Peptides are promising mid-size drugs for its own advantages such as high efficiency, low toxicity and good biocompatibility
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AbstractPeptides are promising mid-size drugs for its own advantages such as high efficiency, low toxicity and good biocompatibility. Covalently bonded peptide-target complex is attracting more and more attention due to its high stability and long duration time in metabolism. We have developed a method named “affinity guided covalent conjugation” (AGCC) that short peptides (within 12 amino acids) can site-specifically recognize their complementary proteins through thiol-chloroacetyl SN2 reaction. Guided by the 3D structure analysis of the wild type complex, a selected position of the protein was mutated to Cystein, while at the same time an alpha-chloroacetyl group was installed at a corresponding position of the peptide. Specific binding interaction between the two brings the reactive groups into close proximity, converts the non reactive Cys residue into a content-dependent reactive site, and induces the nucleophilic reaction that is inert in the absence of the binding event. A comprehensive investigation on the delivery of this system to the in vivo application was further studied to prove the specificity, orthogonality and modularity of the reaction in the living system. A truncated peptide ligand library was designed to target the conserved Cys in the binding pocket of human growth receptor protein2 (Grb2). With the assistance of cell penetrating peptide,the peptide ligand could covalently bonded to the endogenous Grb2 and thus inhibit the Grb2 mediated signaling pathway. This has paved the way for developing AGCC for biology relevant therapeutics.
All Author(s) ListNIE Yunyu
Name of Conference8th Takeda Science Foundation Symposium on PharmaSciences: Biomolecule-Based Medicinal Science: Featuring Mid-Size Drugs
Start Date of Conference21/01/2016
End Date of Conference22/01/2016
Place of ConferenceOsaka
Country/Region of ConferenceJapan
Year2016
Month1
Day21
LanguagesEnglish-United Kingdom
KeywordsPharmaSciences; Takeda

Last updated on 2018-22-01 at 16:04