A5083361438- Peptidase Inhibition and Analysis
- Diabetes Treatment and Management
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- RNA and protein synthesis mechanisms
- Alcohol Consumption and Health Effects
- Porphyrin Metabolism and Disorders
- Monoclonal and Polyclonal Antibodies Research
- Folate and B Vitamins Research
- Computational Drug Discovery Methods
- Pancreatic function and diabetes
- Glycosylation and Glycoproteins Research
- Metabolism, Diabetes, and Cancer
- Lipoproteins and Cardiovascular Health
- Enzyme Structure and Function
- Carbohydrate Chemistry and Synthesis
- Protein Kinase Regulation and GTPase Signaling
- Molecular Biology Techniques and Applications
- Glycogen Storage Diseases and Myoclonus
- Protease and Inhibitor Mechanisms
- Melanoma and MAPK Pathways
- Crystallization and Solubility Studies
- Estrogen and related hormone effects
- DNA and Nucleic Acid Chemistry
Pfizer (United States)
2009-2023
Biotechnology Research Institute
2003
Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and an important illness older adults. No RSV vaccine currently available. The fusion (F) glycoprotein a key antigen for development, its prefusion conformation target most potent neutralizing antibodies. Here, we describe computational experimental strategy designing immunogens that enhance conformational stability immunogenicity F. We obtained optimized after screening nearly 400...
Abstract Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite substantial progression of our structural understanding GPCR activation small molecule and peptide agonists, molecular mechanism protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure human CCR6 bound its endogenous ligand CCL20 an engineered Go....
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent efficiency, molecular details of binding were revealed by first X-ray crystal structures ligand-bound ASGPR. analogue used to make potent di- trivalent binders Extensive characterization function these compounds rapid ASGPR-dependent cellular uptake in vitro high levels liver/plasma selectivity vivo. Assessment biodistribution rodents prototypical...
Abstract We propose the concept of universal fiducials based on a set pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against fusion protein BRIL, an engineered variant apocytochrome b562a. These sABs can bind to BRIL fused either into loops or termini different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure in complex with affinity-matured sAB (BAG2) that bound all systems tested delineates...
N,N-dimethylglycylamido (DMG) derivatives of 6-demethyl-6-deoxytetracycline and doxycycline bind 5-fold more effectively than tetracycline to the high-affinity binding site on Escherichia coli 70S ribosome, which correlates with a 10-fold increase in potency for inhibition E. cell-free translation. The potencies DMG-doxycycline DMG-6-demethyl-6-deoxytetracycline were unaffected by ribosomal resistance factors Tet(M) Tet(O) translation assays whole-cell bioassays conditional Tet(M)-producing strain.
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators this enzyme represent promising opportunity for the treatment type 2 diabetes. Systemically acting glucokinase (liver pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due activation at low levels pancreas, leading inappropriately excessive insulin secretion. It was therefore postulated that liver selective activator may offer effective glycemic control...
Disrupting the binding interaction between proprotein convertase (PCSK9) and epidermal growth factor-like domain A (EGF-A domain) in low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed synthesized, their structures analyzed solution complex with PCSK9. The most potent peptide had an increased affinity for PCSK9 (KD = 0.6 μM) compared...
Glucokinase is a key regulator of glucose homeostasis and small molecule activators this enzyme represent promising opportunity for the treatment Type 2 diabetes. Several glucokinase have advanced to clinical studies demonstrated efficacy; however, many these early candidates also revealed hypoglycemia as risk. In an effort mitigate risk while maintaining efficacy mechanism, we investigated series substituted 2-methylbenzofurans "partial activators" leading identification...
Cathepsin S, a lysosomal cysteine protease of the papain superfamily, has been implicated in preparation MHC class II αβ-heterodimers for antigen presentation to CD4+ T lymphocytes and is considered potential target autoimmune-disease therapy. Selective inhibition this enzyme may be therapeutically useful attenuating hyperimmune responses number disorders. We determined three-dimensional crystal structures human cathepsin S complex with potent covalent inhibitors, aldehyde inhibitor...
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the has been investigated by crystallographic analysis complex ligand-binding domain alpha at resolution 2.0 A. As other SERMs, lasofoxifene diverts from agonist-bound conformation displacing C-terminal AF-2 helix into site which LXXLL motif coactivator proteins would otherwise be able to bind. achieves this effect occupying space normally filled residue Leu 540, as...
Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be viable target for antidiabetic drugs. As part of the evaluation MAP4K4 as novel target, tool compound, 16 (PF-6260933) lead 17 possessing excellent kinome selectivity suitable properties were delivered to establish proof concept vivo. The medicinal chemistry effort led discovery these compounds is described herein together with vivo pharmacokinetic activity model...
Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and human subjects. A novel series cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized evaluated as inhibitors treatment diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor DPP-IV that selective over other...
Abstract SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator dNTP activators/substrates. In addition, the inactive monomeric dimeric forms enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated CDK1 CDK2 at C-terminal threonine 592 (pSAMHD1), localizing stalled forks (RFs) promote their restart. Although phosphorylation has only a small...
Studies have linked the serine-threonine kinase MAP4K4 to regulation of a number biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With majority members our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose observation carboxylic acid-based intermediates employed in discovery efforts retained high inhibitory potency were devoid TDI The...