scholarly journals MetIDfyR, an Open-Source R Package to Decipher Small-Molecule Drugs Metabolism Through High Resolution Mass Spectrometry

2020 ◽  
Author(s):  
Vivian Delcourt ◽  
Agnès Barnabé ◽  
Benoit Loup ◽  
Patrice Garcia ◽  
François André ◽  
...  
Keyword(s):  
Phase I ◽  
Open Source ◽  
Small Molecule ◽  
High Resolution Mass Spectrometry ◽  
R Package ◽  
Spectrometric Data ◽  
Manual Search ◽  
Small Molecule Drugs

<div>After administration to humans or animals, small-molecule drugs most frequently undergo several biochemical transformations by the endogenous enzymatic machinery, called phase I and phase II metabolism. These molecular processes allow organisms to eliminate xenobiotics through modification of their chemical properties and generate metabolites. With recent advances in analytical chemistry, LC-HRMS/MS has become an essential tool for metabolite discovery and detection. Even if most common drug transformations have already been extensively described, manual search of drug metabolites in LC-HRMS/MS datasets is still a common practice in toxicology laboratories, disabling efficient metabolite discovery. Furthermore, the availability of free open-source software for metabolite discovery is still limited.</div><div><br> </div>In this article, we present MetIDfyR, an open-source and cross-platform R package for in-silico drug phase I/II biotransformations prediction and mass-spectrometric data mining. MetIDfyR has proven efficacy for advanced metabolite identification in semi-complex and complex mixtures in in-vitro or in-vivo drug studies and is freely available at https://github.com/agnesblch/MetIDfyR.<br>

MetIDfyR, an Open-Source R Package to Decipher Small-Molecule Drugs Metabolism Through High Resolution Mass Spectrometry

2020 ◽  
Author(s):  
Vivian Delcourt ◽  
Agnès Barnabé ◽  
Benoit Loup ◽  
Patrice Garcia ◽  
François André ◽  
...  
Keyword(s):  
Phase I ◽  
Open Source ◽  
Small Molecule ◽  
High Resolution Mass Spectrometry ◽  
R Package ◽  
Spectrometric Data ◽  
Manual Search ◽  
Small Molecule Drugs

<div>After administration to humans or animals, small-molecule drugs most frequently undergo several biochemical transformations by the endogenous enzymatic machinery, called phase I and phase II metabolism. These molecular processes allow organisms to eliminate xenobiotics through modification of their chemical properties and generate metabolites. With recent advances in analytical chemistry, LC-HRMS/MS has become an essential tool for metabolite discovery and detection. Even if most common drug transformations have already been extensively described, manual search of drug metabolites in LC-HRMS/MS datasets is still a common practice in toxicology laboratories, disabling efficient metabolite discovery. Furthermore, the availability of free open-source software for metabolite discovery is still limited.</div><div><br> </div>In this article, we present MetIDfyR, an open-source and cross-platform R package for in-silico drug phase I/II biotransformations prediction and mass-spectrometric data mining. MetIDfyR has proven efficacy for advanced metabolite identification in semi-complex and complex mixtures in in-vitro or in-vivo drug studies and is freely available at https://github.com/agnesblch/MetIDfyR.<br>

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine and Pyronaridine: In vitro Activity Against SARS-CoV-2 and Potential Mechanisms

2020 ◽  
Author(s):  
Ana C. Puhl ◽  
Ethan James Fritch ◽  
Thomas R. Lane ◽  
Longping V. Tse ◽  
Boyd L. Yount ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Ebola Virus ◽  
Early Stage ◽  
Drug Repurposing ◽  
Marburg Virus ◽  
Small Molecule Drugs ◽  
Speed Up

AbstractSARS-CoV-2 is a newly identified virus that has resulted in over 1.3 M deaths globally and over 59 M cases globally to date. Small molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola virus and demonstrated activity against SARS-CoV-2 in vivo. Most notably the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small molecule drugs that are active against Ebola virus would seem a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg virus in vitro in HeLa cells and of mouse adapted Ebola virus in mouse in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7 and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We have also tested them in a pseudovirus assay and used microscale thermophoresis to test the binding of these molecules to the spike protein. They bind to spike RBD protein with Kd values of 339 nM and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 hence justifying in vivo evaluation. We also provide novel insights into their mechanism which is likely lysosomotropic.

scholarly journals In Vitro Toxicokinetics and Phase I Biotransformation of the Mycotoxin Penitrem A in Dogs

Toxins ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 293 ◽  
Author(s):  
Silvio Uhlig ◽  
Lada Ivanova ◽  
Pauline Voorspoels ◽  
Christiane Kruse Fæste
Keyword(s):  
Phase I ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Absorbed Dose ◽  
Metabolite Profile ◽  
Oxidation Products ◽  
In Vitro Assays ◽  
Penicillium Species

