This application aims to demonstrate that Scanning Unnatural Protease Resistant (SUPR) peptides provide a general solution to the problem of targeting traditionally undruggable proteins. To do this, we will use mRNA display with an expanded genetic code to create a new class highly stabilized, membrane-permeant peptides that can block or modulate protein-protein interactions for two of the most important intracellular proteins conferring the oncogenic phenotype-the activated form of Ras and the Stat3 protein. Our three Specific Aims are: 1) To design stabilized SUPR peptides targeting intracellular "undruggable" proteins involved in cancer transformation or maintenance, 2) To characterize and enhance selected SUPR peptide functions towards cancer drug applications, and 3) To evaluate in vivo characteristics and assess the therapeutic potential of optimized SUPR peptide drug candidates for cancer treatment in mice. Overall, this project is intended to develop novel molecules as well as a general approach to target cancer-relevant proteins that have proved challenging up to this point-so much so that the proteins may be called "undruggable."

Public Health Relevance

The development of novel technologies to inhibit undruggable therapeutic cancer targets is an important public health priority. It can expand our abilities to discover new cancer drugs and improve our abilities to manage cancer. Successful completion of the proposed studies will not only offer many new treatment opportunities for cancer, but also provide new tools for cancer drug discovery.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA170820-03
Application #
8678709
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Liu, Yarong; Fang, Jinxu; Kim, Yu-Jeong et al. (2014) Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol Pharm 11:1651-61
Liu, Yarong; Joo, Kye-Il; Lei, Yuning et al. (2014) Visualization of intracellular pathways of engineered baculovirus in mammalian cells. Virus Res 181:81-91
Liu, Yarong; Xiao, Liang; Joo, Kye-Il et al. (2014) In situ modulation of dendritic cells by injectable thermosensitive hydrogels for cancer vaccines in mice. Biomacromolecules 15:3836-45
Liu, Yarong; Fang, Jinxu; Joo, Kye-Il et al. (2014) Codelivery of chemotherapeutics via crosslinked multilamellar liposomal vesicles to overcome multidrug resistance in tumor. PLoS One 9:e110611
Jalali-Yazdi, Farzad; Corbin, Jasmine M; Takahashi, Terry T et al. (2014) Robust, quantitative analysis of proteins using peptide immunoreagents, in vitro translation, and an ultrasensitive acoustic resonant sensor. Anal Chem 86:4715-22
Howell, Shannon M; Fiacco, Stephen V; Takahashi, Terry T et al. (2014) Serum stable natural peptides designed by mRNA display. Sci Rep 4:6008