Wood J

References (8)

Title : Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening - Krieger_2024_ACS.Infect.Dis__
Author(s) : Krieger IV , Yalamanchili S , Dickson P , Engelhart CA , Zimmerman MD , Wood J , Clary E , Nguyen J , Thornton N , Centrella PA , Chan B , Cuozzo JW , Gengenbacher M , Guie MA , Guilinger JP , Bienstock C , Hartl H , Hupp CD , Jetson R , Satoh T , Yeoman JTS , Zhang Y , Dartois V , Schnappinger D , Keefe AD , Sacchettini JC
Ref : ACS Infect Dis , : , 2024
Abstract : DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.
ESTHER : Krieger_2024_ACS.Infect.Dis__
PubMedSearch : Krieger_2024_ACS.Infect.Dis__
PubMedID: 38577994

Title : Design and Synthesis of Highly Potent and Specific ABHD6 Inhibitors - Malamas_2021_ChemMedChem__
Author(s) : Malamas MS , Lamani M , Farah SI , Mohammad KA , Miyabe CY , Rajarshi G , Wu S , Zvonok N , Chandrashekhar H , Wood J , Makriyannis A
Ref : ChemMedChem , : , 2021
Abstract : Fine-tuning than complete disruption of 2-arachidonoylglycerol (2-AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2-AG. This could be achieved through a/b-hydrolase domain containing 6 (ABHD6) inhibition, which will provide a smaller and safer contribution to 2-AG regulation in the brain. Pharmacological studies with ABHD6 inhibitors have recently been reported, where modulation of ABHD6 activity either through CB1R-dependent or CB1R-independent processes showed promise in preclinical models of epilepsy, neuropathic pain and inflammation. Furthermore in the periphery, ABHD6 modulates 2-AG and other fatty acid monoacylglycerols (MAGs) and is implicated in Type-2 diabetes, metabolic syndrome and potentially other diseases. Herein, we report the discovery of single-digit nanomolar potent and highly specific ABHD6 inhibitors with >1000-fold selectivity against MGL and FAAH. The new ABHD6 inhibitors provide early leads to develop therapeutics for neuroprotection and the treatment of inflammation and diabetes.
ESTHER : Malamas_2021_ChemMedChem__
PubMedSearch : Malamas_2021_ChemMedChem__
PubMedID: 34486233
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6

Title : Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3 - Hosie_2019_Autism.Res_12_1043
Author(s) : Hosie S , Ellis M , Swaminathan M , Ramalhosa F , Seger GO , Balasuriya GK , Gillberg C , Rastam M , Churilov L , McKeown SJ , Yalcinkaya N , Urvil P , Savidge T , Bell CA , Bodin O , Wood J , Franks AE , Bornstein JC , Hill-Yardin EL
Ref : Autism Res , 12 :1043 , 2019
Abstract : Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin-3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin-3 R451C missense mutation (NL3(R451C) ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3(R451C) compared to wild-type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3(R451C) mice, a well-established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3(R451C) mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA-immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3(R451C) mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3(R451C) mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043-1056. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism-associated R451C mutation encoding the neuroligin-3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin-3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.
ESTHER : Hosie_2019_Autism.Res_12_1043
PubMedSearch : Hosie_2019_Autism.Res_12_1043
PubMedID: 31119867
Gene_locus related to this paper: mouse-3neur , human-NLGN3

Title : Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment - Alapafuja_2019_Bioorg.Med.Chem_27_55
Author(s) : Alapafuja SO , Malamas MS , Shukla V , Zvonok A , Miller S , Daily L , Rajarshi G , Miyabe CY , Chandrashekhar H , Wood J , Tyukhtenko S , Straiker A , Makriyannis A
Ref : Bioorganic & Medicinal Chemistry , 27 :55 , 2019
Abstract : Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based (1)H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process "intrinsic reversibility" was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with "tunable' adduct residence time (tau). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by -4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.
ESTHER : Alapafuja_2019_Bioorg.Med.Chem_27_55
PubMedSearch : Alapafuja_2019_Bioorg.Med.Chem_27_55
PubMedID: 30446439

