Wilson C

References (9)

Title : Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity - Green_2023_J.Med.Chem__
Author(s) : Green SR , Wilson C , Eadsforth TC , Punekar AS , Tamaki FK , Wood G , Caldwell N , Forte B , Norcross NR , Kiczun M , Post JM , Lopez-Roman EM , Engelhart CA , Lukac I , Zuccotto F , Epemolu O , Boshoff HIM , Schnappinger D , Walpole C , Gilbert IH , Read KD , Wyatt PG , Baragana B
Ref : Journal of Medicinal Chemistry , : , 2023
Abstract : There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 microM) and in vitro ADMET profiles.
ESTHER : Green_2023_J.Med.Chem__
PubMedSearch : Green_2023_J.Med.Chem__
PubMedID: 37948640
Gene_locus related to this paper: myctu-PKS13

Title : Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13\; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target - Wilson_2022_J.Med.Chem_65_409
Author(s) : Wilson C , Ray P , Zuccotto F , Hernandez J , Aggarwal A , Mackenzie C , Caldwell N , Taylor M , Huggett M , Mathieson M , Murugesan D , Smith A , Davis S , Cocco M , Parai MK , Acharya A , Tamaki F , Scullion P , Epemolu O , Riley J , Stojanovski L , Lopez-Roman EM , Torres-Gomez PA , Toledo AM , Guijarro-Lopez L , Camino I , Engelhart CA , Schnappinger D , Massoudi LM , Lenaerts A , Robertson GT , Walpole C , Matthews D , Floyd D , Sacchettini JC , Read KD , Encinas L , Bates RH , Green SR , Wyatt PG
Ref : Journal of Medicinal Chemistry , 65 :409 , 2022
Abstract : With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.
ESTHER : Wilson_2022_J.Med.Chem_65_409
PubMedSearch : Wilson_2022_J.Med.Chem_65_409
PubMedID: 34910486
Gene_locus related to this paper: myctu-PKS13

Title : An epoxide hydrolase from endophytic Streptomyces shows unique structural features and wide biocatalytic activity - Tormet-Gonzalez_2020_Acta.Crystallogr.D.Struct.Biol_76_868
Author(s) : Tormet-Gonzalez GD , Wilson C , de Oliveira GS , dos Santos JC , de Oliveira LG , Dias MVB
Ref : Acta Crystallographica D Struct Biol , 76 :868 , 2020
Abstract : The genus Streptomyces is characterized by the production of a wide variety of secondary metabolites with remarkable biological activities and broad antibiotic capabilities. The presence of an unprecedented number of genes encoding hydrolytic enzymes with industrial appeal such as epoxide hydrolases (EHs) reveals its resourceful microscopic machinery. The whole-genome sequence of Streptomyces sp. CBMAI 2042, an endophytic actinobacterium isolated from Citrus sinensis branches, was explored by genome mining, and a putative alpha/beta-epoxide hydrolase named B1EPH2 and encoded by 344 amino acids was selected for functional and structural studies. The crystal structure of B1EPH2 was obtained at a resolution of 2.2 and it was found to have a similar fold to other EHs, despite its hexameric quaternary structure, which contrasts with previously solved dimeric and monomeric EH structures. While B1EPH2 has a high sequence similarity to EHB from Mycobacterium tuberculosis, its cavity is similar to that of human EH. A group of 12 aromatic and aliphatic racemic epoxides were assayed to determine the activity of B1EPH2; remarkably, this enzyme was able to hydrolyse all the epoxides to the respective 1,2-diols, indicating a wide-range substrate scope acceptance. Moreover, the (R)- and (S)-enantiomers of styrene oxide, epichlorohydrin and 1,2-epoxybutane were used to monitor enantiopreference. Taken together, the functional and structural analyses indicate that this enzyme is an attractive biocatalyst for future biotechnological applications.
ESTHER : Tormet-Gonzalez_2020_Acta.Crystallogr.D.Struct.Biol_76_868
PubMedSearch : Tormet-Gonzalez_2020_Acta.Crystallogr.D.Struct.Biol_76_868
PubMedID: 32876062
Gene_locus related to this paper: strsq-b1eph2

