Targeted Amino Acid Substitution Overcomes Scale-Up Challenges with the Human C5a-Derived Decapeptide Immunostimulant EP67

Abdulraman M. Alshammari, D. David Smith, Jake Parriott, Jason P. Stewart, Stephen M. Curran, Russell J. McCulloh, Peter A. Barry, Smita S. Iyer, Nicholas Palermo, Joy A. Phillips, Yuxiang Dong, Donald R. Ronning, Jonathan L. Vennerstrom, Sam D. Sanderson, Joseph A. Vetro

Research output: Contribution to journalArticlepeer-review

Abstract

EP67 is a second-generation, human C5a-derived decapeptide agonist of C5a receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to potentiate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Pro7 and N-methyl-Leu8 (Me-Leu8) amino acid residues within EP67 likely induce backbone structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils versus first-generation EP54. The low coupling efficiency between Pro7 and Me-Leu8 and challenging purification by HPLC, however, greatly increase scale-up costs of EP67 for clinical use. Thus, the goal of this study was to determine whether replacing Pro7 and/or Me-Leu8 with large-scale amenable amino acid residues predicted to induce similar structural changes (cyclohexylalanine7 and/or leucine8) sufficiently preserves EP67 activity in primary human mononuclear phagocytes and neutrophils. We found that EP67 analogues had similar potency, efficacy, and selective activation of mononuclear phagocytes over neutrophils. Thus, replacing Pro7 and/or Me-Leu8 with large-scale amenable amino acid residues predicted to induce similar structural changes is a suitable strategy to overcome scale-up challenges with EP67.

Original languageEnglish (US)
Pages (from-to)1169-1181
Number of pages13
JournalACS infectious diseases
Volume6
Issue number5
DOIs
StatePublished - May 8 2020

Keywords

  • EP54
  • complement peptide-derived immunostimulant (CPDI)
  • host-derived immunostimulant
  • host-directed therapy
  • human C5a desArg
  • mucosal adjuvant

ASJC Scopus subject areas

  • Infectious Diseases

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