Peptide Vectors for Intracellular Targeting
Controlling the intracellular localization of synthetic molecules is essential for effective drug development. Nonetheless, rational control over intracellular trafficking of small molecules has remained a challenge. The Kelley lab has engineered peptide-based conjugates to deduce rules for manipulating intracellular localization of bioactive molecules. These compounds also provide useful tools for the cellular delivery of chemically or biologically active species and can be used to study organelle-specific processes.
We have used these vectors to delivery a variety of bioactive cargo to mitochondria. Clinically-utilized anticancer drugs that typically act within the nucleus have been shown to have interesting activities when delivered to mitochondria, and we have also developed a strategy to detoxify antimicrobials within human cells by sequestering the drugs within this organelle.
"Targeted Delivery of Doxorubicin of Doxorubicin to Mitochondria.” G. Chamberlain, D.V. Tulumello, S.O. Kelley, ACS Chemical Biology, 2013, in press.
"Tuning the Activity of Mitochondria-Penetrating Peptides for Delivery or Disruption." K.L. Horton, M.P. Pereira, K.M. Stewart, S.B. Fonseca, S.O. Kelley, Chembiochem, 2012, 13, 476. link
"Maximizing the Therapeutic Window of an Antimicrobial Drug by Imparting Mitochondrial Sequestration in Human Cells " M.P. Pereira, S.O. Kelley, Journal of the American Chemical Society, 2011, 133, 3260. link
"Re-routing Chlorambucil to Mitochondria Enhances Potency and Combats Drug Resistance in Cancer Cells " S.B. Fonseca, M.P. Pereira, R. Mourtada, M. Gronda, R. Hurren, M.D. Minden, A.D. Schimmer, S.O. Kelley, Chemistry and Biology, 2011, 18, 445. link
“Mitochondria-Penetrating Peptides.” K.L. Horton, K.M. Stewart, S.B. Fonseca, Q. Guo, S.O. Kelley, Chemistry & Biology, 2008, 15, 375. link