Title : The zebrafish reference genome sequence and its relationship to the human genome - Howe_2013_Nature_496_498
Author(s) : Howe K , Clark MD , Torroja CF , Torrance J , Berthelot C , Muffato M , Collins JE , Humphray S , McLaren K , Matthews L , Mclaren S , Sealy I , Caccamo M , Churcher C , Scott C , Barrett JC , Koch R , Rauch GJ , White S , Chow W , Kilian B , Quintais LT , Guerra-Assuncao JA , Zhou Y , Gu Y , Yen J , Vogel JH , Eyre T , Redmond S , Banerjee R , Chi J , Fu B , Langley E , Maguire SF , Laird GK , Lloyd D , Kenyon E , Donaldson S , Sehra H , Almeida-King J , Loveland J , Trevanion S , Jones M , Quail M , Willey D , Hunt A , Burton J , Sims S , McLay K , Plumb B , Davis J , Clee C , Oliver K , Clark R , Riddle C , Elliot D , Threadgold G , Harden G , Ware D , Begum S , Mortimore B , Kerry G , Heath P , Phillimore B , Tracey A , Corby N , Dunn M , Johnson C , Wood J , Clark S , Pelan S , Griffiths G , Smith M , Glithero R , Howden P , Barker N , Lloyd C , Stevens C , Harley J , Holt K , Panagiotidis G , Lovell J , Beasley H , Henderson C , Gordon D , Auger K , Wright D , Collins J , Raisen C , Dyer L , Leung K , Robertson L , Ambridge K , Leongamornlert D , McGuire S , Gilderthorp R , Griffiths C , Manthravadi D , Nichol S , Barker G , Whitehead S , Kay M , Brown J , Murnane C , Gray E , Humphries M , Sycamore N , Barker D , Saunders D , Wallis J , Babbage A , Hammond S , Mashreghi-Mohammadi M , Barr L , Martin S , Wray P , Ellington A , Matthews N , Ellwood M , Woodmansey R , Clark G , Cooper J , Tromans A , Grafham D , Skuce C , Pandian R , Andrews R , Harrison E , Kimberley A , Garnett J , Fosker N , Hall R , Garner P , Kelly D , Bird C , Palmer S , Gehring I , Berger A , Dooley CM , Ersan-Urun Z , Eser C , Geiger H , Geisler M , Karotki L , Kirn A , Konantz J , Konantz M , Oberlander M , Rudolph-Geiger S , Teucke M , Lanz C , Raddatz G , Osoegawa K , Zhu B , Rapp A , Widaa S , Langford C , Yang F , Schuster SC , Carter NP , Harrow J , Ning Z , Herrero J , Searle SM , Enright A , Geisler R , Plasterk RH , Lee C , Westerfield M , de Jong PJ , Zon LI , Postlethwait JH , Nusslein-Volhard C , Hubbard TJ , Roest Crollius H , Rogers J , Stemple DL
Ref : Nature , 496 :498 , 2013
Abstract : Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
ESTHER : Howe_2013_Nature_496_498
PubMedSearch : Howe_2013_Nature_496_498
PubMedID: 23594743
Gene_locus related to this paper: danre-1neur , danre-ABHD10b , danre-a9jrf7 , danre-d2x2g3 , danre-e7ezq9 , danre-e7ff77 , danre-ndr3 , danre-nlgn4a , danre-q1mti5 , danre-q6nyz4 , danre-q6p2u2 , danre-q7t359 , danre-q08c93 , danre-A2BGU9 , danre-f1q676 , danre-e7f0z8 , danre-e7ez27 , danre-e7f2w1 , danre-f1qid7 , danre-a0a0g2kru2 , danre-f1qla7 , danre-a9jr90 , danre-e7f070 , danre-f172a , danre-e7fb35 , danre-a7mbu9 , danre-f1qtr2

Title : The genome of Mycobacterium africanum West African 2 reveals a lineage-specific locus and genome erosion common to the M. tuberculosis complex - Bentley_2012_PLoS.Negl.Trop.Dis_6_e1552
Author(s) : Bentley SD , Comas I , Bryant JM , Walker D , Smith NH , Harris SR , Thurston S , Gagneux S , Wood J , Antonio M , Quail MA , Gehre F , Adegbola RA , Parkhill J , de Jong BC
Ref : PLoS Negl Trop Dis , 6 :e1552 , 2012
Abstract : BACKGROUND: M. africanum West African 2 constitutes an ancient lineage of the M. tuberculosis complex that commonly causes human tuberculosis in West Africa and has an attenuated phenotype relative to M. tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: In search of candidate genes underlying these differences, the genome of M. africanum West African 2 was sequenced using classical capillary sequencing techniques. Our findings reveal a unique sequence, RD900, that was independently lost during the evolution of two important lineages within the complex: the "modern" M. tuberculosis group and the lineage leading to M. bovis. Closely related to M. bovis and other animal strains within the M. tuberculosis complex, M. africanum West African 2 shares an abundance of pseudogenes with M. bovis but also with M. africanum West African clade 1. Comparison with other strains of the M. tuberculosis complex revealed pseudogenes events in all the known lineages pointing toward ongoing genome erosion likely due to increased genetic drift and relaxed selection linked to serial transmission-bottlenecks and an intracellular lifestyle. CONCLUSIONS/SIGNIFICANCE: The genomic differences identified between M. africanum West African 2 and the other strains of the Mycobacterium tuberculosis complex may explain its attenuated phenotype, and pave the way for targeted experiments to elucidate the phenotypic characteristic of M. africanum. Moreover, availability of the whole genome data allows for verification of conservation of targets used for the next generation of diagnostics and vaccines, in order to ensure similar efficacy in West Africa.
ESTHER : Bentley_2012_PLoS.Negl.Trop.Dis_6_e1552
PubMedSearch : Bentley_2012_PLoS.Negl.Trop.Dis_6_e1552
PubMedID: 22389744
Gene_locus related to this paper: myctu-cut3 , myctu-cutas1 , myctu-cutas2 , myctu-Rv1069c , myctu-RV1215C , myctu-RV1758 , myctu-RV3452 , myctu-RV3724 , myctu-Rv3802c

