Mn-SpecificRecognitionof Guanidine Drives SelectiveInhibition 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 [Mn^III(TTPPC^2–)]⁺ was selected to insert into the gap of NDUFS2. Experimental and computational analyses revealed that the planar π system of the TTPPC^2– 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, Mn^III(TTPPC^2–)]⁺ 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.