التفاصيل البيبلوغرافية
| العنوان: |
TDP-43 Modulation by Tau‑Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy |
| المؤلفون: |
Vanesa Nozal (9034427), Loreto Martínez-González (2911010), Marta Gomez-Almeria (11896116), Claudia Gonzalo-Consuegra (11896119), Paula Santana (3820921), Apirat Chaikuad (244322), Eva Pérez-Cuevas (11896122), Stefan Knapp (244328), Daniel Lietha (193525), David Ramírez (4053370), Sabrina Petralla (5681105), Barbara Monti (1504795), Carmen Gil (146118), Angeles Martín-Requero (11896125), Valle Palomo (356637), Eva de Lago (4767084), Ana Martinez (1313100) |
| سنة النشر: |
2022 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biophysics, Biochemistry, Cell Biology, Neuroscience, Pharmacology, Immunology, Hematology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, promising therapeutic strategy, motor neuron preservation, future als therapy, valuable lead compound, ttbk1 inhibitors emerge, 29 , valuable inhibitors, vivo <, tubulin kinase, translational modifications, spinal cord, proposing pyrrolopyrimidine, pathological hallmark, new avenue, m2 anti, inflammatory microglia, familiar patients, effective treatment, cell cultures, biological evaluation, animal models |
| الوصف: |
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase–ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound 29 revealed good brain penetration in vivo and was able to reduce TDP-43 phosphorylation not only in cell cultures but also in the spinal cord of transgenic TDP-43 mice. A shift to M2 anti-inflammatory microglia was also demonstrated in vivo . Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine 29 as a valuable lead compound for future ALS therapy. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/journal_contribution/TDP-43_Modulation_by_Tau_Tubulin_Kinase_1_Inhibitors_A_New_Avenue_for_Future_Amyotrophic_Lateral_Sclerosis_Therapy/17750151Test |
| DOI: |
10.1021/acs.jmedchem.1c01942.s001 |
| الإتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c01942.s001Test |
| حقوق: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.B7E0ADE4 |
| قاعدة البيانات: |
BASE |
