Inventor(s): Kui Shen
Abstract
Protein phosphatases are regulatory enzymes in the biochemical pathways of living organisms and have been identified as pathogenic factors in diseases such as diabetes, obesity and cancers. Protein phosphatases are responsible for the dephosphorylation (phosphate removal) of proteins in a cell. Because phosphorylation is a dynamic process that is difficult to quantify and cannot be predicted by an organism genome, it is important to identify phosphoproteins, their phosphorylation sites and phosphatases responsible for their dephosphorylation.
This invention is an efficient method to identify protein phosphatases that involves the use of unnatural amino acids with novel chemical structures, their preparation, derivation and application as biomarkers, inhibitors and probes of protein phosphatases. As biomarkers, the unnatural amino acid derivatives detect the presence of normal or diseased variants of protein phosphatases. As general inhibitors or probes, the unnatural amino acids can facilitate isolation and visualization of protein phosphatases. As specific inhibitors or probes, the unnatural amino acids are mimics of the natural phosphoamino acids that allow for ready incorporation into peptides or analogs to utilize specific interactions enabled by peptide skeletons.
Potential commercial use and users:
The unnatural amino acids, which mimic natural phosphotyrosine, phosphoserine, or phosphothreonine, can be used as biomarkers for drug target identification and validation at various normal and diseased states, such as, but not limited to, diabetes and cancer. The compounds derived from the unnatural amino acids can be applied to biological samples such as cell lysates or cell cultures. The biomarkers can be used for labeling and subsequent monitoring of protein phosphatase activity.
Advantages:
This invention detects the presence of disease by administering an unnatural amino acid, binding it with a phosphatase, detecting a signal and thereby detecting the disease in warm blooded mammals, including humans. These compounds can be applied to biological samples such as cell lysates or cell cultures, or can be administered alone, as an active ingredient orally, subcutaneously or parenterally. The unnatural amino acids are readily modifiable and can take the general form or specific form of inhibitor/probe. They provide a controlled selectivity (specificity) of inhibitors and probes, ranging from class specificity, to sub-class specificity, to absolute specificity, for protein phosphatases acting upon phosphotyrosine. Currently available structures are not as good mimics of natural phosphoamino acids, limiting their specificity.
Related Publications:
Kui Shen, Lixin Qi, Mohini Ravula, and Krzysztof Klimaszewski. "Synthesis and peptide incorporation of an unnatural amino acid containing activity-based probe for protein tyrosine phosphatases." Bioorganic and Medicinal Chemistry Letter, 2009, In press. (Available for viewing through Science Direct)
Status: Patent Pending
Contact Us