title: Screening of Drugs Inhibiting In vitro Oligomerization of Cu/Zn-Superoxide Dismutase with a Mutation Causing Amyotrophic Lateral Sclerosis.
abstract: Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) gene have been shown to cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS). A major pathological hallmark of this disease is abnormal accumulation of mutant SOD1 oligomers in the affected spinal motor neurons. While no effective therapeutics for SOD1-ALS is currently available, SOD1 oligomerization will be a good target for developing cures of this disease. Recently, we have reproduced the formation of SOD1 oligomers abnormally cross-linked via disulfide bonds in a test tube. Using our in vitro model of SOD1 oligomerization, therefore, we screened 640 FDA-approved drugs for inhibiting the oligomerization of SOD1 proteins, and three effective classes of chemical compounds were identified. Those hit compounds will provide valuable information on the chemical structures for developing a novel drug candidate suppressing the abnormal oligomerization of mutant SOD1 and possibly curing the disease.
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University Yokohama, Japan.
authors.forename: Itsuki
authors.initials: I
authors.lastname: Anzai
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University Yokohama, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Toichi
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University Yokohama, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.affiliation: Research Center of Integrative Molecular Systems, Institute for Molecular ScienceOkazaki, Japan; Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies)Okazaki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mukaiyama
authors.affiliation: Research Center of Integrative Molecular Systems, Institute for Molecular ScienceOkazaki, Japan; Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies)Okazaki, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Akiyama
authors.affiliation: Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University Yokohama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
keywords: Cu/Zn-superoxide dismutase; amyotrophic lateral sclerosis; drug screening; protein aggregation; protein misfolding