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.
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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)
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Chemical References |
- PG 97-269
- Peptide Fragments
- Receptors, Vasoactive Intestinal Polypeptide, Type I
- Vasoactive Intestinal Peptide
- Polyethylene Glycols
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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)
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