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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides
ACS applied bio materials, Vol.3(12), pp.8978-8988
21 Dec 2020
PMID: 35019574
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular beta-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (K-D = 667 +/- 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.
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Details
- Title
- Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides
- Creators
- Victoria Harbour - New Jersey Institute of TechnologyCandice Casillas - Stevens Institute of TechnologyZain Siddiqui - New Jersey Institute of TechnologyBiplab Sarkar - New Jersey Institute of TechnologySreya Sanyal - New Jersey Institute of TechnologyPeter Nguyen - New Jersey Institute of TechnologyKa Kyung Kim - New Jersey Institute of TechnologyAbhishek Roy - New Jersey Institute of TechnologyPatricia Iglesias-Montoro - New Jersey Institute of TechnologySaloni Patel - New Jersey Institute of TechnologyFrank Podlaski - Stevens Institute of TechnologyPeter Tolias - Stevens Institute of TechnologyWilliam Windsor - Stevens Institute of TechnologyVivek Kumar - Rutgers, The State University of New Jersey
- Publication Details
- ACS applied bio materials, Vol.3(12), pp.8978-8988
- Publisher
- Amer Chemical Soc
- Number of pages
- 11
- Grant note
- IIP 1903617 / National Science Foundation NSF; National Science Foundation (NSF) R15 EY029504 / National Eye Institute NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) NJIT startup funds NJIT Undergraduate Research and Innovation (URI) program 2019288435 / National Science Foundation GRFP Program
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Identifiers
- 991021956862404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Materials Science, Biomaterials
- Nanoscience & Nanotechnology