosyltransferase domain (ACS-Fall 2024) - "The assay accurately recapitulates the affinity of isofagomine and other inhibitors. This assay will facilitate library screens to find inhibitors with respect to the UDP binding site."

Infectious Disease

Bioinformatic, Enzymatic, and Structural Characterization of Trichuris suis Hexosaminidase HEX-2. (PubMed, Biochemistry) - "HEX-2 has an almost neutral pH optimum and is best inhibited by GalNAc-isofagomine...Its X-ray crystal structure, the first of any subfamily 1 GH20 hexosaminidase to be determined, is closest to Streptococcus pneumoniae GH20C and the active site is predicted to be compatible with accommodating both GalNAc and GlcNAc. The new structure extends our knowledge about this large enzyme family, particularly as T. suis HEX-2 also possesses the key glutamate residue found in human hexosaminidases of either GH20 subfamily, including HEXD whose biological function remains elusive."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease. (PubMed, Commun Chem) - "Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities...Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising β-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 μM in recombinant human GCase activity in Gaucher cell lines."

Journal • Gaucher Disease • Genetic Disorders • Metabolic Disorders

Isofagomine Inhibits Multiple TcdB Variants and Protects Mice from Clostridioides difficile-Induced Mortality. (PubMed, ACS Infect Dis) - "Isofagomine treatment of mouse C. difficile infection also permitted the recovery of the gastrointestinal microbiota, an important barrier to preventing recurring C. difficile infection. The broad specificity of isofagomine supports its potential as a prophylactic to protect against C. difficile-induced morbidity and mortality."

Journal • Preclinical • Gastrointestinal Disorder • Infectious Disease

Expression and metabolism profiles of CVT associated with inflammatory responses and oxygen carrier ability in the brain. (PubMed, CNS Neurosci Ther) - "We explored and analyzed the gene expression and metabolomic characteristics of CVT, revealed the specific inflammatory reaction mechanism of CVT and found the markers in transcriptome and metabolism levels. It points out the direction for CVT early diagnosis and treatment."

Journal • Cardiovascular • Hematological Disorders • Inflammation • Ischemic stroke • Thrombosis • Venous Thromboembolism • IL1A • TNFRSF14

Structural basis for inhibition of a GH116 β-glucosidase and its missense mutants by GBA2 inhibitors: Crystallographic and quantum chemical study. (PubMed, Chem Biol Interact) - "In line with the experimental data for the inhibitors that have been tested, the favorable interaction energy between the inhibitors and the TxGH116 protein followed the trend: isofagomine > 1-deoxynojirimycin > glucoimidazole > N-butyl-deoxynojirimycin ≈ N-nonyl-deoxynojirimycin > conduritol B epoxide ≈ azepane 1 > azepane 2. The obtained structural and energetic properties and comparison to the GBA2 model can lead to understanding of structural requirement for inhibitor binding in GH116 to aid the design of high potency GBA2 inhibitors."

Journal • Gaucher Disease • Genetic Disorders • Metabolic Disorders

Design and synthesis of iso-allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase. (PubMed, Org Biomol Chem) - "Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC = 9.3 μM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine."

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"Crab beignets at Loretta's Authentic Pralines at 2101 N Rampart St. in Marigny. Not at their touristy branch in French Market. Because it's savory it doesn't count in your number of times to eat sweet beignets in a day. Miss Loretta supports local kids in creative ways" (@sara_paredesrn)

Rottlerin Stimulates Exosome/Microvesicle Release Via the Increase of Ceramide Levels Mediated by Ampk in an In Vitro Model of Intracellular Lipid Accumulation. (PubMed, Biomedicines) - "The reduction of hexosylceramide levels by rottlerin was attributed to the increase of β-glucosidase (glucosylceramidase) activity, and the effects of rottlerin were abrogated by β-glucosidase inhibitors such as isofagomine D-tartrate and AMP-deoxynojirimycin...The results showed that the decrease in intracellular lipid deposition induced by rottlerin was mediated by β-glucosidase activation and exosome/microvesicle release via the AMPK pathway. Rottlerin consumption could represent an additional health benefit in lysosomal deposition diseases."

Journal • Preclinical • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • AMPK

Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol. (PubMed, Int J Mol Sci) - "The sugar mimetic isofagomine (IFG) strongly inhibits β-Glu, while ABX exerts its inhibitory effect in the micromolar range. Additional β-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize β-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification."

