Synthesizing an inhibitor of Thimet Oligopeptidase (TOP) may reveal more about TOP's function both in vitro and in vivo. According to the Shrimpton Lab, cFP, a tripeptide shown in Figure 1A, is an effective competitive inhibitor of TOP in vitro; however, in vivo, cFP was hydrolyzed at the alanine-tyrosine bond. The hydrolysis products confounded the experiment in two ways. The pieces were found to be 1/1,000th times as potent as the intact cFP. Second, the components were inhibiting other endopeptidases besides TOP. Thus, cFP was not a viable inhibitor, so Shrimpton et al. synthesized another inhibitor, JA-2, which is a modified version of cFP with an Aib amino acid replacing the second alanine as shown in Figure 1B. JA-2 is non-hydrolyzable in vivo. However, JA-2 resulted in secondary side effects not expected when inhibiting TOP. Thus, to find out if JA-2 inhibits other proteins besides TOP, another inhibitor must be synthesized. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/240nm/uploads/38823_fig.1.jpg' alt='' />The goal of this study is to use solution phase peptide synthesis to make a non-hydrolyzable version of cFP that has a minor change to the molecule: changing the oxygen of the second alanine to a sulfur. The thioamide version of the cFP inhibitor is expected to be less susceptible to cleavage in vivo. It is expected that the thiopeptide in Figure 1C may be a more specific inhibitor to TOP than JA-2.

Solution phase peptide synthesis of thioamide TOP inhibitor

247th National Meeting (2014)

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