TY - JOUR
T1 - Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides
AU - Harbour, Victoria
AU - Casillas, Candice
AU - Siddiqui, Zain
AU - Sarkar, Biplab
AU - Sanyal, Sreya
AU - Nguyen, Peter
AU - Kim, Ka Kyung
AU - Roy, Abhishek
AU - Iglesias-Montoro, Patricia
AU - Patel, Saloni
AU - Podlaski, Frank
AU - Tolias, Peter
AU - Windsor, William
AU - Kumar, Vivek
N1 - Funding Information:
We would like to thank NJIT startup funds (for V.K.) and the NJIT Undergraduate Research and Innovation (URI) program. V.K. acknowledges support from the National Eye Institute NIH R15 EY029504 and National Science Foundation NSF IIP 1903617. V.H. acknowledges support from the National Science Foundation GRFP Program (2019288435).
Publisher Copyright:
© 2020 ACS. All rights reserved.
PY - 2020/12/21
Y1 - 2020/12/21
N2 - 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.
AB - 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.
KW - LDL
KW - PCSK9
KW - cholesterol metabolism
KW - peptide amphiphiles
KW - self-assembly
UR - http://www.scopus.com/inward/record.url?scp=85097870356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097870356&partnerID=8YFLogxK
U2 - 10.1021/acsabm.0c01229
DO - 10.1021/acsabm.0c01229
M3 - Article
AN - SCOPUS:85097870356
SN - 2576-6422
VL - 3
SP - 8978
EP - 8988
JO - ACS Applied Bio Materials
JF - ACS Applied Bio Materials
IS - 12
ER -