The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

Abstract

Efficient methods for the regulation of intracellular O₂˙⁻ and H₂O₂ levels, without altering intracellular processes, are urgently required for the rapidly growing interest in ROS signaling, as ROS signaling has been confirmed to be involved in a series of basic cellular processes including proliferation, differentiation, growth and migration. Intracellular H₂O₂ is formed mainly via the catalytic dismutation of O₂˙⁻ by SODs including SOD1, SOD2 and SOD3. Thus, the intracellular levels of O₂˙⁻ and H₂O₂ can directly be controlled through regulating SOD1 activity. Here, based on the active site structure and catalytic mechanism of SOD1, we developed a new type of efficient and specific SOD1 inhibitors which can directly change the intracellular levels of H₂O₂ and O₂˙⁻. These inhibitors inactivate intracellular SOD1 via localization into the SOD1 active site, thereby coordinating to the Cu²⁺ in the active site of SOD1, blocking the access of O₂˙⁻ to Cu²⁺, and breaking the Cu²⁺/Cu⁺ catalytic cycle essential for O₂˙⁻ dismutation. The reduced ERK1/2 phosphorylation induced by the specific SOD1 inactivation-mediated decrease of intracellular H₂O₂ levels reveals the potential of these specific SOD1 inhibitors in understanding and regulating ROS signaling. Furthermore, these specific SOD1 inhibitors also lead to selectively elevated cancer cell apoptosis, indicating that these kinds of SOD1 inhibitors might be candidates for lead compounds for cancer treatment.