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ARKIVOC : free online journal of organic chemistry / Arkat-USA, Inc (1)
Journal of biomolecular screening (1)
BLASS, BENJAMIN E. (1)
CASSEL, JOEL A. (1)
Du, Yanming (1)
Jaffe, Eileen K. (1)
PAWLYK, AARON C. (1)
REITZ, ALLEN B. (1)
Ramirez, Ursula D. (1)
Reitz, Allen B. (1)
Smith, Garry R. (1)
Stith, Linda (1)
Year of Publication
Development of a Novel Nonradiometric Assay for Nucleic Acid Binding to TDP-43 Suitable for High-Throughput Screening Using AlphaScreen® Technology
CASSEL, JOEL A.
BLASS, BENJAMIN E.
PAWLYK, AARON C.
Journal of biomolecular screening
TAR DNA binding protein 43 (TDP-43) is a nucleic acid binding protein that is associated with the pathology of cystic fibrosis and neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. We have developed a robust, quantitative, nonradiometric high-throughput assay measuring oligonucleotide binding to TDP-43 using AlphaScreen® technology. Biotinylated single-stranded TAR DNA (bt-TAR-32) and 6 TG repeats (bt-TG6) bound with high affinity to TDP-43, with KD values of 0.75 nM and 0.63 nM, respectively. Both oligonucleotides exhibited slow dissociation rates, with half-lives of 750 min for bt-TAR-32 and 150 min for bt-TG6. The affinities of unlabeled oligonucleotides, as determined by displacement of either bt-TAR-32 or bt-TG6, were consistent with previous reports of nucleic acid interactions with TDP-43, where increasing TG or UG repeats yield greater affinity. A diversity library of 7360 compounds was screened for inhibition of TDP-43 binding to bt-TAR-32, and a series of compounds was discovered with nascent SAR and IC50 values ranging from 100 nM to 10 μM. These compounds may prove to be useful biochemical tools to elucidate the function of TDP-43 and may lead to novel therapeutics for indications where the TDP-43 nucleic acid interaction is causal to the associated pathology.
TDP-43; AlphaScreen; TAR DNA; ALS; cystic fibrosis
Pseudomonas aeruginosa porphobilinogen synthase assembly state regulators: hit discovery and initial SAR studies
Ramirez, Ursula D.
Smith, Garry R.
Jaffe, Eileen K.
ARKIVOC : free online journal of organic chemistry / Arkat-USA, Inc
Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of the essential heme, chlorophyll and vitamin B12 heme pigments. PBGS activity is regulated by assembly state, with certain oligomers exhibiting biological activity and others either partially or completely inactive, affording an innovative means of allosteric drug action. Pseudomonas aeruginosa PBGS is functionally active as an octamer, and inactive as a dimer. We have identified a series of compounds that stabilize the inactive P. aeruginosa dimer by a computational prescreen followed by native PAGE gel mobility shift analysis. From those results, we have prepared related thiadiazoles and evaluated their ability to regulate P. aeruginosa PBGS assembly state.
Protein assembly state; porphobilinogen synthase (PBGS); Pseudomonas aeruginosa
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