R. Alhazmi, S. Darwish, S. Fong, K. Parang, S. Yang
Chapman University School of Pharmacy,
Keywords: APE/Ref-1 inhibitor, melanoma, cyclic polypeptide, drug delivery, anti-tumor activity
Summary:Human malignant melanoma exhibits impaired redox status and abnormal redox-regulated signal pathways. Induced as an adaptive response to reactive oxygen species (ROS) and reactive nitrogen species (RNS), a multi-functional protein called APE/Ref-1 serves as a redox chaperone and modulator of many nuclear transcription factors maintaining intracellular redox status. Our previous studies showed that knockdown of APE/Ref-1 significantly sensitized melanoma cells to chemo-treatment and reduced their metastatic potential, suggesting APE/Ref-1 may be a potential druggable target for human melanoma. Utilizing three-dimensional modeling and virtual docking, we have screened compounds from 35 chemical vendors with a total number of more than 7 million. Through extensive chemical modifications of our top-ranked candidates, we have successfully synthesized novel APE/Ref-1 inhibitors #R21, which exhibited promising anti-tumor activity both in vitro and in vivo. However, due to the hydrophobic characteristic of compound R21, it has been challenging to administer via intraperitoneal injection as increased precipitation was evident once diluted in 0.9% sodium chloride. In our study, we are using a cell-penetrating cyclic peptide nano drug delivery system designed to transport molecular cargo across the cellular membrane using non-covalent interactions between the molecular cargo and peptide. The peptide, consisting of alternating arginine (R) and tryptophan (W) amino acids, generates nanoparticles through self-assembly and intermolecular interactions of hydrophobic and positively-charged amino acids. We have previously shown that the cyclic peptide allows more efficient cellular internalization and nuclear delivery of anticancer and antiviral agents. Notably, our study also revealed that the cyclic peptide itself significantly reduced the expression levels of APE/Ref-1 and sensitized melanoma cells to cisplatin-induced cytotoxicity. More study is underway to determine the underlying mechanisms. By conjugating the cyclic peptide as a nano drug delivery agent with novel-designed specific APE/Ref-1 inhibitors, we hope to develop an effective strategy for melanoma therapy with improved efficacy and drug delivery.