5 results on '"Aimee Reynolds"'
Search Results
2. Discovery of a Novel, Highly Potent and Orally Bioavailable Pyrrolidinone Indole Series of Irreversible Myeloperoxidase (MPO) Inhibitors
- Author
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Jean B. Regard, Tyler J. Harrison, Jake Axford, Laura Axford, Lac Lee, Xianglin Ren, Lin Deng, Aimee Reynolds, Justin Mao, Qian Liu, Anup Patnaik, Evan Cohick, Micah Hollis-Symynkywicz, Sally Loi, Simone Riek, David Dunstan, MooJe Sung, Nathaniel F. Ware, Lawrence G. Hamann, Jovita Marcinkeviciene, Andrew W. Patterson, and Martin L. Marro
- Subjects
History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
3. BET bromodomain inhibitors regulate keratinocyte plasticity
- Author
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Gabi Schutzius, Michael Faller, Aimee Reynolds, Ralph Tiedt, Julia Klopp, Florian Fuchs, Laure C. Bouchez, Federico Tortelli, Nelly Leroy, Jonathan J. Turner, Guglielmo Roma, Simona Cotesta, Armin Beyerbach, Peter Drueckes, Shola M Richards, Debora Bonenfant, Heinrich Rueeger, Heinz Ruffner, Jutta Blank, Rémi Terranova, Peter Tarsa, Frederic Grandjean, Florian Nigsch, Sebastian Bergling, Natalie Dales, Alexandra Aebi, Paul W. Manley, Markus Schirle, Christian Kolter, Tewis Bouwmeester, Rene Hemmig, Sukhdeep Sahambi, Lori L. Jennings, Walter Carbone, Felix Lohmann, Alfred Zimmerlin, Jun Li, Susan Kirkland, Steffen Renner, Mathias Frederiksen, Vickie Driver, Amy Berwick, Florence Zink, Jason R. Thomas, Andrea Vaupel, Chris Dimitri, Vito Guagnano, Viktoria Gruber, Malvina Louis, Caroline Gubser Keller, and Adrian Salathe
- Subjects
Keratinocytes ,Male ,Protein family ,Transcription, Genetic ,Phenotypic screening ,Primary Cell Culture ,Cell Cycle Proteins ,Wounds, Nonpenetrating ,Small Molecule Libraries ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Re-Epithelialization ,In vivo ,Skin Ulcer ,medicine ,Fluorescence Resonance Energy Transfer ,Animals ,Humans ,Protein Isoforms ,Protein Precursors ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,integumentary system ,Epidermis (botany) ,business.industry ,030302 biochemistry & molecular biology ,Cell Biology ,In vitro ,Bromodomain ,High-Throughput Screening Assays ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer research ,Epidermis ,Keratinocyte ,business ,Ex vivo ,Transcription Factors - Abstract
Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.
- Published
- 2019
4. Discovery of 1-((6-Aminopyridin-3-yl)Methyl)-3-(4-Bromophenyl)Urea as a Potent, Irreversible Myeloperoxidase Inhibitor
- Author
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Sally Loi, Lac Lee, Jean Regard, Dominique Custeau, Andrew Patterson, Lin Deng, Julien Papillon, Aimee Reynolds, Tyler Harrison, Micah Hollis-Symynkywicz, Jovita Marcinkeviciene, Lawrence G. Hamann, Anup Patnaik, Xianglin Ren, Jutta Blank, Nigel Casson, Laura Axford, Toshiyuki Honda, Lisa Ames, Lihe Zhang, and Martin L. Marro
- Subjects
0301 basic medicine ,Male ,Aminopyridines ,Biological Availability ,Pharmacology ,medicine.disease_cause ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Thyroid peroxidase ,In vivo ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Aorta ,Peroxidase ,chemistry.chemical_classification ,Inflammation ,biology ,Chemistry ,Bioavailability ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Enzyme ,Myeloperoxidase ,Urea ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery ,Oxidative stress ,Ex vivo - Abstract
Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.
- Published
- 2018
5. Real Time Measurement of PEG Shedding from Lipid Nanoparticles in Serum via NMR Spectroscopy
- Author
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Noah P. Gardner, Keith Bowman, Chandra Vargeese, Stephen C Wilson, Srinivasan Rajan, Sunita Yadav, Stephany Michelle Standley, Jeremy Baryza, Adnan Zunic, Cameron Lee, Aimee Reynolds, Mark E Keegan, Vahide Ozlem Agir, and Parul Parmar
- Subjects
Male ,Small interfering RNA ,Liposome ,Magnetic Resonance Spectroscopy ,Chemistry ,Pharmaceutical Science ,Nanoparticle ,Nanotechnology ,Lipids ,Micelle ,Polyethylene Glycols ,Rats ,Supramolecular assembly ,Surface coating ,Liposomes ,Drug Discovery ,Drug delivery ,PEG ratio ,Animals ,Nanoparticles ,Molecular Medicine ,RNA, Small Interfering ,Blood Chemical Analysis - Abstract
Small interfering RNA (siRNA) is a novel therapeutic modality that benefits from nanoparticle mediated delivery. The most clinically advanced siRNA-containing nanoparticles are polymer-coated supramolecular assemblies of siRNA and lipids (lipid nanoparticles or LNPs), which protect the siRNA from nucleases, modulate pharmacokinetics of the siRNA, and enable selective delivery of siRNA to target cells. Understanding the mechanisms of assembly and delivery of such systems is complicated by the complexity of the dynamic supramolecular assembly as well as by its subsequent interactions with the biological milieu. We have developed an ex vivo method that provides insight into how LNPs behave when contacted with biological fluids. Pulsed gradient spin echo (PGSE) NMR was used to directly measure the kinetics of poly(ethylene) glycol (PEG) shedding from siRNA encapsulated LNPs in rat serum. The method represents a molecularly specific, real-time, quantitative, and label-free way to monitor the behavior of a nanoparticle surface coating. We believe that this method has broad implications in gaining mechanistic insights into how nanoparticle-based drug delivery vehicles behave in biofluids and is versatile enough to be applied to a diversity of systems.
- Published
- 2015
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