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Antibody Binding Specificity for Kappa (Vκ) Light Chain-containing Human (IgM) Antibodies: Polysialic Acid (PSA) Attached to NCAM as a Case Study
Published on: June 29, 2016
Structural requirements for the binding of non-steroidal anti-inflammatory drugs to the 78 kDa gastrin binding
1University Department of Surgery, Austin Campus, A&RMC, Studley Rd., Heidelberg, Vic. 3084, Australia. g.baldwin@surgeryaustin.unimelb.edu.au
Abstract:
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the proliferation of colorectal carcinoma cell lines in vitro and reduce the risk of colorectal carcinoma in vivo. The good correlation observed between the potency of NSAIDs as inhibitors of colorectal carcinoma cell proliferation and as antagonists of a 78 kDa gastrin binding protein (GBP) suggested that blockade of the GBP might contribute to the anti-proliferative effects of NSAIDs [G.S. Baldwin, V.J. Murphy, Z. Yang, T. Hashimoto, J. Pharmacol. Exp. Ther. 286 (1998) 1110-1114]. The most potent NSAID investigated was sulindac sulphide, which had an IC50 value of 40 microM. In order to investigate the structural requirements for binding to the GBP, 26 analogues of sulindac sulphide and sulindac sulphoxide were tested for their ability to inhibit the binding of iodinated gastrin to the GBP. Six of the analogues inhibited gastrin binding by more than 50% at a concentration of 1 mM. The IC50 values estimated by computer fitting of titration data were in the range of 280-940 microM. Comparison of the analogue structures suggests that a substituent with a carboxyl group is preferred in the R2 position. In addition the location of the NSAID binding site within the GBP structure was investigated. NSAIDs bound to both the N- and C-terminal halves of the GBP, and the affinities determined were similar to the values previously reported for the full-length GBP. The results reported herein represent the first step in the rational design of more potent GBP antagonists, some of which may be useful for the treatment of colorectal carcinoma.
Insights
Non-steroidal anti-inflammatory drugs (NSAIDs) show anti-proliferative effects on colorectal carcinoma by blocking gastrin binding protein (GBP). Structural analysis of NSAID analogues reveals key features for potent GBP antagonism, aiding in the development of new cancer treatments.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Non-steroidal anti-inflammatory drugs (NSAIDs) demonstrate inhibitory effects on colorectal carcinoma cell proliferation in vitro and reduce cancer risk in vivo.
- A strong correlation exists between NSAID potency in inhibiting colorectal carcinoma cell proliferation and their antagonism of a 78 kDa gastrin binding protein (GBP).
- This suggests that blocking GBP may contribute to the anti-proliferative actions of NSAIDs.
Purpose of the Study:
- To investigate the structural requirements for NSAID binding to the gastrin binding protein (GBP).
- To identify key structural features of NSAID analogues that enhance their ability to antagonize GBP.
- To lay the groundwork for the rational design of more potent GBP antagonists for colorectal carcinoma treatment.
Main Methods:
- Tested 26 analogues of sulindac sulphide and sulindac sulphoxide for their ability to inhibit iodinated gastrin binding to GBP.
- Determined IC50 values for inhibition of gastrin binding using computer fitting of titration data.
- Investigated the location of the NSAID binding site within the GBP structure.
Main Results:
- Six analogues inhibited gastrin binding by over 50% at 1 mM, with IC50 values ranging from 280-940 microM.
- A substituent with a carboxyl group in the R2 position was found to be preferred for GBP binding.
- NSAIDs were found to bind to both N- and C-terminal halves of GBP with affinities comparable to those for the full-length protein.
Conclusions:
- The study provides crucial insights into the structural basis of NSAID-GBP interaction.
- Identified structural features that can be exploited for designing more effective GBP antagonists.
- These findings represent a significant step towards developing novel therapeutic agents for colorectal carcinoma targeting GBP.
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