Journal • Gaucher Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Respiratory Diseases

Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues. (PubMed, Nat Commun) - "Iminosugars, isofagomine and noeuromycin mimic the transition state and inhibit both TcdA and TcdB by forming ternary complexes with Tcd and UDP, a product of the TcdA- and TcdB-catalyzed reactions. Both iminosugars prevent TcdA- and TcdB-induced cytotoxicity in cultured mammalian cells by preventing glucosylation of Rho GTPases. Iminosugar transition state analogues of the Tcd toxins show potential as therapeutics for C. difficile pathology."

Journal • Infectious Disease

[VIRTUAL] Inhibition of clostridium difficile TcdA and TcdB toxins with transition state analogues (ACS-Sp 2021) - "Isofagomine and noeuromycin were the most potent iminosugars identified and display uncompetitive inhibition, suggesting that both iminosugars act by binding to the enzyme-UDP complex...Finally, we confirmed that both iminosugars protected Tcd-induced rounding of IMR90 cells as visualized by light microscopy. We also showed through western blot analysis of IMR90 cell lysates that both iminosugars prevent Tcd induced toxicity by preventing the glycosylation of Rho GTPases, thereby demonstrating potential as new treatments for C. difficile."

Gastrointestinal Disorder • Inflammation

Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity. (PubMed, Commun Biol) - "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. 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."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor

[VIRTUAL] NOVEL THERAPIES FOR GBA-PARKINSON DISEASE (ADPD 2021) - "We have used the GCase chaperones ambroxol and isofagomine in in vitro and in vivo models of the N370S and L444P GBA mutations, these represent the commonest pathogenic mutations associated with PD...Alternative strategies include substrate reduction therapy using venglustat, a glucosylceramide synthase inhibitor. This drug is currently in a Phase II study in GBA-PD to assess safety and target engagement, with an extension to assess impact on clinical progression over 12 months. Gene-based therapies are also in Phase II development with the intention of using CND-delivered wild-type GBA and vector to increase GCase levels and production."

CNS Disorders • Gaucher Disease • Gene Therapies • Genetic Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • GBA

Nickel(II) carbonyl, ammonia, and aceto-nitrile complexes supported by a pyridine dipyrrolide pincer ligand. (PubMed, Acta Crystallogr E Crystallogr Commun) - "The CO stretch of the nickel-bound carbon monoxide ligand of [pyrrpy]Ni(CO) has been observed at 2101 cm. The ammonia and aceto-nitrile complexes, [pyrrpy]Ni(NH) and [pyrrpy]Ni(NCMe) feature all-nitro-gen coordination spheres around nickel consisting of different N-donor ligand types."

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Substituent position of iminocyclitols determines the potency and selectivity for gut microbial xenobiotic-reactivating enzymes. (PubMed, J Med Chem) - "N1 of uronic isofagomine (2) made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition (K ≥ 11 nM)...In comparison with 2, there is 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs."

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[VIRTUAL] New compound increasing glucocerebrosidase activity on primary cell cultures obtained from patients with GBA-associated Parkinson’s disease (MDS Congress 2020) - "Last data showed that small molecule chaperones as ambroxol or isofagomine (IFG) could cross the BBB and help mutant GCase refold and traffic correctly to lysosomes... N2 compound and IFG increase GCase activity in macrophages from GBA-PD patients. It is interesting to note that the effectiveness of restoring the GCase activity strongly depended on the type of GBA mutations. In the case of N370S the effectiveness in restoration of GCase activity was compatible with well-known GCase molecular chaperone IFG."

CNS Disorders • Parkinson's Disease • GBA

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine. (PubMed, Molecules) - "Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for G-gangliosidosis and Morquio B disease."

Journal • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Imino- and azasugar protonation inside human acid β-glucosidase, the enzyme defective in Gaucher disease. (PubMed, Angew Chem Int Ed Engl) - "In this study we show, using photoinduced electron transfer (PET), that 1-deoxynojirimycin and isofagomine derivatives are protonated by human acid β-glucosidase when bound even if completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1-deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme."

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Assessing costs and benefits of improved soil quality management in remediation projects: A study of an urban site contaminated with PAH and metals. (PubMed, Sci Total Environ) - "A framework for ecological risk assessments (ERAs) within the APPLICERA - APPLICable site-specific Environmental Risk Assessment research project promotes assessments that consider other soil quality parameters than only contaminant concentrations...Although the presented Tier 3 ERA is more expensive and time-consuming than the more traditional Tier 1 ERA approach, it has the potential to lower the costs of remediation actions, decrease greenhouse gas emissions, reduce other environmental impacts, and minimise socio-economic losses. Furthermore, the remediation actions stemming from the Tier 3 ERA were predicted to exert far less negative ES effects than the actions proposed based on the results of the Tier 1 ERA."

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