Conjugates bearing multiple formyl-methionyl peptides display enhanced binding to but not activation of phagocytic cells

Shahriar Pooyan, Bo Qiu, Marion M. Chan, Dunne Fong, Patrick J. Sinko, Michael J Leibowitz, Stanley Stein

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

N-Formyl-methionyl peptides can specifically bind to surface receptors on phagocytic cells. A single copy of N-formyl-methionine-leucine-phenylalanine (fMLF) covalently linked to a poly(ethylene glycol)-based polymer displayed reduced binding avidity (Kd = 190 nM) for differentiated HL-60 cells relative to free fMLF (Kd = 28 nM). Increasing the number of fMLF residues (up to eight) attached to a single polymer results in enhanced avidity for these cells (Kd = 0.18 nM), which appears to be independent of whether the polymer backbone is linear or branched. However, no conjugate showed enhanced ability to activate phagocytic cells, relative to the free peptide (EC50 = 5 nM), as measured by transient stimulation of release of calcium ions from intracellular stores into the cytoplasm. A polymer bearing four fMLF and four digoxigenin residues showed specific enhancement in binding to differentiated HL-60 cells and mouse peritoneal macrophages in situ relative to a polymer lacking fMLF; no such enhancement was seen in binding to receptor-negative lymphocytic Jurkat cells. These results suggest that multiple fMLF residues linked to a drug-delivery polymer can be used to target appended drugs to phagocytic cells with relatively little toxicity due to cellular activation.

Original languageEnglish (US)
Pages (from-to)216-223
Number of pages8
JournalBioconjugate Chemistry
Volume13
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

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