Publications by authors named "Dominic S Alonzi"
Article Synopsis
- - The COVID Moonshot was a collaborative, open-science effort focused on finding a new drug to inhibit the SARS-CoV-2 main protease, which is crucial for the virus's survival.
- - Researchers developed a novel noncovalent, nonpeptidic inhibitor that stands out from existing drugs targeting the same protease, employing advanced techniques like machine learning and high-throughput structural biology.
- - Over 18,000 compound designs, 490 ligand-bound x-ray structures, and extensive assay data were generated and shared openly, creating a comprehensive and accessible knowledge base for future drug discovery efforts against coronaviruses.
Article Synopsis
- Dendritic cells are key players in the immune response to dengue virus (DENV) and are significantly affected by the virus.
- Research shows that specific deoxynojirimycin (DNJ) derivatives can provide antiviral effects against DENV in immature dendritic cells, mirroring results seen in macrophages.
- The antiviral action of DNJ derivatives involves inhibiting an enzyme called ER α-glucosidase I, leading to decreased viral secretion and reduced inflammatory response in infected cells.
Article Synopsis
- - Mucopolysaccharidosis type IIIB is a serious neurological disorder caused by insufficient levels of the enzyme NAGLU, leading to harmful buildup of heparan sulfate in the body.
- - The study investigated a pharmacological chaperone strategy aimed at improving the activity of NAGLU in cells from affected patients, utilizing structures of existing inhibitors to develop new compounds.
- - Among the 17 new iminosugar C-glycosides created, one non-functionalized β-homoiminosugar unexpectedly emerged as the most effective, enhancing mutant NAGLU activity by 2.4 times at optimal concentration.
Severe acute respiratory syndrome coronavirus 2 is the causative pathogen of the COVID-19 pandemic which as of March 29, 2021, has claimed 2 776 175 lives worldwide. Vaccine development efforts focus on the viral trimeric spike glycoprotein as the main target of the humoral immune response. Viral spikes carry glycans that facilitate immune evasion by shielding specific protein epitopes from antibody neutralization, and antigen efficacy is influenced by spike glycoprotein production in vivo.
View Article and Find Full Text PDFUDP-glucose:glycoprotein glucosyltransferase (UGGT) flags misfolded glycoproteins for ER retention. We report crystal structures of full-length Chaetomium thermophilum UGGT (CtUGGT), two CtUGGT double-cysteine mutants, and its TRXL2 domain truncation (CtUGGT-ΔTRXL2). CtUGGT molecular dynamics (MD) simulations capture extended conformations and reveal clamping, bending, and twisting inter-domain movements.
View Article and Find Full Text PDFArticle Synopsis
- Mammalian N-linked glycosylation is essential for the proper functioning and processing of glycoproteins, involving a series of modifications in the endoplasmic reticulum and Golgi apparatus.
- MANEA is a key enzyme that trims N-linked glycans and enables certain glycoproteins to bypass standard trimming processes in the ER.
- The study reveals the structure of MANEA and how it interacts with inhibitors, highlighting its potential for therapeutic applications against diseases like cancer and viral infections by disrupting glycosylation pathways.
Article Synopsis
- - Influenza and dengue viruses are growing global health threats, relying on the host's endoplasmic reticulum for their survival and replication.
- - A study identified a genetic defect in a specific enzyme (ER α-glucosidase I) that provides resistance to these viruses, highlighting it as a potential antiviral target.
- - Research shows that a single dose of a compound called UV-4B can prevent death in infected mice, even if given 48 hours after infection, paving the way for new treatment strategies for viral diseases.
Article Synopsis
- Targeting the endoplasmic reticulum quality control (ERQC) pathway is proposed as a promising antiviral strategy by focusing on two essential ER resident α-glucosidases.
- Researchers have determined the crystal structures of murine α-glucosidase II, revealing important details about its structure and the effects of specific antiviral iminosugar inhibitors, some of which are in clinical trials for dengue fever.
