Medicine and Health Sciences Commons^™

Cerium Dioxide, A Jekyll And Hyde Nanomaterial, Can Increase Basal And Decrease Elevated Inflammation And Oxidative Stress, Robert Yokel, Marsha L. Ensor, Hemendra J. Vekaria, Patrick G. Sullivan, David J. Feola, Arnold Stromberg, Michael T. Tseng, Douglas A. Harrison

Pharmaceutical Sciences Faculty Publications

It was hypothesized that the catalyst nanoceria can increase oxidative

stress/inflammation from the basal state and reduce it from the elevated state .

Nanoceria are cleared by macrophages. To test the hypothesis, M0 (non-polarized),

M1- (classically activated, pro-inflammatory), and M2-like (alternatively activated,

regulatory phenotype) RAW 264.7 macrophages were nanoceria exposed. Responses

were quantified by arginase activity, IL-1ß level, cell oxygen consumption rate (OCR),

the glycolysis stress test (GST), morphology determined by light microscopy,

macrophage phenotype marker expression and morphology using a novel three

dimensional immunohistochemical method, and RT-qPCR. Nanoceria blocked

arginase and IL-1ß effects, increased M0 cell OCR and GST …

Sex Differences In Kappa Opioid Receptor Agonist Mediated Attenuation Of Chemotherapy-Induced Neuropathic Pain In Mice, Kelly F. Paton, Dan Luo, Anne C. La Flamme, Thomas E. Prisinzano, Bronwyn M. Kivell

Pharmaceutical Sciences Faculty Publications

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and …

Similarly Efficacious Anti-Malarial Drugs Sj733 And Pyronaridine Differ In Their Ability To Remove Circulating Parasites In Mice, Arya Sheelanair, Aleksandra S. Romanczuk, Rosemary A. Aogo, Rohit Nemai Haldar, Lianne I. M. Lansink, Deborah Cromer, Yandira G. Salinas, R. Kiplin Guy, James S. Mccarthy, Miles P. Davenport, Ashraful Haque, David S. Khoury

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.

METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine …

Direct Nose To The Brain Nanomedicine Delivery Presents A Formidable Challenge, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

This advanced review describes the anatomical and physiological barriers and mechanisms impacting nanomedicine translocation from the nasal cavity directly to the brain. There are significant physiological and anatomical differences in the nasal cavity, olfactory area, and airflow reaching the olfactory epithelium between humans and experimentally studied species that should be considered when extrapolating experimental results to humans. Mucus, transporters, and tight junction proteins present barriers to material translocation across the olfactory epithelium. Uptake of nanoparticles through the olfactory mucosa and translocation to the brain can be intracellular via cranial nerves (intraneuronal) or other cells of the olfactory epithelium, or extracellular …

Total Synthesis Of Decahydroquinoline Poison Frog Alkaloids Ent-Cis-195a And Cis-211a, Takuya Okada, Naizhen Wu, Katsuki Takashima, Jungoh Ishimura, Hiroyuki Morita, Takuya Ito, Takeshi Kodama, Yuhei Yamasaki, Shin-Ichi Akanuma, Yoshiyuki Kubo, Ken-Ichi Hosoya, Hiroshi Tsuneki, Tsutomu Wada, Toshiyasu Sasaoka, Takahiro Shimizu, Hideki Sakai, Linda P. Dwoskin, Syed R. Hussaini, Ralph A. Saporito, Naoki Toyooka

Pharmaceutical Sciences Faculty Publications

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from the common key intermediate 11 in a divergent fashion, and the absolute stereochemistry of natural cis-211A was determined to be 2R, 4aR, 5R, 6S, and 8aS. Interestingly, the absolute configuration of the parent decahydroquinoline nuclei of cis-211A was the mirror image of that …

