Macrocyclic Statine‐Based Inhibitors of BACE‐1

Abstract

Minimal sequence requirements for binding of substrate-derived statine peptides to the aspartyl enzyme were established on the basis of the X-ray cocrystal structure of the hydroxyethylene-octapeptide OM00-3 in complexation with BACE-1. With this information to hand, macrocyclic compounds that conformationally restrict and preorganize the peptide backbone for an entropically favoured binding to the enzyme active site cleft were designed. By means of a side chain-to-side chain ring closure between two aspartyl residues in the P2 and P3' positions through phenylene-1,3-dimethanamine, a 23-membered ring structure was obtained; this structure retained an extended conformation of the peptide backbone, including the transition state analogue statine for tight interactions with the two aspartyl residues of the active centre. The conformational preorganization of the inhibitor molecule was verified by NMR structural analysis and was then confirmed by the crystal structure of the BACE-1/inhibitor complex. Detailed insights into the binding mode of this macrocyclic inhibitor explained its moderate binding affinity in cell-free assays (K(i)=2.5 microM) and yielded precious information for possible structural optimization in view of the lack of steric clashes of the macrocycle with the flap domain of the enzyme.

The Binding Mechanism of a Peptidic Cyclic Serine Protease Inhibitor

“…[21][22][23][24] In an interesting study, solution structures of statine-based cyclic peptidic inhibitors were determined by NMR spectroscopy, energetics of binding to its target, the aspartyl protease BACE-1 (β-secretase) was measured by ITC and the structure of the complex was determined by X-ray crystallography. 25 These statinebased cyclic peptidic inhibitors were optimized to adopt a preorganized conformation in solution that reduced the entropic loss upon formation of complex with BACE-1. Similarly, the rather large entropic contribution of upain-1 binding to uPA opens up the possibility of improving the affinity of the core peptide by reducing the entropic loss during binding without affecting the binding mode (ΔH) of the peptide.…”

Anti-amyloidogenic Heterocyclic Peptides

“…Several studies have reported macroheterocyclic peptidomimetic inhibitors of β-secretases (Fig. 8c, d) that fit into the relatively large-size active site of the aspartic peptidase [109,[121][122][123][124]. Macrocyclic ethers and lactones have been used to pre-organize and stabilize bioactive conformations with improved activity and physicochemical properties relative to the linear counterparts (reviewed in [125]).…”

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

“…[Barrow et al, 2008]; and (9) tyramines [Kuglstatter et al, 2008]. Some of the designs also introduce macrocyclic constraints [Barazza et al, 2007;Hanessian et al, 2006;Lindsley et al, 2007;Rojo et al, 2006;Stachel et al, 2006] based on the observation of close contacts between portions of the inhibitors as bound in the BACE-1 active site.…”