Strategies in the design and development of (TAR) DNA-binding protein 43 (TDP-43) binding ligands.

TitleStrategies in the design and development of (TAR) DNA-binding protein 43 (TDP-43) binding ligands.
Publication TypeJournal Article
Year of Publication2021
AuthorsRao, PPN, Shakeri, A, Zhao, Y, Calon, F
JournalEur J Med Chem
Volume225
Pagination113753
Date Published2021 Dec 05
ISSN1768-3254
KeywordsAnimals, DNA-Binding Proteins, Drug Development, Humans, Ligands, Molecular Structure, Oligonucleotides, Peptides, Small Molecule Libraries
Abstract

The human transactive responsive (TAR) DNA-binding protein 43 (TDP-43) is involved in a number of physiological processes in the body. Its primary function involves RNA regulation. The TDP-43 protein is also involved in many diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and even cancers. These TDP-43 mediated diseases are collectively called as TDP-43 proteinopathies. Intense research in the last decade has increased our understanding on TDP-43 structure and function in biology. The three-dimensional structures of TDP-43 domains such as N-terminal domain (NTD), RNA-recognition motif-1 (RRM1), RNA-recognition motif-2 (RRM2) and the C-terminal domain (CTD) or low-complexity domain (LCD) have been solved. These structures have yielded insights into novel binding sites and pockets at various TDP-43 domains, which can be targeted by designing a diverse library of ligands including small molecules, peptides and oligonucleotides as molecular tools to (i) study TDP-43 function, (ii) develop novel diagnostic agents and (iii) discover disease-modifying therapies to treat TDP-43 proteinopathies. This review provides a summary on recent progress in the development of TDP-43 binding ligands and uses the solved structures of various TDP-43 domains to investigate putative ligand binding regions that can be exploited to discover novel molecular probes to modulate TDP-43 structure and function.

DOI10.1016/j.ejmech.2021.113753
Alternate JournalEur J Med Chem
PubMed ID34388383