A5017187552- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- SARS-CoV-2 and COVID-19 Research
- Immune Cell Function and Interaction
- Antimicrobial Resistance in Staphylococcus
- Viral Infectious Diseases and Gene Expression in Insects
- Antibiotic Resistance in Bacteria
- Malaria Research and Control
- Bacterial Genetics and Biotechnology
- Tuberculosis Research and Epidemiology
- Respiratory viral infections research
- Neuropeptides and Animal Physiology
- Research on Leishmaniasis Studies
- Microbial Natural Products and Biosynthesis
- Clostridium difficile and Clostridium perfringens research
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- Cancer therapeutics and mechanisms
- Trypanosoma species research and implications
- Chemical Synthesis and Analysis
- interferon and immune responses
- Drug Transport and Resistance Mechanisms
- Biochemical Analysis and Sensing Techniques
- Lipoproteins and Cardiovascular Health
Merck & Co., Inc., Rahway, NJ, USA (United States)
2014-2024
United States Military Academy
2018-2022
Walter and Eliza Hall Institute of Medical Research
2021
GTx (United States)
2021
Torrey Pines Institute For Molecular Studies
2008
Scripps Research Institute
2008
Cubist Pharmaceuticals (United States)
2001
NKT Therapeutics (United States)
2001
University of Connecticut
1998
Rockefeller University
1989-1991
Dietary cholesterol consumption and intestinal absorption contribute to plasma levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays critical role in cholesterol. NPC1L1 expression enriched brush border membrane enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit substantial reduction absorbed cholesterol, which...
ABSTRACT The contribution of seven known and nine predicted genes or operons associated with multidrug resistance to the susceptibility Escherichia coli W3110 was assessed for 20 different classes antimicrobial compounds that include antibiotics, antiseptics, detergents, dyes. Strains were constructed deletions in major facilitator superfamily, nodulation-cell division family, small ATP-binding cassette outer membrane factors. agar dilution MICs 35 determined strains (MDR) pumps. Deletions...
The Gpbar1 [G-protein-coupled BA (bile acid) receptor 1] is a recently identified cell-surface that can bind and activated by BAs, but its physiological role unclear. Using targeted deletion of the gene in mice, we show plays critical maintenance bile lipid homoeostasis. Mice lacking expression were viable, developed normally did not significant difference levels cholesterol, BAs or any other constituents. However, they form cholesterol gallstones when fed cholic acid-containing high-fat...
Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled (GPCR) and target for the development of therapeutics obesity. The structure-based MCH-R1 other GPCR antagonists hampered by lack an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands used explicitly to shape optimize binding site) followed docking-based virtual screening. Top scoring compounds identified...
Artemisin combination therapy (ACT) is the main treatment option for malaria, which caused by intracellular parasite Plasmodium. However, increased resistance to ACT highlights importance of finding new drugs. Recently, aspartic proteases Plasmepsin IX and X (PMIX PMX) were identified as promising drug targets. In this study, we describe dual inhibitors PMIX PMX, including WM382, that block multiple stages Plasmodium life cycle. We demonstrate PMX a master modulator merozoite invasion direct...
The symptoms of Clostridium difficile infections are caused by two exotoxins, TcdA and TcdB, which target host colonocytes binding to unknown cell surface receptors, at least in part via their combined repetitive oligopeptide (CROP) domains. A combination the anti-TcdA antibody actoxumab anti-TcdB bezlotoxumab is currently under development for prevention recurrent C. infections. We demonstrate here through various biophysical approaches that binds specific regions within N-terminal half...
New inhibitors of wall teichoic acid biosynthesis restore susceptibility drug-resistant staphylococci to β-lactam antibiotics.
The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. production β-lactamase key mechanism contributing imipenem in P. aeruginosa. Relebactam novel inhibitor, active against class A C β-lactamases, that shown restore susceptibility. In series studies, we assessed the interaction relebactam with mechanisms involved carbapenem what extent might overcome non-susceptibility.
Orphan G-protein-coupled receptors are a large class of whose cognate ligands unknown. SP9155 (also referred to as AQ27 and GPR103) is an orphan receptor originally cloned from human brain cDNA library. was found be predominantly expressed in brain, heart, kidney, retina, testis. Phylogenetic analysis shows that shares high homology with Orexin, NPFF, cholecystokinin (CCK) receptors, but identification the endogenous ligand for has not been reported. In this study, we have used novel method...
Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for development novel antifungals. Characterization inhibitors one enzyme in GPI anchor pathway, Gwt1, has generated interest exploration targets this pathway further study. Utilizing a chemical genomics-based screening platform referred to as Candida albicans fitness test (CaFT), we have identified Gwt1 second glycosylphosphatidylinositol (GPI) cell wall Mcd4. We...
Abstract : Missense substitutions in the presenilin 1 (PS1) and 2 (PS2) proteins are associated with early‐onset familial Alzheimer's disease. We have used yeast‐two‐hybrid coimmunoprecipitation methods to show that large cytoplasmic loop domains of PS1 PS2 interact specifically three members armadillo protein family, including β‐catenin, p0071, a novel neuronal‐specific protein—neural plakophilin‐related (NPRAP). The NPRAP interaction occurs between arm repeats residues 372‐399 at...
The histamine H<sub>4</sub> receptor is a novel G-protein–coupled with unique pharmacological profile. distribution of mRNA suggests that it may play role in the regulation immune function, particularly respect to allergy and asthma. To define histamine-binding site this receptor, molecular modeling site-directed mutagenesis were used predict alter amino acids residing pocket. effects these alterations on binding activation then assessed. Our results indicate Asp<sup>94</sup> (3.32)...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces degradation of low-density lipoprotein receptor (LDLR) in the liver. It is being pursued as a therapeutic target for LDL-cholesterol reduction. Earlier genome-wide gene expression studies showed that PCSK9 over-expression HepG2 cells resulted up-regulation genes cholesterol biosynthesis and down-regulation stress response pathways; however, it was not known whether these changes were directly regulated by or secondary to...
Modern medicine is founded on the discovery of penicillin and subsequent small molecules that inhibit bacterial peptidoglycan (PG) cell wall synthesis. However, new chemically mechanistically distinct classes PG inhibitors has become exceedingly rare, prompting speculation intracellular enzymes involved in precursor synthesis are not 'druggable' targets. Here, we describe a β-lactam potentiation screen to identify augment activity β-lactams against methicillin-resistant Staphylococcus aureus...
Clostridium difficile is a major nosocomial pathogen that produces two exotoxins, TcdA and TcdB, with TcdB thought to be the primary determinant in human disease. are large, multidomain proteins, each harboring cytotoxic glucosyltransferase domain delivered into cytosol from endosomes via translocation after receptor-mediated endocytosis of toxins cell surface. Although there currently no known host receptors for TcdA, three cell-surface have been identified: CSPG4, NECTIN3, FZD1/2/7. The...
ABSTRACT Molnupiravir, an oral prodrug of N-hydroxycytidine (NHC), previously demonstrated broad in vitro antiviral activity against multiple RNA viruses and has shown a high barrier to the development resistance. Here, we present NHC recent SARS-CoV-2 variants results resistance selection studies better understand potential for viral NHC. omicron (BA.1, BA.1.1, BA.2, BA.4, BA.4.6, BA.5, BQ.1.1, XBB.1, XBB.1.5), alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), lambda (C.37),...
Trypanosomes and related protozoan parasites lack glutathione reductase possess instead a closely enzyme that serves as the reductant of bis(glutathione)-spermidine conjugate, trypanothione. The human parasite enzymes have mutually exclusive substrate specificities, providing route for design therapeutic agents by specific inhibition enzyme. We report here three-dimensional structure trypanothione from Crithidia fasciculata show it resembles reductase. In particular, core surrounding...
A molecular model of the human melanin-concentrating hormone (MCH) peptide was constructed and docked into a helical, bacteriorhodopsin-based recently identified MCH receptor. From this hormone-receptor complex, potential sites agonist-receptor interaction were identified, site-directed mutagenesis used to substitute residues predicted reside within receptor binding pocket. Substitution Asp<sup>123</sup>(3.32) in third transmembrane domain resulted loss detectable <sup>125</sup>I-MCH...
ABSTRACT Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA TcdB. Actoxumab bezlotoxumab human monoclonal antibodies that neutralize cytotoxic/cytopathic effects TcdB, respectively. In a phase II clinical study, actoxumab-bezlotoxumab combination reduced rate CDI recurrence in patients who were also treated with standard-of-care antibiotics. However, it is not known whether antibody will be...