Outstanding Superoxide Dismutase Catalytic Activity Of Simple Peptide-Based Nickel(II) Complexes.

Area of Science:

• Biochemistry
• Inorganic Chemistry
• Medicinal Chemistry

Background:

• Reactive oxygen species (ROS), including the superoxide anion (O2⋅-), are tightly regulated in vivo.
• Superoxide dismutases (SODs) are enzymes that catalyze the dismutation of superoxide radicals.
• Developing synthetic mimics of SODs is crucial for understanding their mechanisms and for therapeutic applications.

Purpose of the Study:

• To design and synthesize a novel, highly active synthetic nickel-based superoxide dismutase (NiSOD) mimic.
• To investigate the effect of charge modification on the catalytic activity and stability of the NiSOD mimic.
• To elucidate the structure-activity relationship of the NiSOD mimic based on its coordination environment and charge distribution.

Main Methods:

• Utilized the Amino-Terminal Cu(II)- and Ni(II)-binding (ATCUN) peptide motif for Ni(II) coordination.
• Synthesized a pentapeptide H-Cys-His-Cys-Arg-Arg-NH2 and a modified version with an additional arginine.
• Characterized the Ni(II) coordination modes (N3S1 and N2S2) at physiological pH.
• Measured catalytic activity (kcat) and stability under catalytic conditions.

Main Results:

• Achieved the highest reported catalytic activity (kcat = 8.6(4)×10^6 L·mol^-1·s^-1) for a synthetic NiSOD mimic.
• The catalyst demonstrated stability and quantitative superoxide consumption within the first second (up to 37 catalytic cycles).
• Increasing the global charge of the Ni(II) complex by adding an extra arginine did not affect catalytic performance.

Conclusions:

• The developed NiSOD mimic exhibits unprecedented catalytic efficiency and stability.
• Charge distribution, rather than the overall charge, is a critical factor influencing the reactivity of the NiSOD mimic.
• This work provides insights into the design principles for developing potent SOD mimics for biological and therapeutic applications.