Affinity capillary electrophoresis for identification of active drug candidates in myotonic dystrophy type 1
Myotonic dystrophy type 1 (DM1) is an autosomal dominantly inherited degenerative disease with a slow progression. At the present, there is no commercially available treatment, but sustained effort is currently undertaken for the development of a promising lead compound. In the present paper we report the development of a fast, versatile, and cost-effective affinity capillary electrophoresis (ACE) method for the screening and identification of potential drug candidates targeting pathological ARN probes relevant for DM1. The affinity studies were conducted in physiologically relevant conditions using 50 mM HEPES buffer (pH 7.4) in a fused silica capillary dynamically coated with poly(ethylene oxide), by testing a library of potential ligands against (CUG)50 RNA as target probe with a total run time of 4-5 h/ligand. For the most promising ligands, their affinity parameters were assessed and some results formerly reported on the affinity of pentamidine (PTMD) and neomycin against CUG repeats were confirmed. To the best of the authors' knowledge, the estimated binding stoichiometry for some of the tested compounds (i.e., ~ 121:1 for PTMD against the tested RNA probe) is reported for the first time. Additionally, the potential of a novel pentamidine like compound, namely 1,2-ethane bis-1-amino-4-benzamidine (EBAB) with much lower in vivo toxicity than its parent compound has also been confirmed studying its effect on a live cell model by fluorescence microscopy. Further tests, such as the evaluation of the rescue in the mis-splicing of the involved genes, can be performed to corroborate the potential therapeutic value of EBAB in DM1 treatment. Graphical abstract ᅟ.
| Errataetall: |
ErratumIn: Anal Bioanal Chem. 2019 Jan;411(2):545. - PMID 30443771 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
|---|---|
| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:410 |
|---|---|
| Enthalten in: |
Analytical and bioanalytical chemistry - 410(2018), 18 vom: 07. Juli, Seite 4495-4507 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Neaga, Ioan O [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.08.2018 Date Revised 14.08.2018 published: Print-Electronic ErratumIn: Anal Bioanal Chem. 2019 Jan;411(2):545. - PMID 30443771 Citation Status MEDLINE |
|---|
| doi: |
10.1007/s00216-018-1107-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM283837195 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM283837195 | ||
| 003 | DE-627 | ||
| 005 | 20231225041828.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00216-018-1107-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0946.xml |
| 035 | |a (DE-627)NLM283837195 | ||
| 035 | |a (NLM)29736701 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Neaga, Ioan O |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Affinity capillary electrophoresis for identification of active drug candidates in myotonic dystrophy type 1 |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.08.2018 | ||
| 500 | |a Date Revised 14.08.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Anal Bioanal Chem. 2019 Jan;411(2):545. - PMID 30443771 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Myotonic dystrophy type 1 (DM1) is an autosomal dominantly inherited degenerative disease with a slow progression. At the present, there is no commercially available treatment, but sustained effort is currently undertaken for the development of a promising lead compound. In the present paper we report the development of a fast, versatile, and cost-effective affinity capillary electrophoresis (ACE) method for the screening and identification of potential drug candidates targeting pathological ARN probes relevant for DM1. The affinity studies were conducted in physiologically relevant conditions using 50 mM HEPES buffer (pH 7.4) in a fused silica capillary dynamically coated with poly(ethylene oxide), by testing a library of potential ligands against (CUG)50 RNA as target probe with a total run time of 4-5 h/ligand. For the most promising ligands, their affinity parameters were assessed and some results formerly reported on the affinity of pentamidine (PTMD) and neomycin against CUG repeats were confirmed. To the best of the authors' knowledge, the estimated binding stoichiometry for some of the tested compounds (i.e., ~ 121:1 for PTMD against the tested RNA probe) is reported for the first time. Additionally, the potential of a novel pentamidine like compound, namely 1,2-ethane bis-1-amino-4-benzamidine (EBAB) with much lower in vivo toxicity than its parent compound has also been confirmed studying its effect on a live cell model by fluorescence microscopy. Further tests, such as the evaluation of the rescue in the mis-splicing of the involved genes, can be performed to corroborate the potential therapeutic value of EBAB in DM1 treatment. Graphical abstract ᅟ | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Affinity capillary electrophoresis | |
| 650 | 4 | |a Fluorescence in situ hybridization | |
| 650 | 4 | |a Ligand screening | |
| 650 | 4 | |a Myotonic dystrophy type 1 | |
| 650 | 4 | |a Pentamidine | |
| 650 | 7 | |a 1,2-ethane bis-1-amino-4-benzamidine |2 NLM | |
| 650 | 7 | |a Benzamidines |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
| 650 | 7 | |a Pentamidine |2 NLM | |
| 650 | 7 | |a 673LC5J4LQ |2 NLM | |
| 700 | 1 | |a Hambye, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Bodoki, Ede |e verfasserin |4 aut | |
| 700 | 1 | |a Palmieri, Claudio |e verfasserin |4 aut | |
| 700 | 1 | |a Ansseau, Eugénie |e verfasserin |4 aut | |
| 700 | 1 | |a Belayew, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Oprean, Radu |e verfasserin |4 aut | |
| 700 | 1 | |a Blankert, Bertrand |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Analytical and bioanalytical chemistry |d 1995 |g 410(2018), 18 vom: 07. Juli, Seite 4495-4507 |w (DE-627)NLM118176722 |x 1618-2650 |7 nnns |
| 773 | 1 | 8 | |g volume:410 |g year:2018 |g number:18 |g day:07 |g month:07 |g pages:4495-4507 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00216-018-1107-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 410 |j 2018 |e 18 |b 07 |c 07 |h 4495-4507 | ||