Title : Structure of a soluble epoxide hydrolase identified in Trichoderma reesei - Wilson_2017_Biochim.Biophys.Acta_1865_1039
Author(s) : Wilson C , de Oliveira GS , Adriani PP , Chambergo FS , Dias MVB
Ref : Biochimica & Biophysica Acta , 1865 :1039 , 2017
Abstract : Epoxide hydrolases (EHs) are enzymes that have high biotechnological interest for the fine and transformation industry. Several of these enzymes have enantioselectivity, which allows their application in the separation of enantiomeric mixtures of epoxide substrates. Although two different families of EHs have been described, those that have the alpha/beta-hidrolase fold are the most explored for biotechnological purpose. These enzymes are functionally very well studied, but only few members have three-dimensional structures characterised. Recently, a new EH from the filamentous fungi Trichoderma reseei (TrEH) has been discovered and functionally studied. This enzyme does not have high homology to any other EH structure and have an enatiopreference for (S)-(-) isomers. Herein we described the crystallographic structure of TrEH at 1.7A resolution, which reveals features of its tertiary structure and active site. TrEH has a similar fold to the other soluble epoxide hydrolases and has the two characteristic hydrolase and cap domains. The enzyme is predominantly monomeric in solution and has also been crystallised as a monomer in the asymmetric unit. Although the catalytic residues are conserved, several other residues of the catalytic groove are not, and might be involved in the specificity for substrates and in the enantioselectivy of this enzyme. In addition, the determination of the crystallographic structure of TrEH might contribute to the rational site direct mutagenesis to generate an even more stable enzyme with higher efficiency to be used in biotechnological purposes.
ESTHER : Wilson_2017_Biochim.Biophys.Acta_1865_1039
PubMedSearch : Wilson_2017_Biochim.Biophys.Acta_1865_1039
PubMedID: 28502798
Gene_locus related to this paper: hypjq-g0r7e2

Title : Prolonged Paralysis Following Emergent Cesarean Section with Succinylcholine Despite Normal Dibucaine Number - Ellison_2016_W.V.Med.J_112_44
Author(s) : Ellison M , Grose B , Howell S , Wilson C , Lenz J , Driver R
Ref : W V Med J , 112 :44 , 2016
Abstract : Prolonged paralysis due to a quantitative or qualitative deficiency of pseudocholinesterase activity is an uncommon but known side effect of succinylcholine. We describe a patient who experienced prolonged paralysis following administration of succinylcholine for general anesthesia and endotracheal intubation for an emergent cesarean section despite laboratory evidence of normal enzyme function. The patient required mechanical ventilation in the intensive care unit for several hours following surgery. The patient was extubated following return of full muscle strength and had a good outcome. The enzyme responsible for the metabolism of succinylcholine, pseudocholinesterase, was determined to be low in quantity in this patient but was functionally normal. This low level, by itself, was unlikely to be solely responsible for the prolonged paralysis. The patient likely had an abnormal pseudocholinesterase enzyme variant that is undetectable by standard laboratory tests.
ESTHER : Ellison_2016_W.V.Med.J_112_44
PubMedSearch : Ellison_2016_W.V.Med.J_112_44
PubMedID: 27025119

