Generation of PEGylated VPAC1-selective antagonists that inhibit proliferation of a lung cancer cell line.

Abstract

Vasoactive intestinal peptide (VIP) binds to two receptors, VPAC1 and VPAC2. Non-selective VIP antagonists have been shown to inhibit human cancer cell proliferation and reduce tumor growth in mice. Many human cancers over-express VPAC1 but not VPAC2. We show that VPAC1-selective antagonists can inhibit human cancer cell proliferation and identify five positions in the VPAC1-selective antagonist PG 97-269 that may be responsible for VPAC1 selectivity. Position 16 appears to be particularly critical for selectivity, as demonstrated in the replacement of Arg16 of PG 97-269 with the native VIP amino acid; this single change results in greatly reduced VPAC1 binding and selectivity. Finally, we show that site-specific conjugation with a 22kDa polyethylene glycol (PEG) at the C-terminus of VPAC1-selective antagonists further improves VPAC1-selective binding and has minimal effect on antagonistic activity. Our studies have further solidified VPAC1 as a cancer target and offer the possibility of generating highly potent VPAC1-selective antagonists with minimal number of mutations to reduce the risk of immunogenicity and potentially prolonged duration of action to allow more efficient treatment regimen.

• Authors: Clark Q Pan, Sarah Hamren, Steve Roczniak, Irene Tom, Mary DeRome
• Journal: Peptides (Peptides) Vol. 29 Issue 3 Pg. 479-86 (Mar 2008) ISSN: 0196-9781 [Print] United States
• PMID: 17942192 (Publication Type: Journal Article)

Chemical References

• PG 97-269
• Peptide Fragments
• Receptors, Vasoactive Intestinal Polypeptide, Type I
• Vasoactive Intestinal Peptide
• Polyethylene Glycols

Topics

• Amino Acid Sequence
• Animals
• CHO Cells
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cricetinae
• Cricetulus
• Electrophoresis, Polyacrylamide Gel
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Molecular Sequence Data
• Peptide Fragments (chemistry, pharmacology)
• Polyethylene Glycols (chemistry)
• Protein Binding (drug effects)
• Radioimmunoassay
• Receptors, Vasoactive Intestinal Polypeptide, Type I (antagonists & inhibitors, genetics, metabolism)
• Sequence Homology, Amino Acid
• Structure-Activity Relationship
• Vasoactive Intestinal Peptide (chemistry, pharmacology)