Accession Number : ADA585745


Title :   Protein Aggregation Inhibitors for ALS Therapy


Descriptive Note : Final rept. 1 Jul 2010-30 Jun 2013


Corporate Author : NORTHWESTERN UNIV EVANSTON IL


Personal Author(s) : Silverman, Richard B ; Morimoto, Richard I ; Ferrante, Robert J ; Kirsch, Donald R ; Diamond, Betty


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a585745.pdf


Report Date : Jul 2013


Pagination or Media Count : 87


Abstract : Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, leading to death within 3-5 years. Gulf War veterans, and military personnel in general, exhibit a significant increased risk of developing ALS. There is no effective treatment for ALS; riluzole, the only FDA-approved drug for ALS, extends median survival by only 2-3 months. The genetic linkage of several mutations in the gene for Cu/Zn superoxide dismutase (SOD 1) in some cases of familial ALS provided the first indication of a potential causal factor in the disease. We identified three chemotypes (pyrazolones, cyclohexane-1,3-diones, and pyrimidine-2,4,6-triones) that provide protection from toxicity and block aberrant protein aggregation caused by mutant SOD1. Each of these chemotypes was modified to improve potency and pharmacological properties; our best compounds in each chemotype extended life of the ALS mouse model by 13%, 13%, and 31% (10 mg/kg bid), respectively. Maximum tolerated doses of all were high, indicating low toxicity. Four approaches were taken to identify protein target(s) of the pyrazole class. Affinity bait experiments identified proteins involved in proteasomal activation; photoaffinity experiments identified heat shock protein (HSP) 27 and related proteins. All of these results provide new potential treatments for ALS.


Descriptors :   *PHYSICAL DISABILITIES , *SPINAL CORD , ABNORMALITIES , CEREBRAL CORTEX , DAMAGE , DEATH , DISEASES , DOSAGE , DRUGS , GENES , GENETICS , LIFE EXPECTANCY(SERVICE LIFE) , MILITARY PERSONNEL , NERVE CELLS , PHARMACOLOGY , POTENCY , PROTECTION , PROTEINS , SHOCK , SUPEROXIDE DISMUTASE , TOXICITY


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE