A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides

Research output: Contribution to journalArticle

Authors

  • Anna Wolska
  • Larry Lo
  • Denis O. Sviridov
  • Mohsen Pourmousa
  • Milton Pryor
  • Soumitra S. Ghosh
  • Rahul Kakkar
  • Michael Davidson
  • Sierra Wilson
  • Richard W. Pastor
  • Steven K. Drake
  • Antony Cougnoux
  • Ming Jing Wu
  • Saskia B. Neher
  • Lita A. Freeman
  • Jingrong Tang
  • Marcelo Amar
  • Matt Devalaraja
  • Alan T. Remaley

External Institution(s)

  • National Institutes of Health
  • Corvidia Therapeutics
  • University of North Carolina at Chapel Hill

Details

Original languageEnglish (US)
Article numbereaaw7905
JournalScience Translational Medicine
Volume12
Issue number528
StatusPublished - Jan 29 2020
Peer-reviewedYes

Abstract

Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II-deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr−/−) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl−/−) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.

Citation formats

APA

Wolska, A., Lo, L., Sviridov, D. O., Pourmousa, M., Pryor, M., Ghosh, S. S., ... Remaley, A. T. (2020). A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides. Science Translational Medicine, 12(528), [eaaw7905]. https://doi.org/10.1126/scitranslmed.aaw7905

Harvard

Wolska, A, Lo, L, Sviridov, DO, Pourmousa, M, Pryor, M, Ghosh, SS, Kakkar, R, Davidson, M, Wilson, S, Pastor, RW, Goldberg, IJ, Basu, D, Drake, SK, Cougnoux, A, Wu, MJ, Neher, SB, Freeman, LA, Tang, J, Amar, M, Devalaraja, M & Remaley, AT 2020, 'A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides', Science Translational Medicine, vol. 12, no. 528, eaaw7905. https://doi.org/10.1126/scitranslmed.aaw7905