Abstract
Borologs containing peptide boronates are new bifunctional biologically active molecules which bind to and inhibit thrombin. These compounds are designed based on the C-terminal sequence of hirudin. The inhibitors consists of four parts, i) an active site inhibitor, D-Phe Pro-Boro(aa)-OPin. ii) an anion binding exosite association moiety, Hirudin, iii) a spacer to link these components and iv) a novel ‘flexor’ non-peptide unit to allow correct orientation. The bivalent nature of the inhibitor [-D-PheProBoroBpgOPin]CO(CH 2) 3COGly 2Hir enhanced binding up to 10 fold greater than the corresponding native peptide Z-D-PheProBoroBpgOPin or the mixture of non covalently linked units, and resulted in a potent and selective inhibitor of thrombin having a Ki of 0.6nM. For the synthesis of these compounds suitably protected aminoboronate derivatives were shown to be compatible with FMOC solid phase chemistry.
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