A5088242356- Proteoglycans and glycosaminoglycans research
- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Protease and Inhibitor Mechanisms
- SARS-CoV-2 and COVID-19 Research
- Cancer, Hypoxia, and Metabolism
- Influenza Virus Research Studies
- Platelet Disorders and Treatments
- Angiogenesis and VEGF in Cancer
- Gut microbiota and health
- Cystic Fibrosis Research Advances
- Polysaccharides Composition and Applications
- Fibroblast Growth Factor Research
- Growth Hormone and Insulin-like Growth Factors
- Computational Drug Discovery Methods
- Cancer Cells and Metastasis
- Monoclonal and Polyclonal Antibodies Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Click Chemistry and Applications
- Immune Response and Inflammation
- Immunotherapy and Immune Responses
- Herpesvirus Infections and Treatments
- Inflammatory Bowel Disease
- Neonatal Respiratory Health Research
- Connective tissue disorders research
Virginia Commonwealth University
2015-2024
Hunter Holmes McGuire VA Medical Center
2021
Virginia BioTechnology Research Park
2018-2020
Abstract Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using computational strategy on library of 46 656 heparan sulfate hexasaccharides we identified rare sequence consisting consecutive glucuronic acid 2‐ O ‐sulfate residues as targeting HCII. This and four other unique were chemically synthesized. The designed was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, closely...
SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led identification only eight sequences as potent antagonists; results were supported by detailed dual-filter...
Glycosaminoglycans (GAGs) interact with many proteins to regulate processes such as hemostasis, cell adhesion, growth and differentiation viral infection. Yet, majority of these interactions remain poorly understood at a molecular level. A major reason for this state is the phenomenal structural diversity GAGs, which has precluded analysis specificity their interactions. We had earlier presented computational protocol predicting "high-specificity" GAG sequences based on combinatorial virtual...
Identifying smaller sulfated glycan fragments that recognize target proteins with high affinity is highly challenging. In this work, we show microarray screening of 53 small helped identify distinct monosaccharide to tetrasaccharide bind multiple isoforms SARS-CoV-2 spike glycoprotein (SgP) affinity. Our library consisted natural and unnatural sequences a wide range sulfation levels. The features arose from the presence phosphate or fluoro groups on GAG scaffold as well sulfate modification...
Although plasmin inhibitors could be used in multiple disorders, their use has been restricted to preventing blood loss hemostatic dysregulation because of poor efficacy and adverse effects current agents. We reasoned that a new class direct offer better efficacy, selectivity, safety discovered by exploiting allosterism plasmin, protease homologous other allosteric serine proteases. report on the synthesis, biological activity, mechanism action group small molecules, called non-saccharide...
High mobility group box 1 (HMGB1) is an alarmin released from macrophages after infection or inflammation and a biomarker of lung disease progression in patients with cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits the release HMGB1 murine triggered by neutrophil elastase both vivo vitro. shuttles between nucleus cytoplasm. When acetylated at lysine residues nuclear localization signal domains, sequestered cytoplasm fated for secretion. In this study, we...
Although heparan sulfate (HS) has been implicated in facilitating entry of enveloped viruses including herpes simplex virus (HSV), small molecules that effectively compete with this abundant, cell surface macromolecule remain unknown. We reasoned HSV-1 involving its glycoprotein D (gD) binding to HS could be competitively targeted through small, synthetic, nonsaccharide glycosaminoglycan mimetics (NSGMs). Screening a library NSGMs identified distinct group bound gD affinities 8-120 nM....
Chemokines promote directional cell migration through binding to G-protein-coupled receptors, and as such are involved in a large array of developmental, homeostatic pathological processes. They also interact with heparan sulfate (HS), the functional consequences which depend on respective location receptor- HS-binding sites, detail that remains elusive for most chemokines. Here, set up biochemical framework investigate how HS can regulate CXCL13 activity, we solved solution structure...
Glycosaminoglycans (GAGs) are key natural biopolymers that exhibit a range of biological functions including growth and differentiation. Despite this multiplicity function, GAG sequences have not yielded drugs because problems heterogeneity synthesis. Recently, several homogenous non-saccharide glycosaminoglycan mimetics (NSGMs) been reported as agents displaying major therapeutic promise. Yet, it remains unclear whether sulfated NSGMs structurally mimic GAGs. To address this, we developed...
Glycosaminoglycans (GAGs) represent a formidable frontier for chemists, biochemists, biologists, medicinal chemists and drug delivery specialists because of massive structural complexity. GAGs are arguably the most complex, natural linear biopolymers with theoretical diversity orders magnitude higher than proteins nucleic acids. Yet, this remains generally untapped. Computational approaches offer major routes to understand GAG structure dynamics so as enable novel applications these...
The COVID-19 pandemic caused by SARS-CoV-2 is in immediate need of an effective antidote. Although the Spike glycoprotein (SgP) has been shown to bind heparins, structural features this interaction, role a plausible heparan sulfate proteoglycan (HSPG) receptor, and antagonism pathway through small molecules remain unaddressed. Using vitro cellular assay, we demonstrate HSPGs modified 3-O-sulfotransferase isoform-3, but not isoform-5, preferentially increased SgP-mediated cell-to-cell fusion...
MDA-9/Syntenin, a key scaffolding protein and molecular hub involved in diverse range of cell signaling responses, has proved to be challenging target for the design discovery small molecule probes. In this paper, we report on synthesis ligands protein. Genetic algorithm-based computational five-eight step three molecules led with affinities 1-3 µM, 20-60-fold improvement over literature reports. The strategies, coupled structure-dependent gain or loss affinity, afford deduction principles...
Human milk contains biologically important amounts of transforming growth factor-β2 isoform (TGF-β2), which is presumed to protect against inflammatory gut mucosal injury in the neonate. In preclinical models, enterally administered TGF-β2 can experimental necrotizing enterocolitis, an bowel necrosis premature infants. this study, we investigated whether TGF-β bioactivity human preterm could be enhanced for therapeutic purposes by adding recombinant (rTGF-β2) prior feeding. Milk-borne was...
The insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal activation of IGF-1R by its cognate ligand IGF1 inhibited shorter, soluble heparan sulfate (HS) sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, phenomenon directly opposed to traditional relationship known for GAG-protein systems. inhibition arises from smaller...
The structural diversity of natural sulfated glycosaminoglycans (GAGs) presents major promise for discovery chemical biology tools or therapeutic agents. Yet, few GAGs have been identified so far to exhibit this promise. We reasoned that a simple approach identify such is explore sequences containing rare residues, example, 2-O-sulfonated glucuronic acid (GlcAp2S). Genetic algorithm-based computational docking and filtering suggested GlcAp2S heparan sulfate (HS) may highly selective...
Cystic fibrosis (CF) is a disease of dysregulated salt and fluid homeostasis that results in the massive accumulation neutrophil elastase, resulting lung degradation death. The current CF therapy relies on inhaled deoxyribonuclease hypertonic saline but does not address elastolytic lung. We reasoned allosteric agents targeting heparin-binding site elastase would offer therapeutic paradigm. Screening library 60 nonsaccharide glycosaminoglycan mimetics (NSGMs) led to discovery 23 hits against...