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Org Biomol Chem. 2013 Mar 21;11(11):1848-57. doi: 10.1039/c3ob27469a. Epub 2013 Jan 29.

Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization.

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Clemens-Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, 64287 Darmstadt, Germany.


Herein we report a convenient strategy for the development of novel, highly-potent peptidic inhibitors of the trypsin-like serine protease matriptase based on the monocyclic variant of the sunflower trypsin inihibitor-1 (SFTI-1[1,14]). We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties. This compound library comprising 6 peptides and 16 triazole-containing peptidomimetics was established via structure-guided rational design and synthesized using a divergent strategy employing "copper-click" chemistry. The most favorable amino acid substitutions were combined in one framework yielding potent SFTI-1-derived matriptase inhibitor-1 (SDMI-1) and the truncated dodecapeptide variant (SDMI-2) with single-digit nanomolar inhibition constants. In silico studies indicated that the improved matriptase affinity compared to the parent peptide is caused by the successful establishment of additional favorable proton donor-acceptor interactions between basic inhibitor side chains and acidic residues on the surface of the target enzyme. SDMI-1 and 2 are potent inhibitors of the pharmaceutically relevant protease matriptase at a near physiological pH and, thus, may find applications in therapy or diagnostics.

[Indexed for MEDLINE]

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