Landomycins As Glutathione-Depleting Agents And Natural Fluorescent Probes For Cellular Michael Adduct-Dependent Quinone Metabolism, Alessio Terenzi, Mery La Franca, Sushilla Van Schoonhoven, Rostyslav Panchuk, Álvaro Martínez, Petra Heffeter, Redding Gober, Christine Pirker, Petra Vician, Christian R. Kowol, Rostyslav Stoika, Luca Salassa, Jürgen Rohr, Walter Berger

Pharmaceutical Sciences Faculty Publications

Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While …

Rapid-Onset Anti-Stress Effects Of A Kappa-Opioid Receptor Antagonist, Ly2795050, Against Immobility In An Open Space Swim Paradigm In Male And Female Mice, Caroline Baynard, Thomas E. Prisinzano, Eduardo R. Butelman

Pharmaceutical Sciences Faculty Publications

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the …

Autoradiographic Localization Of [3h]-Nisoxetine Binding Sites In The Cns Of Male And Female Japanese Quail, Shannon E. Eaton, James R. Pauly, Deann M. Hopkins, Chana K. Akins

Pharmaceutical Sciences Faculty Publications

Background

In the central nervous system of mammals, transporters localized on the presynaptic nerve terminals regulate the reuptake of neurotransmitters. These transporters are selective for a specific neurotransmitter such as dopamine (DA) and norepinephrine (NE). Specifically in the synapse, the dopamine transporter (DAT) reuptakes DA and the norepinephrine transporter (NET) reuptakes NE. However previous research has found that avian species do not have a gene for DAT, and therefore, birds may be using the NET to clear both NE and DA from the synapse. The current study aimed to extend this finding by localizing NET expression in male and female …

Neuron-Derived Extracellular Vesicles Modulate Microglia Activation And Function, Hui Peng, Brock T. Harvey, Christopher I. Richards, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of …

Design, Synthesis, And Preliminary Evaluation Of A Potential Synthetic Opioid Rescue Agent, Sidnee L. Hedrick, Dan Luo, Sophia Kaska, Kumar Kulldeep Niloy, Karen Jackson, Rupam Sarma, Jamie Horn, Caroline Baynard, Markos Leggas, Eduardo R. Butelman, Mary Jeanne Kreek, Thomas E. Prisinzano

Pharmaceutical Sciences Faculty Publications

BACKGROUND: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, …

Endophytes Of Brazilian Medicinal Plants With Activity Against Phytopathogens, Jucélia Iantas, Daiani Cristina Savi, Renata Da Silva Schibelbein, Sandriele Aparecida Noriler, Beatriz Marques Assad, Guilherme Dilarri, Henrique Ferreira, Jürgen Rohr, Jon S. Thorson, Khaled A. Shaaban, Chirlei Glienke

Pharmaceutical Sciences Faculty Publications

Plant diseases caused by phytopathogens are responsible for significant crop losses worldwide. Resistance induction and biological control have been exploited in agriculture due to their enormous potential. In this study, we investigated the antimicrobial potential of endophytic fungi of leaves and petioles of medicinal plants Vochysia divergens and Stryphnodendron adstringens located in two regions of high diversity in Brazil, Pantanal, and Cerrado, respectively. We recovered 1,304 fungal isolates and based on the characteristics of the culture, were assigned to 159 phenotypes. One isolate was selected as representative of each phenotype and studied for antimicrobial activity against phytopathogens. Isolates with better …

Genomic Data From Nsclc Tumors Reveals Correlation Between Shp-2 Activity And Pd-L1 Expression And Suggests Synergy In Combining Shp-2 And Pd-1/Pd-L1 Inhibitors, Keller J. Toral, Mark A. Wuenschel, Esther P. Black

Pharmaceutical Sciences Faculty Publications

The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition …

Innovative Computational Methods For Pharmaceutical Problem Solving A Review Part I: The Drug Development Process, Heather R. Campbell, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Computational methods have provided pharmaceutical scientists and engineers a means to go beyond what's possible with experimental testing alone. Providing a means to study active pharmaceutical ingredients (API), excipients, and drug interactions at or near-atomic levels. This paper provides a review of this and other innovative computational methods used for solving pharmaceutical problems throughout the drug development process. Part one of two this paper will emphasize the role of computational methods and game theory in solving pharmaceutical challenges.

