Interaction of cisplatin with human superoxide dismutase

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of misfolded proteins, particularly human superoxide dismutase (hSOD1).
• Oxidized and demetalated forms of hSOD1 are prone to aggregation, contributing to ALS pathogenesis.

Purpose of the Study:

• To investigate the interaction between cisplatin and human superoxide dismutase (hSOD1).
• To evaluate cisplatin's potential in preventing and reversing hSOD1 aggregation, a hallmark of ALS.

Main Methods:

• Studied the binding of cisplatin to various forms of hSOD1, including the disulfide oxidized apo form.
• Determined the dissociation constant for cisplatin-hSOD1 interaction.
• Assessed cisplatin's effect on the aggregation, dissolution, and monomerization of demetalated oxidized hSOD1 in vitro and in cell models.

Main Results:

• Cisplatin binds to the disulfide oxidized apo form of hSOD1 with a dissociation constant of 37 ± 3 μM, specifically interacting with Cysteine 111 (Cys111).
• Cisplatin also binds to Cu(2)-Zn(2) and Zn(2)-Zn(2) forms of hSOD1.
• Cisplatin effectively inhibits the aggregation of demetalated oxidized hSOD1 and dissolves existing hSOD1 oligomers in vitro and within cells.

Conclusions:

• Cisplatin demonstrates significant potential as a therapeutic lead compound for amyotrophic lateral sclerosis (ALS).
• Its ability to interact with and disrupt hSOD1 aggregates offers a novel therapeutic strategy for ALS.