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Open AccessFeature PaperArticle

Activating the Intrinsic Pathway of Apoptosis Using BIM BH3 Peptides Delivered by Peptide Amphiphiles with Endosomal Release

1
Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
2
Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
3
Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73071, USA.
Materials 2019, 12(16), 2567; https://doi.org/10.3390/ma12162567
Received: 29 June 2019 / Revised: 2 August 2019 / Accepted: 5 August 2019 / Published: 12 August 2019
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Abstract

Therapeutic manipulation of the BCL-2 family using BH3 mimetics is an emerging paradigm in cancer treatment and immune modulation. For example, peptides mimicking the BIM BH3 helix can directly target the full complement of anti- and pro-apoptotic BCL-2 proteins to trigger apoptosis. This study has incorporated the potent BH3 α-helical death domain of BIM into peptide amphiphile (PA) nanostructures designed to facilitate cellular uptake and induce cell death. This study shows that these PA nanostructures are quickly incorporated into cells, are able to specifically bind BCL-2 proteins, are stable at physiologic temperatures and pH, and induce dose-dependent apoptosis in cells. The incorporation of a cathepsin B cleavable linker between the BIM BH3 peptide and the hydrophobic tail resulted in increased intracellular accumulation and mitochondrial co-localization of the BIM BH3 peptide while also improving BCL-2 family member binding and apoptotic reactivation. This PA platform represents a promising new strategy for intracellular therapeutic peptide delivery for the disruption of intracellular protein:protein interactions. View Full-Text
Keywords: peptide amphiphile; peptide therapeutics; cathepsin; BCL-2 family; BIM; BH3-only; apoptosis peptide amphiphile; peptide therapeutics; cathepsin; BCL-2 family; BIM; BH3-only; apoptosis
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Schnorenberg, M.R.; Bellairs, J.A.; Samaeekia, R.; Acar, H.; Tirrell, M.V.; LaBelle, J.L. Activating the Intrinsic Pathway of Apoptosis Using BIM BH3 Peptides Delivered by Peptide Amphiphiles with Endosomal Release. Materials 2019, 12, 2567.

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