Innovative Computational Methods For Pharmaceutical Problem Solving A Review Part Ii: Serious Gaming, Heather R. Campbell, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Serious gaming has begun to take a foothold in pharmaceutical problem-solving. Companies such as Akili's Interactive are seeing success in the form of positive clinical trial results and FDA approval of digital therapeutics. Academic researchers have begun exploring novel uses for serious gaming in the way of protein design and more with promising results. This paper provides a review of such topics in addition to topics of game repurposing- repurposing a game originally intended for entertainment into a serious game-such as Minecraft and America's Army. Reviewing these topics this paper shows the utility of serious gaming as a tool for …

Laser Irradiation As A Novel Alternative To Detach Intact Particulate Matter Collected On Air Filters, Seyed-Mohammadreza Samaee, Rahim Molaei, Robert A. Yokel, Hedieh Pazokian

Pharmaceutical Sciences Faculty Publications

Airborne particulate matter (PM) is collected on specific filters. For subsequent testing, the PM should be detached intact from the filter. Liquid extraction (LE), the standard method to detach PM from air filter surfaces, is challenging and can be tedious. Laser irradiation has been used to characterize PM on filters, but not to detach PM from filters for subsequent testing. A feasibility study was conducted to assess the potential of laser irradiation to detach PM from air filters. Laser-detached PM was deposited on a pre-weighed glass plate. PM detachment and collection were conducted in a single step. PM-coated air filters …

Monetary Incentives For Producing Counterfeit, Adulterated, And Misbranded Medicine: Case Studies And Examples, Heather R. Campbell, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Background: Pharmaceutical fraud can be very profitable. Those working in pharmaceuticals are in a tempting position as the nature of the product and supply is complex, making detection of fraud difficult and expensive. However, a reliable pharmaceutical supply can often be a life-or-death situation for patients. Thus, when detection of fraud occurs, a Regulator's Dilemma often emerges (recall a drug for which a supplier is the sole source, or allow a substandard product to be sold)—generally resulting in pharmaceutical companies receiving minimal penalties even for the worst acts. Despite pharmaceutical companies' unique leverage over regulators and profitability, studies are rare …

The Preparation Temperature Influences The Physicochemical Nature And Activity Of Nanoceria, Robert A. Yokel, Wendel Wohlleben, Johannes Georg Keller, Matthew L. Hancock, Jason M. Unrine, D. Allan Butterfield, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Cerium oxide nanoparticles, so-called nanoceria, are engineered nanomaterials prepared by many methods that result in products with varying physicochemical properties and applications. Those used industrially are often calcined, an example is NM-212. Other nanoceria have beneficial pharmaceutical properties and are often prepared by solvothermal synthesis. Solvothermally synthesized nanoceria dissolve in acidic environments, accelerated by carboxylic acids. NM-212 dissolution has been reported to be minimal. To gain insight into the role of high-temperature exposure on nanoceria dissolution, product susceptibility to carboxylic acid-accelerated dissolution, and its effect on biological and catalytic properties of nanoceria, the dissolution of NM-212, a solvothermally synthesized nanoceria …

Functional Activation Of Newborn Neurons Following Alcohol-Induced Reactive Neurogenesis, Natalie N. Nawarawong, Chelsea G. Nickell, Deann M. Hopkins, James R. Pauly, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Abstinence after alcohol dependence leads to structural and functional recovery in many regions of the brain, especially the hippocampus. Significant increases in neural stem cell (NSC) proliferation and subsequent “reactive neurogenesis” coincides with structural recovery in hippocampal dentate gyrus (DG). However, whether these reactively born neurons are integrated appropriately into neural circuits remains unknown. Therefore, adult male rats were exposed to a binge model of alcohol dependence. On day 7 of abstinence, the peak of reactive NSC proliferation, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. After six weeks, rats underwent Morris Water Maze (MWM) training then were …

