Macrocyclic statine-based inhibitors of BACE-1

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Aspartyl enzymes, such as Beta-secretase 1 (BACE-1), play a crucial role in amyloid precursor protein processing.
• Inhibitors of BACE-1 are sought as potential therapeutics for Alzheimer's disease.
• Understanding enzyme-inhibitor interactions at a molecular level is key for drug design.

Purpose of the Study:

• To establish minimal sequence requirements for substrate-derived statine peptide binding to aspartyl enzymes.
• To design and synthesize novel macrocyclic inhibitors that preorganize the peptide backbone for enhanced binding to BACE-1.
• To elucidate the binding mode of these macrocyclic inhibitors within the BACE-1 active site.

Main Methods:

• X-ray cocrystallography of BACE-1 in complex with a hydroxyethylene-octapeptide (OM00-3).
• Design and synthesis of a 23-membered macrocyclic inhibitor via side chain-to-side chain ring closure.
• Nuclear Magnetic Resonance (NMR) structural analysis to verify conformational preorganization.
• X-ray crystallography of the BACE-1/macrocyclic inhibitor complex.

Main Results:

• Established minimal sequence requirements for statine peptide binding to BACE-1.
• Designed and synthesized a macrocyclic inhibitor that retains an extended peptide backbone conformation and transition state analogue (statine).
• Confirmed conformational preorganization of the macrocycle through NMR and crystal structures.
• Observed moderate binding affinity (K(i)=2.5 microM) with no steric clashes with the BACE-1 flap domain.

Conclusions:

• Macrocyclic compounds can conformationally restrict and preorganize peptide backbones for entropically favored binding.
• The designed macrocyclic inhibitor demonstrates a viable strategy for targeting BACE-1.
• The structural insights gained provide a foundation for further optimization of BACE-1 inhibitors for Alzheimer's disease therapy.