Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors

Area of Science:

• Molecular Biology
• Drug Discovery
• Cancer Biology

Background:

• Anti-apoptotic BCL-2 proteins prevent cell death by binding pro-apoptotic BH3 domains.
• Cancer cells exploit this mechanism, leading to resistance against chemotherapy.
• BFL-1, a BCL-2 homolog, is implicated in various cancers and remains an undrugged target.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting the anti-apoptotic protein BFL-1.
• To create an irreversible inhibitor for BFL-1 using a covalent stapled peptide approach.

Main Methods:

• Designed stapled BH3 peptides incorporating acrylamide warheads.
• Utilized the unique cysteine juxtaposition at the BFL-1/NOXA BH3 interface for covalent targeting.
• Investigated irreversible inhibition of BFL-1.

Main Results:

• Developed stapled BH3 peptides capable of irreversible BFL-1 inhibition.
• Demonstrated a novel covalent targeting strategy for BFL-1.
• Established a new therapeutic approach for cancers with high BFL-1 expression.

Conclusions:

• Covalent stapled peptide inhibitors represent a promising therapeutic strategy for targeting pathologic protein interactions.
• This approach can overcome resistance mechanisms in cancers by irreversibly inhibiting anti-apoptotic proteins like BFL-1.
• The findings pave the way for developing new treatments for BCL-2 family-mediated cancers.