- The study uncovers new regions of the enzyme that affect its function and shows how the enzyme's structure changes when it interacts with glycoproteins, providing insights into its substrate specificity and activity.
Article Synopsis
- * ToP-DNJ, a new antiviral iminosugar-tocopherol conjugate, is designed to target the liver and immune cells for antiviral treatment.
- * The drug effectively inhibits ER α-glucosidase II and shows significant action only in immune cells, highlighting the benefits of combining native metabolites for improved selectivity in drug design.
Glycoproteins traversing the eukaryotic secretory pathway begin life in the endoplasmic reticulum (ER), where their folding is surveyed by the 170-kDa UDP-glucose:glycoprotein glucosyltransferase (UGGT). The enzyme acts as the single glycoprotein folding quality control checkpoint: it selectively reglucosylates misfolded glycoproteins, promotes their association with ER lectins and associated chaperones, and prevents premature secretion from the ER. UGGT has long resisted structural determination and sequence-based domain boundary prediction.
View Article and Find Full Text PDFArticle Synopsis
- * By targeting glucosidases, iminosugars prevent viral proteins from properly interacting with the host's folding machinery, causing misfolding and providing antiviral effects against various viruses.
- * Since iminosugars act on host enzymes rather than the viruses themselves, they are less likely to become ineffective due to viral mutations, highlighting their potential as broad-spectrum antiviral treatments.
Article Synopsis
- Iminosugars, specifically NB-DNJ and MON-DNJ, were tested for safety and antiviral effects against Ebola virus in guinea pigs, showing no adverse effects at administered dosages.
- NB-DNJ indicated some potential efficacy, with 1 out of 4 treated infected guinea pigs surviving and others showing improved health, while MON-DNJ provided no protective benefits.
- However, follow-up studies did not confirm the antiviral effects of iminosugars, suggesting further research is needed to develop more effective versions.
Article Synopsis
- The biosynthesis of enveloped viruses relies on the host cell's endoplasmic reticulum (ER) glycoprotein quality control (QC) machinery, which could be targeted for antiviral development.
- Researchers analyzed the main ERQC enzyme, ER α-glucosidase II (α-GluII), using small-angle X-ray scattering (SAXS) and crystal structures to understand its function and interaction with ligands and antiviral compounds.
- Findings reveal that the enzyme requires conformational changes for optimal function, and targeting specific sites with iminosugar antivirals could enhance drug design for treating viral infections like dengue fever.
Article Synopsis
- Research indicates that iminosugars, previously thought to primarily inhibit α-glucosidases in the endoplasmic reticulum (ER), may have multiple antiviral mechanisms impacting various viral infections, including dengue virus (DENV).
- Celgosivir, a type of bicyclic iminosugar, has shown promise as an antiviral agent in treating DENV in clinical models and has been confirmed to inhibit DENV secretion in human macrophages.
- The study establishes that the antiviral effectiveness of iminosugars against DENV is more closely related to ER α-glucosidase inhibition rather than the processing of glycolipids, highlighting the need for further exploration of iminosugar mechanisms.
The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection.
View Article and Find Full Text PDFArticle Synopsis
- - Iminosugars can inhibit viruses by blocking specific enzymes needed for their replication, making them promising antiviral agents against various viral infections.
- - These compounds are already approved for treating conditions like diabetes and Gaucher's disease, indicating they are generally safe for human use.
- - The study highlights a new iminosugar called UV-12, which shows effectiveness against dengue and influenza in animal models and has favorable drug-like properties, warranting further investigation.
Article Synopsis
- * Research shows that GSL synthesis is crucial for osteoclast activation in MM, and myeloma cells produce GSLs that enhance this activation, particularly GM3.
- * Inhibiting GSL synthesis with drugs like NB-DNJ can prevent OC development, reduce bone damage in MM cases, and shows promise for treating osteolytic bone diseases.
Article Synopsis
- GNE is a key enzyme involved in producing sialic acid, which is important for glycosylation, and mutations in GNE cause GNE myopathy, a rare neuromuscular disorder.
