School of Chemistry - Research Publications

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Author: HOSSAIN, MOHAMMED × Author: Karas, John × Author: Separovic, Frances × End date: 2015 × Start date: 2012 × Type: Journal Article ×

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    Total chemical synthesis of a heterodimeric interchain bis-lactam-linked Peptide: application to an analogue of human insulin-like Peptide 3.
    Karas, J ; Shabanpoor, F ; Hossain, MA ; Gardiner, J ; Separovic, F ; Wade, JD ; Scanlon, DB (Hindawi Limited, 2013)
    Nonreducible cystine isosteres represent important peptide design elements in that they can maintain a near-native tertiary conformation of the peptide while simultaneously extending the in vitro and in vivo half-life of the biomolecule. Examples of these cystine mimics include dicarba, diselenide, thioether, triazole, and lactam bridges. Each has unique physicochemical properties that impact upon the resulting peptide conformation. Each also requires specific conditions for its formation via chemical peptide synthesis protocols. While the preparation of peptides containing two lactam bonds within a peptide is technically possible and reported by others, to date there has been no report of the chemical synthesis of a heterodimeric peptide linked by two lactam bonds. To examine the feasibility of such an assembly, judicious use of a complementary combination of amine and acid protecting groups together with nonfragment-based, total stepwise solid phase peptide synthesis led to the successful preparation of an analogue of the model peptide, insulin-like peptide 3 (INSL3), in which both of the interchain disulfide bonds were replaced with a lactam bond. An analogue containing a single disulfide-substituted interchain lactam bond was also prepared. Both INSL3 analogues retained significant cognate RXFP2 receptor binding affinity.
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    2-Nitroveratryl as a Photocleavable Thiol-Protecting Group for Directed Disulfide Bond Formation in the Chemical Synthesis of Insulin
    Karas, JA ; Scanlon, DB ; Forbes, BE ; Vetter, I ; Lewis, RJ ; Gardiner, J ; Separovic, F ; Wade, JD ; Hossain, MA (WILEY-V C H VERLAG GMBH, 2014-07-28)
    Chemical synthesis of peptides can allow the option of sequential formation of multiple cysteines through exploitation of judiciously chosen regioselective thiol-protecting groups. We report the use of 2-nitroveratryl (oNv) as a new orthogonal group that can be cleaved by photolysis under ambient conditions. In combination with complementary S-pyridinesulfenyl activation, disulfide bonds are formed rapidly in situ. The preparation of Fmoc-Cys(oNv)-OH is described together with its use for the solid-phase synthesis of complex cystine-rich peptides, such as insulin.