Title : Species variation in small molecule components of animal vitreous - Mains_2012_Invest.Ophthalmol.Vis.Sci_53_4778
Author(s) : Mains J , Tan LE , Zhang T , Young L , Shi R , Wilson C
Ref : Invest Ophthalmol Vis Sci , 53 :4778 , 2012
Abstract : PURPOSE: We characterized differences in biochemical composition of the vitreous of different animal species with respect to small molecule constituents. METHODS: Vitreous samples were extracted from sheep, pig, Dutch Belted rabbits, and New Zealand white rabbits. The vitreous samples were investigated for acetylcholinesterase (AChE) activity and, in addition, were subjected to metabolomics determination using mass spectrometry. RESULTS: AChE activity varied across the species investigated with greater activity noted in larger animals. Principal component analysis demonstrated species differentiation in relation to metabolomic profile. Key peaks identified the importance of animal diet on small molecule composition of the vitreous. CONCLUSIONS: Our results highlighted principal and consistent differences in small molecule composition and enzymatic activity of the vitreous depending on species. Interesting differences were demonstrated, showing that diet potentially can impact on components of and metabolites contained within the vitreous. Material will be exchanged between vascular and retinal tissue with the vitreous compartment and as a nonvascular, slowly equilibrating "sink" might reflect changes in transporter activity. As a first step, understanding the differences in the metabolic profile of vitreous from different species may impact interpretation of such activity across different species.
ESTHER : Mains_2012_Invest.Ophthalmol.Vis.Sci_53_4778
PubMedSearch : Mains_2012_Invest.Ophthalmol.Vis.Sci_53_4778
PubMedID: 22669713

Title : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy - Pratley_2009_Diabetes.Obes.Metab_11_167
Author(s) : Pratley RE , Kipnes MS , Fleck PR , Wilson C , Mekki Q
Ref : Diabetes Obes Metab , 11 :167 , 2009
Abstract : AIM: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy.
METHODS: After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings].
RESULTS: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively.
CONCLUSIONS: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.
ESTHER : Pratley_2009_Diabetes.Obes.Metab_11_167
PubMedSearch : Pratley_2009_Diabetes.Obes.Metab_11_167
PubMedID: 19125778

Title : Muscarinic and nicotinic cholinergic mechanisms in the mesostriatal dopamine systems - Zhou_2003_Neuroscientist_9_23
Author(s) : Zhou FM , Wilson C , Dani JA
Ref : Neuroscientist , 9 :23 , 2003
Abstract : The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette's syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson's disease.
ESTHER : Zhou_2003_Neuroscientist_9_23
PubMedSearch : Zhou_2003_Neuroscientist_9_23
PubMedID: 12580337

Title : Nonstriatal dopamine D1 receptors regulate striatal acetylcholine release in vivo - Acquas_1997_J.Pharmacol.Exp.Ther_281_360
Author(s) : Acquas E , Wilson C , Fibiger HC
Ref : Journal of Pharmacology & Experimental Therapeutics , 281 :360 , 1997
Abstract : The role of dopamine (DA) D1 receptors in the regulation of acetylcholine (ACh) release in the striatum was studied using in vivo microdialysis in freely moving rats. Systemic administration of the full D1 DA receptor agonist A-77636 (4 micromol/kg) increased striatal ACh release by 53% above the base line and decreased DA release by 33%. Local application of A-77636 (10 and 100 microM) by reverse dialysis was without effect on either striatal ACh or DA release. Systemic administration of the D1 DA receptor antagonist SCH 23390 (0.74 micromol/kg) or SCH 39166 (1.42 micromol/kg) blocked the stimulation of striatal ACh release produced by systemic A-77636 (4 micromol/kg). Local perfusion of either SCH 23390 or SCH 39166 did not decrease basal ACh release. Furthermore, when applied locally via the dialysis probe, SCH 23390 (12 microM) or SCH 39166 (50 microM) failed to attenuate the stimulation of striatal ACh release produced by systemic A-77636. Similarly, d-amphetamine (5.42 micromol/kg)-induced increases in striatal ACh release were not modified by simultaneous local perfusion with SCH 39166 (50 microM). These findings are consistent with the hypothesis that D1 receptor activation stimulates ACh release in the striatum. However, because local application of D1 receptor agonists and antagonists fail to influence ACh release, the relevant D1 receptors are not located in the striatum. The use of unphysiological dialysis conditions (high concentrations of acetylcholinesterase (AChE) inhibitors, high Ca++ concentrations and an absence of Mg++ in the perfusion fluid) may account for some earlier suggestions that local D1 receptors regulate ACh release in the striatum.
ESTHER : Acquas_1997_J.Pharmacol.Exp.Ther_281_360
PubMedSearch : Acquas_1997_J.Pharmacol.Exp.Ther_281_360
PubMedID: 9103518