Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides

Victoria Harbour, Candice Casillas, Zain Siddiqui, Biplab Sarkar, Sreya Sanyal, Peter Nguyen, Ka Kyung Kim, Abhishek Roy, Patricia Iglesias-Montoro, Saloni Patel, Frank Podlaski, Peter Tolias, William Windsor, Vivek Kumar

Research output: Contribution to journalArticlepeer-review

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 β-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 (KD = 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.

Original languageEnglish (US)
Pages (from-to)8978-8988
Number of pages11
JournalACS Applied Bio Materials
Volume3
Issue number12
DOIs
StatePublished - Dec 21 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biomaterials
  • Biomedical Engineering
  • Biochemistry, medical

Keywords

  • LDL
  • PCSK9
  • cholesterol metabolism
  • peptide amphiphiles
  • self-assembly

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