The tremorgenic mycotoxin penitrem A is produced by Penicillium species as a secondary metabolite on moldy food and feed. Dogs are sometimes exposed to penitrem A by consumption of spoiled food waste or fallen fruit. The lipophilic toxin crosses the blood-brain barrier and targets neuroreceptors and neurotransmitter release mechanisms in the central and peripheral nervous systems. Typical symptoms of penitrem A intoxication are periodical or continuous tremors, which can be passing, persistent or lethal, depending on the absorbed dose. There is presently no information on the biotransformation and toxicokinetics of penitrem A in dogs. The aim of the present study was therefore to identify potential metabolites of the toxin by performing in vitro biotransformation assays in dog liver microsomes. Analyses by liquid chromatography coupled to high-resolution mass spectrometry led to the provisional identification of eleven penitrem A phase I metabolites, which were tentatively characterized as various oxidation products. Furthermore, elimination parameters determined in in vitro assays run under linear kinetics were used for in vitro-to-in vivo extrapolation of the toxicokinetic data, predicting a maximal bioavailability of more than 50%. The metabolite profile detected in the in vitro assays was similar to that observed in the plasma of an intoxicated dog, confirming the predictive capability of the in vitro approach.

scholarly journals Biomonitoring of Enniatin B1 and Its Phase I Metabolites in Human Urine: First Large-Scale Study

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 415
Author(s):  
Yelko Rodríguez-Carrasco ◽  
Alfonso Narváez ◽  
Luana Izzo ◽  
Anna Gaspari ◽  
Giulia Graziani ◽  
...  
Keyword(s):  
Phase I ◽  
Human Urine ◽  
Large Scale ◽  
High Resolution Mass Spectrometry ◽  
Mean Value ◽  
Toxicological Studies ◽  
In Vivo Analysis ◽  
Ultrahigh Performance Liquid Chromatography

Enniatins (Enns) are mycotoxins produced by Fusarium spp. which are a fungus widely spread throughout cereals and cereal-based products. Among all the identified enniatins, Enn B1 stands as one of the most prevalent analogues in cereals in Europe. Hence, the aim of this study was to evaluate for the first time the presence of Enn B1 and its phase I metabolites in 300 human urine samples using an ultrahigh-performance liquid chromatography high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) methodology. Enn B1 was detected in 94.3% of samples ranging from 0.007 to 0.429 ng/mL (mean value: 0.065 ng/mL). In accordance with previous in vitro and in vivo analysis, hydroxylated metabolites (78.0% samples) and carbonylated metabolites (66.0% samples) were tentatively identified as the major products. Results from this biomonitoring study point to a frequent intake of Enn B1 in the studied population, suggesting that in-depth toxicological studies are needed in order to understand the potential effects in humans.

Establishment of an In Vitro–In Vivo Correlation for Melanin Binding and the Extension of the Ocular Half-Life of Small-Molecule Drugs

2019 ◽  
Vol 16 (12) ◽  
pp. 4890-4901 ◽  
Author(s):  
Paulina Jakubiak ◽  
Carina Cantrill ◽  
Arto Urtti ◽  
Rubén Alvarez-Sánchez
Keyword(s):  
Small Molecule ◽  
Half Life ◽  
Small Molecule Drugs ◽  
Melanin Binding

scholarly journals MetIDfyR: An Open-Source R Package to Decipher Small-Molecule Drug Metabolism through High-Resolution Mass Spectrometry

2020 ◽  
Vol 92 (19) ◽  
pp. 13155-13162
Author(s):  
Vivian Delcourt ◽  
Agnès Barnabé ◽  
Benoit Loup ◽  
Patrice Garcia ◽  
François André ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Drug Metabolism ◽  
Open Source ◽  
Small Molecule ◽  
High Resolution Mass Spectrometry ◽  
R Package ◽  
Small Molecule Drug ◽  
High Resolution Mass ◽  
Resolution Mass

scholarly journals Cyclodextrin-Based Supramolecular Complexes of Osteoinductive Agents for Dental Tissue Regeneration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 136
Author(s):  
Masahiko Terauchi ◽  
Atsushi Tamura ◽  
Yoshinori Arisaka ◽  
Hiroki Masuda ◽  
Tetsuya Yoda ◽  
...  
Keyword(s):  
Growth Factors ◽  
Bone Formation ◽  
Small Molecule ◽  
Tissue Regeneration ◽  
Alveolar Bone ◽  
Inclusion Complexation ◽  
Dental Tissue ◽  
Polyelectrolyte Complexes ◽  
Small Molecule Drugs

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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