This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Many potent and specific peptides suffer problems of short or sub-optimal duration. A possible solution to such problems involves conjugation to macromolecules such as polyethylene glycol (PEG) that are slowly eliminated from the body, and thus prolong the action of the attached peptide. For peptide therapeutics, it is usually essential that the unchanged drug be released from the macromolecule with timing appropriate to satisfy the need. Current approaches often use cleavable linkers to attach the peptide to the macromolecule by a linker that cleaves because of the effect of an enzyme, or physiological environment. Although such approaches are often successful, they usually do not allow prediction or control of the rate of drug release and hence the duration of action. The objective of this project is a) to develop a novel platform technology that allows site-specific attachment of a macromolecule -- PEG or pegylated dendrimers ?to peptides, and b) to develop technology for predictable, chemically-controlled release of such peptides. If successful, a) we will have developed general technology for controlled release of peptides from macromolecules that could be broadly applied and set the stage for future applications of such technology to therapeutic peptides. The UCSF mass spectrometry facility collaboration will allow us to confirm the structures of linker-drug, PEG-linker drug and dendrimer-linker-drug conjugates. It may also enable determination of the latter two in pharmacokinetic studies.
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