Mn-Specific Recognition of Guanidine Drives Selective Inhibition of Complex I

Developing
structurally well-defined targeted drugs is an effective
way to enhance the chemotherapy efficacy. Herein, a target mitochondrial
complex I (complex I) inhibitor was developed for the key methylation
site ARG-85 in the key subunit NDUFS2. Based on the unique :NHC–
group of guanidyl and the surrounding environment of ARG-85, the macrocyclic
and bulky manganese porphyrin complex [MnIII(TTPPC2–)]+ was selected to insert into the gap
of NDUFS2. Experimental and computational analyses revealed that the
planar π system of the TTPPC2– ligand and
the rotatable benzene ring stably bind between the :NHC–
group of ARG-85 and the manganese metal center, a medium-strong Lewis
acid. The Mn-specific recognition of guanidine drives the selective
inhibition of complex I activity. Further, MnIII(TTPPC2–)]+ was modified into targeted nanoformulation
Mn NPs. In vitro and in vivo experiments confirmed the efficient and
mechanism inhibition of complex I activity, offering a novel strategy
for targeted drug development.