Signal transduction of hyaluronic acid-peptide conjugate for formyl peptide receptor like 1 receptor.

Abstract

Agonistic and antagonistic peptides for formyl peptide receptor like 1 (FPRL1) receptor have been investigated as novel drug candidates for inflammatory diseases such as sepsis, asthma, and rheumatoid arthritis. In this work, a novel protocol for the synthesis of hyaluronic acid (HA)-peptide (CWRYMVm) conjugate for FPRL1 receptor was successfully developed for further clinical applications of peptide drugs. Aminoethyl methacrylated HA (HAAEMA) was synthesized by the coupling reaction of tetrabutyl ammonium salt of HA (HA-TBA) and AEMA using benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP) in dimethyl sulfoxide (DMSO). Then, HA-AEMA was conjugated with CWRYMVm in water via Michael addition reaction between methacrylate group of HA-AEMA and thiol group in cysteine. The formation of HA-peptide conjugate was confirmed by 1H NMR and gel permeation chromatography (GPC). The average number of conjugated peptide molecules could be controlled from 5 to 23 per single HA chain. The HA-peptide conjugate showed serum stability longer than four days. In Vitro signal transduction activity of the HA-peptide conjugate for FPRL1 receptor was confirmed from the elevated levels of phospho-extracellular signal-regulated kinase (pERK) and calcium ion in FPRL1 overexpressing RBL-2H3 cells. The partially decreased biological activity of HA-peptide conjugates by the steric hindrance of HA was recovered after its degradation by hyaluronidase treatment.

• Authors: Eun Ju Oh, Jung-Wook Kim, Ji-Hyun Kong, Sung Ho Ryu, Sei Kwang Hahn
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 19 Issue 12 Pg. 2401-8 (Dec 2008) ISSN: 1520-4812 [Electronic] United States
• PMID: 19007292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ethylamines
• Methacrylates
• Oligopeptides
• Organophosphorus Compounds
• Receptors, Formyl Peptide
• Sulfhydryl Compounds
• benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
• N,N-diisopropylethylamine
• Hyaluronic Acid
• Extracellular Signal-Regulated MAP Kinases
• Calcium
• Dimethyl Sulfoxide

Topics

• Amino Acid Sequence
• Animals
• Calcium (metabolism)
• Cattle
• Cell Line
• Dimethyl Sulfoxide (chemistry)
• Ethylamines (chemistry)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hyaluronic Acid (chemistry)
• Intracellular Space (drug effects, metabolism)
• Methacrylates (chemistry)
• Oligopeptides (blood, chemistry, metabolism, pharmacology)
• Organophosphorus Compounds (chemistry)
• Receptors, Formyl Peptide (metabolism)
• Signal Transduction (drug effects)
• Sulfhydryl Compounds (chemistry)