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

Efficient methods for the regulation of intracellular O(2)˙(–) and H(2)O(2) 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 H(2)O(2) is formed mainly via the catalytic dismutation of O(2)˙(–) by SODs including SOD1, SOD2 and SOD3. Thus, the intracellular levels of O(2)˙(–) and H(2)O(2) 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 H(2)O(2) and O(2)˙(–). These inhibitors inactivate intracellular SOD1 via localization into the SOD1 active site, thereby coordinating to the Cu(2+) in the active site of SOD1, blocking the access of O(2)˙(–) to Cu(2+), and breaking the Cu(2+)/Cu(+) catalytic cycle essential for O(2)˙(–) dismutation. The reduced ERK1/2 phosphorylation induced by the specific SOD1 inactivation-mediated decrease of intracellular H(2)O(2) 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.