Correction To Some Statements About Aluminum In Sulaiman Et Al., Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Sitosterolemia: Twenty Years Of Discovery Of The Function Of Abcg5abcg8, Kori Williams, Allison Segard, Gregory A. Graf

Pharmaceutical Sciences Faculty Publications

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty …

Clinical Pharmacology And Dosing Regimen Optimization Of Neonatal Opioid Withdrawal Syndrome Treatments, Fei Tang, Chee M. Ng, Henrietta S. Bada, Markos Leggas

Pharmaceutical Sciences Faculty Publications

In this paper, we review the management of neonatal opioid withdrawal syndrome (NOWS) and clinical pharmacology of primary treatment agents in NOWS, including morphine, methadone, buprenorphine, clonidine, and phenobarbital. Pharmacologic treatment strategies in NOWS have been mostly empirical, and heterogeneity in dosing regimens adds to the difficulty of extrapolating study results to broader patient populations. As population pharmacokinetics (PKs) of pharmacologic agents in NOWS become more well-defined and knowledge of patient-specific factors affecting treatment outcomes continue to accumulate, PK/pharmacodynamic modeling and simulation will be powerful tools to aid the design of optimal dosing regimens at the patient level. Although there …

Selecting An Anti-Malarial Clinical Candidate From Two Potent Dihydroisoquinolones, Yizhe Chen, Fangyi Zhu, Jared T. Hammill, Gloria Holbrook, Lei Yang, Burgess Freeman, Karen L. White, David M. Shackleford, Kathleen G. O'Loughlin, Susan A. Charman, Jon C. Mirsalis, R. Kiplin Guy

Pharmaceutical Sciences Faculty Publications

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described.

METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived …

Immunomodulatory Effects Of Azithromycin Revisited: Potential Applications To Covid-19, Vincent J. Venditto, Dalia Haydar, Ahmed K. Abdel-Latif, John C. Gensel, Michael I. Anstead, Michelle G. Pitts, Jarrod W. Creameans, Timothy J. Kopper, Chi Peng, David J. Feola

Pharmaceutical Sciences Faculty Publications

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on …

Comprehensive Analysis Of Nac Transcription Factor Family Uncovers Drought And Salinity Stress Response In Pearl Millet (Pennisetum Glaucum), Ambika Dudhate, Harshraj Shinde, Pei Yu, Daisuke Tsugama, Shashi Kumar Gupta, Shenkui Liu, Tetsuo Takano

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Pearl millet (Pennisetum glaucum) is a cereal crop that possesses the ability to withstand drought, salinity and high temperature stresses. The NAC [NAM (No Apical Meristem), ATAF1 (Arabidopsis thaliana Activation Factor 1), and CUC2 (Cup-shaped Cotyledon)] transcription factor family is one of the largest transcription factor families in plants. NAC family members are known to regulate plant growth and abiotic stress response. Currently, no reports are available on the functions of the NAC family in pearl millet.

RESULTS: Our genome-wide analysis found 151 NAC transcription factor genes (PgNACs) in the pearl millet genome. Thirty-eight …

Nalfurafine Reduces Neuroinflammation And Drives Remyelination In Models Of Cns Demyelinating Disease, Lisa Denny, Afnan Al Abadey, Katharina Robichon, Nikki Templeton, Thomas E. Prisinzano, Bronwyn M. Kivell, Anne C. La Flamme

Pharmaceutical Sciences Faculty Publications

Objectives: Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. There is currently no cure for MS, and finding effective treatments to prevent disease progression has been challenging. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists like U50,488 are not suitable for clinical use because of a poor side-effect profile, nalfurafine is a potent, clinically used KOR agonist with a favorable side-effect profile.