- Research using various models, including patient cells and mice, showed that both neutral and sialylated glycosphingolipids (GSLs) were elevated in GNE myopathy.
- Supplementing with N-acetylmannosamine (ManNAc) reduced GSL levels in affected cells, suggesting a connection between sialic acid synthesis disruption and increased GSLs, indicating potential for GSLs as biomarkers in sialic acid metabolism disorders.
Biologically active conformations of the IgG1 Fc homodimer are maintained by multiple hydrophobic interactions between the protein surface and the N-glycan. The Fc glycan modulates biological effector functions, including antibody-dependent cellular cytotoxicity (ADCC) which is mediated in part through the activatory Fc receptor, FcγRIIIA. Consistent with previous reports, we found that site-directed mutations disrupting the protein-carbohydrate interface (F241A, F243A, V262E, and V264E) increased galactosylation and sialylation of the Fc and, concomitantly, reduced the affinity for FcγRIIIA.
View Article and Find Full Text PDFArticle Synopsis
- The Ho crossed aldol condensation technique enables the synthesis of branched iminosugars, including enantiomers of isoDMDP, isoDGDP, and isoDAB, which are compared to their linear natural product counterparts.
- L-IsoDMDP is synthesized in 11 steps with a 45% yield from d-lyxonolactone and is identified as a strong inhibitor of gut disaccharidases, outperforming the current diabetes drug miglitol in managing hyperglycemia.
- The ability of L-isoDMDP to partially restore function in defective CFTR cells suggests its potential in treating cystic fibrosis, with a comparison to other treatments like miglustat and isoLAB.
Article Synopsis
- Host α-glucosidases I and II are crucial for the proper folding of viral proteins, and their inhibition causes misfolding and decreased virus release.
- CM-10-18, an imino sugar inhibitor, has been shown to protect against dengue virus lethality in mice.
- The study identifies three CM-10-18 derivatives with enhanced antiviral effects against hemorrhagic fever viruses, showing promise as potential treatments for diseases like Marburg and Ebola.
Article Synopsis
- Endoplasmic reticulum-associated degradation (ERAD) is a crucial process that removes misfolded proteins from the endoplasmic reticulum for breakdown by the ubiquitin/proteasome system.
- Researchers studied free oligosaccharides (FOS) from glycoproteins undergoing ERAD to gain insights into the overall mechanisms involved, rather than just focusing on specific model proteins.
- Their findings suggest a new pathway for degrading glycoproteins that have not passed quality control, characterized by unique FOS types produced in the ER, which differ from commonly recognized FOS produced through traditional misfolding routes.
Article Synopsis
- - The study assessed the effectiveness of the iminosugar drug UV-4 in protecting AG129 mice from severe dengue virus (DENV) infections that resemble dengue hemorrhagic fever/dengue shock syndrome.
- - UV-4 demonstrated significant benefits, including reduced mortality, lower levels of the virus in the bloodstream and vital tissues, and diminished inflammatory responses without affecting the production of anti-DENV antibodies.
- - These promising findings support further development of UV-4 as a targeted antiviral treatment for dengue, leading towards phase I human clinical trials.
Article Synopsis
- * It explains that while glucosidases I and II are primarily responsible for this process, endo-α-mannosidase can act as a backup in certain situations, especially when glucosidases are inhibited.
- * The research found that in bovine cells, the endomannosidase has a limited substrate range and is genetically regulated, suggesting it is adapted to function effectively even when other enzymes have reduced activity.
Article Synopsis
- The study introduces a new method for enhancing the accuracy of analyzing oligosaccharide mixtures using HILIC by incorporating an internal standard, specifically 4-aminobenzoic acid ethyl ester (4-ABEE).
- This internal standard allows for more reliable calculations of glucose unit (GU) values by co-injecting 4-ABEE with 2-aminobenzoic acid (2-AA)-labelled oligosaccharides, using both UV absorption and fluorescence detection.
- The innovative approach improves the consistency of GU values by minimizing the impact of gradient variations during the separation process.