Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities

被引:30
作者
Soares, Pedro [1 ]
Silva, Catia [1 ]
Chavarria, Daniel [1 ]
Silva, Filomena S. G. [2 ]
Oliveira, Paulo J. [2 ,3 ]
Borges, Fernanda [1 ]
机构
[1] Univ Porto, Fac Sci, Dept Chem & Biochem, CIQUP IMS, Porto, Portugal
[2] Univ Coimbra, CNC CNC Ctr Neurosci & Cell Biol, CIBB Ctr Innovat Biomed & Biotechnol, P-3004504 Coimbra, Portugal
[3] Univ Coimbra, IIUC Inst Interdisciplinary Res, P-3030789 Coimbra, Portugal
基金
欧盟地平线“2020”;
关键词
Amyotrophic Lateral Sclerosis; Mitochondria; Oxidative stress; Ferroptosis; Hypoxia-inducible factor; Nuclear Factor kappa B; NF-KAPPA-B; HYPOXIA-INDUCIBLE FACTOR; TRANSGENIC MOUSE MODEL; MOTOR-NEURON DEGENERATION; OXIDASE INHIBITOR DRUGS; EARLY PARKINSON-DISEASE; IRON CHELATOR; DOUBLE-BLIND; SUPEROXIDE-DISMUTASE; CEREBROSPINAL-FLUID;
D O I
10.1016/j.arr.2022.101790
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major reg-ulators of hypoxia and inflammation - HIF and NF-kappa B - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi -target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.
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页数:20
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