Piperine Derivatives Enhance Fusion and Axonal Transport of Mitochondria by Activating Mitofusins

Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum pharmacological activities. The molecular bases for many piperine’s biological effects are incompletely defined. We noted that chemical structure piperine generally conforms to pharmacophore model small bioactive molecules activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated fusion in MFN-deficient cells with EC50 ~8 nM. synthesized analogs having structural features predicted optimize activation defined structure-activity relationships (SAR) live-cell elongation assays. When optimal spacing was maintained between amide aromatic groups derivatives were potent activators. Compared prototype phenylhexanamide activator, 2, novel containing piperidine exhibited markedly enhanced passive membrane permeability no loss fusogenic potency. Lead compounds 5 8 motility cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, only improved transport sciatic nerve axons CMT2A mice. represent new class activators potential pharmaceutical advantages.