Methods: Using the experimental autoimmune encephalomyelitis (EAE) model, the effect …

A Brief Review Of Fda’S Novel Tools For Ensuring Pharmaceutical Quality In The Human Drug Supply Chain, Heather R. Campbell, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Purpose

Pharmaceutical manufacturers execute quality control operations and Good Manufacturing Practices (GMP) to provide safe drugs. The Federal Drug and Food Administration (FDA) is tasked with ensuring manufacturers are performing such procedures. Faced with limited resources the FDA has developed novel tools to aid pharmaceutical manufacturing oversight. This paper briefly reviews these tools.

Methods

Current inspection approaches employed by the FDA are identified by searching the FDA’s guidances, the Code of Federal Regulations, public reports and other online resources.

Outcomes

Industry

A risk-based site selection model (SSM) is used to prioritize on-site inspections for FDA investigators. Theoretically, the SSM allows …

Recovery Of Hippocampal-Dependent Learning Despite Blunting Reactive Adult Neurogenesis After Alcohol Dependence, Chelsea G. Nickell, K. Ryan Thompson, James R. Pauly, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Background:

The excessive alcohol drinking that occurs in alcohol use disorder (AUD) causes neurodegeneration in regions such as the hippocampus, though recovery may occur after a period of abstinence. Mechanisms of recovery are not clear, though reactive neurogenesis has been observed in the hippocampal dentate gyrus following alcohol dependence and correlates to recovery of granule cell number.

Objective:

We investigated the role of neurons born during reactive neurogenesis in the recovery of hippocampal learning behavior after 4-day binge alcohol exposure, a model of an AUD. We hypothesized that reducing reactive neurogenesis would impair functional recovery.

Methods:

Adult male rats were …

The Acute Effects Of The Atypical Dissociative Hallucinogen Salvinorin A On Functional Connectivity In The Human Brain, Manoj K. Doss, Darrick G. May, Matthew W. Johnson, John M. Clifton, Sidnee L. Hedrick, Thomas E. Prisinzano, Roland R. Griffiths, Frederick S. Barrett

Pharmaceutical Sciences Faculty Publications

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the …

A Thorough Analysis And Categorization Of Bacterial Interrupted Adenylation Domains, Including Previously Unidentified Families, Taylor A. Lundy, Shogo Mori, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

Interrupted adenylation (A) domains are key to the immense structural diversity seen in the nonribosomal peptide (NRP) class of natural products (NPs). Interrupted A domains are A domains that contain within them the catalytic portion of another domain, most commonly a methylation (M) domain. It has been well documented that methylation events occur with extreme specificity on either the backbone (N-) or side chain (O- or S-) of the amino acid (or amino acid-like) building blocks of NRPs. Here, through taxonomic and phylogenetic analyses as well as multiple sequence alignments, we evaluated the similarities and …

Develop A High-Throughput Screening Method To Identify C-P4h1 (Collagen Prolyl 4-Hydroxylase 1) Inhibitors From Fda-Approved Chemicals, Shike Wang, Kuo-Hao Lee, Nathália Victoria Araujo, Chang-Guo Zhan, Vivek M. Rangnekar, Ren Xu

Pharmaceutical Sciences Faculty Publications

Collagen prolyl 4-hydroxylase 1 (C-P4H1) is an α-ketoglutarate (α-KG)-dependent dioxygenase that catalyzes 4-hydroxylation of proline on collagen. C-P4H1-induced prolyl hydroxylation is required for proper collagen deposition and cancer metastasis. Therefore, targeting C-P4H1 is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. However, no C-P4H1 inhibitors are available for clinical testing, and the high content assay is currently not available for C-P4H1 inhibitor screening. In the present study, we developed a high-throughput screening assay by quantifying succinate, a byproduct of C-P4H-catalyzed hydroxylation. C-P4H1 is the major isoform of collagen prolyl 4-hydroxylases (CP4Hs) that contributes the majority prolyl 4-hydroxylase …