Conjugates Bearing Multiple Formyl-Methionyl Peptides Display Enhanced Binding to but Not Activation of Phagocytic Cells

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• 作者：Shahriar Pooyan ; Bo Qiu ; Marion M. Chan ; Dunne Fong ; Patrick J. Sinko ; Michael J. Leibowitz ; and Stanley Stein
• 刊名：Bioconjugate Chemistry
• 出版年：2002
• 出版时间：March 2002
• 年：2002
• 卷：13
• 期：2
• 页码：216 - 223
• 全文大小：86K
• 年卷期：v.13,no.2(March 2002)
• ISSN：1520-4812

文摘

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