Insulin is the first polypeptide hormone discovered. But it still doesn't have an antagonist?
The question is why would you need an antagonist? Experimental or clinical use?
The clinical case where the the use an insulin receptor antagonist is practical is pancreatic insulinomas,but surgical removal of the tumors is a curative procedure. In short as research has shown insulin secretion is tightly regulated by the islet cells. The other option for its usage is to block the process of desensitization of the insulin receptor which is suggested as mechanism of insulin resistance. But insulin receptor desensitization as a mechanism insulin resistance is very debatable theory.
I understand your point. To fullfill your goal, if you have any connection with staff at your center operating within basic/translational sciences, you can try to design peptidomimetic antagonists to prevent protein-protein interaction at the level of the insulin receptor. A methodological paper is enclosed:
Curr Protein Pept Sci. 2005 Apr;6(2):151-69.
Also, I came across this paper: Citation: Knudsen L, Hansen BF, Jensen P, Pedersen TÅ, Vestergaard K, et al. (2012) Agonism and Antagonism at the Insulin Receptor. PLoS ONE 7(12): e51972. doi:10.1371/journal.pone.0051972
The abstract is enclosed. I suppose you can give it a try.
Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B’29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1–10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints (3H-thymidine incorporation), and not on metabolic endpoints (14C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity (3H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B’29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.
The use of the same antagonist has been successfully validated by another group:
Biochem Biophys Res Commun. 2010 Jul 23;398(2):260-5. doi: 10.1016/j.bbrc.2010.06.070. Epub 2010 Jun 19.
Good luck with your work. Hope this can be of help
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