Title : Signatures of adaptation to obligate biotrophy in the Hyaloperonospora arabidopsidis genome - Baxter_2010_Science_330_1549
Author(s) : Baxter L , Tripathy S , Ishaque N , Boot N , Cabral A , Kemen E , Thines M , Ah-Fong A , Anderson R , Badejoko W , Bittner-Eddy P , Boore JL , Chibucos MC , Coates M , Dehal P , Delehaunty K , Dong S , Downton P , Dumas B , Fabro G , Fronick C , Fuerstenberg SI , Fulton L , Gaulin E , Govers F , Hughes L , Humphray S , Jiang RH , Judelson H , Kamoun S , Kyung K , Meijer H , Minx P , Morris P , Nelson J , Phuntumart V , Qutob D , Rehmany A , Rougon-Cardoso A , Ryden P , Torto-Alalibo T , Studholme D , Wang Y , Win J , Wood J , Clifton SW , Rogers J , Van den Ackerveken G , Jones JD , McDowell JM , Beynon J , Tyler BM
Ref : Science , 330 :1549 , 2010
Abstract : Many oomycete and fungal plant pathogens are obligate biotrophs, which extract nutrients only from living plant tissue and cannot grow apart from their hosts. Although these pathogens cause substantial crop losses, little is known about the molecular basis or evolution of obligate biotrophy. Here, we report the genome sequence of the oomycete Hyaloperonospora arabidopsidis (Hpa), an obligate biotroph and natural pathogen of Arabidopsis thaliana. In comparison with genomes of related, hemibiotrophic Phytophthora species, the Hpa genome exhibits dramatic reductions in genes encoding (i) RXLR effectors and other secreted pathogenicity proteins, (ii) enzymes for assimilation of inorganic nitrogen and sulfur, and (iii) proteins associated with zoospore formation and motility. These attributes comprise a genomic signature of evolution toward obligate biotrophy.
ESTHER : Baxter_2010_Science_330_1549
PubMedSearch : Baxter_2010_Science_330_1549
PubMedID: 21148394
Gene_locus related to this paper: hyaae-m4b4d8 , hyaae-m4b4e0 , hyaae-m4bkr1 , hyaae-m4bkw7

Title : Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor alpha and gamma ligands - White_2003_Proteomics_3_505
Author(s) : White IR , Man WJ , Bryant D , Bugelski P , Camilleri P , Cutler P , Hayes W , Holbrook JD , Kramer K , Lord PG , Wood J
Ref : Proteomics , 3 :505 , 2003
Abstract : Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and are intimately involved in lipid metabolism and energy homeostasis. Activation of these receptors in rodents can lead to hepatomegaly and ultimately hepatic carcinogenesis although the mechanisms by which these processes occur are poorly understood. To further our understanding of these processes and to discriminate between different PPAR mediated signalling pathways, a proteomic approach has been undertaken to identify changes in protein expression patterns in Sprague Dawley rat liver following dosing with a PPARalpha agonist (Wyeth 14643), a PPARgamma agonist (Troglitazone) and a compound with mixed PPARalpha/gamma agonist activity (SB-219994). Using one-and-two-dimensional electrophoresis of tissue lysates a diverse range of protein abundance changes was observed in these tissues. Whilst a number of these proteins have PPAR response elements (PPREs) in their respective promoters, another group was detected whose expression has been documented to be sensitive to peroxisome proliferator administration. Most notably within these groups, proteins involved in lipid catabolism displayed increased expression following drug administration. A further subset of proteins, with less obvious biological implications, also showed altered expression patterns. Where available, sequences upstream of the coding regions of genes not previously known to have PPREs were searched with positional consensus matrices for the presence of PPREs in an attempt to validate these changes. Using such an approach putative PPARgamma and PPARdelta response elements were discovered upstream of the tubulin beta coding region. There was limited overlap in observed protein abundance changes between the three groups, and where this was the case (cytosolic epoxide hydrolase, peroxisomal bifunctional enzyme, hydroxymethyl glutaryl CoA, synthase, long chain acyl-CoA thioesterase), expression of these proteins had previously been shown to be under the control of PPAR activity.
ESTHER : White_2003_Proteomics_3_505
PubMedSearch : White_2003_Proteomics_3_505
PubMedID: 12687617