Proteins that behave as switches hold great promise as selective protein therapeutics. Previous studies by the PI have demonstrated that protein switches can be engineered by creating a large number of different fusions between two genes and subjecting these gene fusions to evolution in the lab. Such directed evolution strategies will be used to develop and improve protein switches to effectively activate prodrugs selectively in cancer cells. These switches will be evaluated for their ability to eliminate tumor xenographs in vivo using endogenous expression and via systemic delivery. These switches in combination with the appropriate prodrug have potential as a targeted therapeutic for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066972-11
Application #
8641375
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Gerratana, Barbara
Project Start
2003-07-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
$385,920
Indirect Cost
$139,149
Name
Johns Hopkins University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ribeiro, Lucas Ferreira; Tullman, Jennifer; Nicholes, Nathan et al. (2016) A xylose-stimulated xylanase-xylose binding protein chimera created by random nonhomologous recombination. Biotechnol Biofuels 9:119
Nicholes, N; Date, A; Beaujean, P et al. (2016) Modular protein switches derived from antibody mimetic proteins. Protein Eng Des Sel 29:77-85
Choi, Jay H; Zayats, Maya; Searson, Peter C et al. (2016) Electrochemical activation of engineered protein switches. Biotechnol Bioeng 113:453-6
Choi, Jay H; Ostermeier, Marc (2015) Rational design of a fusion protein to exhibit disulfide-mediated logic gate behavior. ACS Synth Biol 4:400-6
Choi, Jay H; Laurent, Abigail H; Hilser, Vincent J et al. (2015) Design of protein switches based on an ensemble model of allostery. Nat Commun 6:6968
Chaikind, Brian; Ostermeier, Marc (2014) Directed evolution of improved zinc finger methyltransferases. PLoS One 9:e96931
Wright, R Clay; Khakhar, Arjun; Eshleman, James R et al. (2014) Advancements in the development of HIF-1α-activated protein switches for use in enzyme prodrug therapy. PLoS One 9:e114032
Valdes, Gilmer; Schulte, Reinhard W; Ostermeier, Marc et al. (2014) The High-Affinity Maltose Switch MBP317-347 has Low Affinity for Glucose: Implications for Targeting Tumors with Metabolically Directed Enzyme Prodrug Therapy. Chem Biol Drug Des 83:266-71
Kanwar, Manu; Wright, R Clay; Date, Amol et al. (2013) Protein switch engineering by domain insertion. Methods Enzymol 523:369-88
Guntas, Gurkan; Kanwar, Manu; Ostermeier, Marc (2012) Circular permutation in the ýý-loop of TEM-1 ýý-lactamase results in improved activity and altered substrate specificity. PLoS One 7:e35998

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