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PEGylated Mitochondria-Targeted Drugs Have Potential in Cancer Treatment

PEGylation is the process of linking one or more polyethylene glycol (PEG) chains to a protein, peptide, or small molecule. In their article, “Combining PEGylated mito‑atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation,” published in Scientific Reports, Department of Biophysics researchers – Balaraman Kalyanaraman, PhD, chair and professor of biophysics and the Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research, and Gang Cheng, PhD, assistant professor – in collaboration with Micael Hardy, PhD, of Aix-Marseille Université, France, and Ming You, MD, PhD, of Houston Methodist Research Institute, discuss their discovery that that PEGylation of mitochondria-targeted atovaquone (Mito-ATO) forms a new and very potent class of OXPHOS inhibitors and antiproliferative agents.

PEGylation can improve a drug’s solubility and stability, increase serum half-life, and reduce immunogenicity without compromising activity. Depending on the chain length (n), at nanomolar concentrations, Mito-(PEG)n-ATO analogs selectively inhibit both complex I- and complex III-induced oxygen consumption in human pancreatic and brain cancer cells. Mito-PEG10-ATO synergistically enhances the antiproliferative potencies of inhibitors of monocarboxylate transport and glutaminase enzymes and of glutamine uptake in pancreatic and brain cancer cells. This combinatorial modality has translational potential in cancer treatment.