0428同步年報-2021-全

046 ACTIVITY REPORT 2021 Given the specific mode of recognition of metal II -(Chro) 2 complexes at G4C2 DNA, the team confirmed in Drosophila (fruit fly) models of ALS/FTD that the compound complexes can alleviate the motor deficits caused by neuronal toxicity and suppress the locomotor deficits ( Fig. 3(d) ). Previous studies have shown that Drosophila is an excellent model organism for study of neurological diseases and discovery of antineurological drugs. The results of the current study thus open the possibility of using a DNA-binding compound to treat the pathogenesis of diseases associated with G4C2 repeat expansion. The extensive research conducted by the team of Hou and his collaborators, from X-ray crystallography and biophysical analysis in vitro to animal model in vivo , confirms the importance of targeting DNA duplexes in the context of disease. This study not only provides a new direction for drug development against ALS and FTD, but is also likely to open new possibilities for the treatment of other neurological diseases. (Reported by Roshan Satange, National Chung Hsing University) This report features the work of Ming-Hon Hou and his collaborators published in Nucleic Acids Res. 49 , 16 (2021). TPS 05A Protein Microcrystallography TLS 15A1 Biopharmaceuticals Protein Crystallography • X-ray Crystallography • Biological Macromolecules, Neurological Diseases, DNA Structures, Life Science References 1. A. E. Renton, et al ., Neuron 72 , 257 (2011). 2. S.-C. Ling, M. Polymenidou, D. W. Cleveland, Neuron 79 , 416 (2013). 3. R. Balendra, A. M. Isaacs, Nat. Rev. Neurol. 14 , 544 (2018). 4. C.-R. Jhan, R. Satange, S.-C. Wang, J.-Y. Zeng, Y.-C. Horng, P. Jin, S. Neidle, M.-H. Hou, Nucleic Acids Res. 49 , 9526 (2021). Fig. 3 : (a) Chemical structure of chromomycin A3 (Chro) dimer in presence of Nickel(II) (Ni II (Chro) 2 ). (b) Overall crystal structure of the Ni II (Chro) 2 -G4C2 DNA complex. (c) Superimposition of the structures of G4C2 DNA duplex (blue) and CPX1 of Ni II (Chro) 2 -DNA (pink). (d) Effects of metal II (Chro) 2 on G4C2 repeat toxicity in the Drosophila showing inhibition of the neuronal toxicity in the fly eye and suppression of the locomotor deficits. [Reproduced from Ref. 4]