Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 138, Issue 18, Pages 5848-5859Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b11759
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Funding
- National Institutes of Health [GM084152]
- University of Minnesota Supercomputer Institute
- University of Minnesota Imaging Center
- Nikon Center of Excellence
- University of Minnesota Graduate School
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Photoremovable protecting groups are important for a wide range of applications in peptide chemistry. Using Fmoc-Cys(Bhc-MOM)-OH, peptides containing a Bhc-protected cysteine residue can be easily prepared. However, such protected thiols can undergo isomerization to a dead-endproduct (a 4-methylcoumarin-3-yl thibethet) upon photolysis. To circumvent that photoisomerization problem, we explored the use of nitrodibenzofuran (NDBF) for thiol protection by preparing cysteine-containing peptides where the thiol is masked with an NDBF group. This was accomplished by synthesizing Fmoc-Cys(NDBF)-OH and incorporating that residue into peptides by standard solid-phase peptide synthesis procedures. Irradiation with 365 run light or two-photon excitation with 800 nm light resulted in efficient deprotection: To probe biological utility, thiol group uncaging was carried out using a peptide derived from the protein K-Ras4B yield a sequence that is a known substrate for protein farnesyltransferase; irradiation of the NDBF-caged peptide in the presence of the enzyme resulted in the formation of the farnesylated product. Additionally, incubation of human ovarian carcinoma (SKOV3) cells with an NDBF-caged version of a farnesylated peptide followed by UV irradiation resulted in migration of the peptide from the cytosol/Golgi to the plasma membrane due:to enzymatic palmitoylation. Overall, the high cleavage:efficiency devoid of side reactions and significant two-photon cross-section of NDBF render it superior to Bhc for thiol group caging. This protecting group should be useful for a plethora of applications ranging from the development of light-activatable cysteine-containing peptides to the development of light-sensitive biomaterials.
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