A5013975673- Retinoids in leukemia and cellular processes
- Advanced Fluorescence Microscopy Techniques
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Retinal Development and Disorders
- Chemical Synthesis and Analysis
- Cancer, Hypoxia, and Metabolism
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Click Chemistry and Applications
- Amino Acid Enzymes and Metabolism
- Crystallization and Solubility Studies
- Nanoplatforms for cancer theranostics
- Ubiquitin and proteasome pathways
- Biochemical and Molecular Research
- Microbial Metabolites in Food Biotechnology
- Food composition and properties
- ATP Synthase and ATPases Research
- Synthesis and biological activity
- Biochemical Acid Research Studies
- Crystallography and molecular interactions
- Microbial Metabolic Engineering and Bioproduction
- Adenosine and Purinergic Signaling
- Pancreatic function and diabetes
- Biotin and Related Studies
Cayman Chemical (United States)
2018-2025
Michigan State University
2014-2024
University of Tehran
2017
Abstract UDP‐3‐ O ‐( R ‐3‐hydroxymyristoyl)‐ N ‐acetylglucosamine deacetylase (LpxC) is a Zn 2+ that essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 ( ‐(( S )‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1 ,2 )‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was first LpxC inhibitor to reach human clinical testing and discovered have dose‐limiting cardiovascular toxicity transient hypotension without compensatory tachycardia. Herein we...
<title>Abstract</title> Aryl-fluorosulfates are mild electrophiles that very stable in biological media and vivo can efficiently react with the side chains of Lys, Tyr, or His residues, when properly juxtaposed by a high-affinity ligand. A more powerful approach to derive novel ligands would consist starting from covalent adduct building ligand off those initial interactions. While this strategy has been proven for Cys molecular fragments containing targeting such as acrylamides,...
Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening unique small molecules retaining capacity for selective BLVRB inhibition as novel platelet-enhancing strategy. Two classes are identified, NMR spectroscopy co-crystallization studies confirm binding...
Modulating disease-relevant protein–protein interactions (PPIs) using pharmacological tools is a critical step toward the design of novel therapeutic strategies. Over years, however, targeting PPIs has proven very challenging task owing to large interfacial areas. Our recent efforts identified possible routes for potent and selective inhibitors structure-based covalent Lys residues. In this present study, we report on design, synthesis, characterizations first Lys-covalent BH3 peptide that...
Several novel and effective cysteine targeting (Cys) covalent drugs are in clinical use. However, the target area containing a druggable Cys residue is limited. Therefore, methods for creating that different residues being looked for; examples of such ligands include those lysine (Lys) tyrosine (Tyr). Though histidine (His) side chain more frequently found protein binding locations has higher desirable nucleophilicity, surprisingly limited research been done to specifically this residue,...
Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase (GOT1)] support cellular redox homeostasis. As such, small molecule inhibitors target GOT1 could serve starting points for development of new therapies cancer. We ran high-throughput...
Covalent drugs provide pharmacodynamic and pharmacokinetic advantages over reversible agents. However, covalent strategies have been developed mostly to target cysteine (Cys) residues, which are rarely found in binding sites. Among other nucleophilic residues that could be principle used for the design of drugs, histidine (His) has not given proper attention despite being an attractive residue pursue but underexplored. Aryl fluorosulfates, a mild electrophile is very stable biological media,...
Branching enzymes (BEs) are essential in the biosynthesis of starch and glycogen play critical roles determining fine structure these polymers. The substrates BEs long carbohydrate chains that interact with via multiple binding sites on enzyme's surface. By controlling branched-chain length distribution, can mediate physiological properties moieties; however, mechanism structural determinants this specificity remain mysterious. In study, we identify a large dodecaose surface rice BE I (BEI)...
Cellular retinol-binding proteins (CRBPs) I and II, which are members of the intracellular lipid-binding protein (iLBP) family, retinoid chaperones that responsible for transport delivery both retinol retinal. Although structures retinol-bound CRBPI CRBPII known, no structure a retinal-bound CRBP has been reported. In addition, human (hCRBPII) shows partial occupancy noncanonical conformation in binding pocket. Here, hCRBPII with fully occupying pocket It is further shown derivative seen...
Protein conformational switches or allosteric proteins play a key role in the regulation of many essential biological pathways. Nonetheless, implementation protein design applications has proven challenging, with only few known examples that are not derivatives naturally occurring systems. We have discovered domain-swapped (DS) dimer hCRBPII undergoes large and robust change upon retinal binding, making it potentially powerful template for switches. Atomic resolution structures apo-...
Several investigational nitric oxide donors were originally created to correct vascular endothelial dysfunction in cardiovascular diseases. These 48 compounds contain an urea-like moiety attached the well-known NO isosorbide 2- and 5-mononitrate. CR-0305 CR-0202 synthesized found be nontoxic cell lines HMEC-1, A549/hACE2 VeroE6. induced vasodilation human coronary arteries ex vivo. Since can also have antiviral properties, a study of drug-protein interactions with SARS-CoV-2 was undertaken...
Human cellular retinol binding protein II (hCRBPII) was used as a engineering platform to rationally regulate absorptive and emissive properties of covalently bound fluorogenic dye. We demonstrate the thio-dapoxyl analog via formation protonated imine between an active site lysine residue chromophore's aldehyde. Rational manipulation electrostatics pocket results in 204 nm shift absorption 131 emission. The is readily expressed mammalian systems binds with exogenously delivered fluorophore...
Domain-swapping is a mechanism for evolving new protein structure from extant scaffolds, and has been an efficient protein-engineering strategy tailoring functional diversity. However, domain swapping can only be exploited if it controlled, especially in cases where various folds coexist. Herein, we describe the of domain-swapped trimer iLBP family member hCRBPII, suggest trimerization. It further shown that trimerization favored by strategic installation disulfide bond, thus demonstrating...
The activity of the receptor tyrosine kinase EphA4 has been implicated in several pathologies including oncology (gastric and pancreatic cancers) neurodegenerative diseases (amyotrophic lateral sclerosis Alzheimer's disease). However, advances validating as a possible drug target have limited by lack suitable pharmacological inhibitors. Recently, we reported on design potent agonistic agents targeting its ligand binding domain (LBD). Based previous studies with phage display cyclic peptide...
Urea transport protein B, the product of gene SLC14A1 , facilitates urea, water and urea analogues across cell membranes. mRNA is overexpressed in human vascular endothelial cells culture under hypoxic (1% oxygen) conditions compared with normoxia. This leads to out likely contributes reduction eNOS (endothelial nitric oxide synthase) pathway activity hypoxia. NO has antiviral activity. Novel compounds were developed by binding a urea-like moiety backbone generic agent isosorbide...