The back cover picture shows two views at 150 degree rotation of vitamin B12 conjugated to the potent anti- hyperglycemia peptide glucagon-like peptide-1 (GLP-1). The conjugate displays similar receptor binding and agonism to unconjugated GLP-1, including insulin potentiation from human transplant pancreatic islet cells, which bodes well for oral delivery of GLP-1 through the B12 dietary pathway. For more details, see the Communication by Robert P. Doyle et al. on p. 582 ff.
From the free press department… The cover for the April, 2013 issue of ChemMEDChem (just the cover art this time, no theoretical content in the associated article. All the theory's figured out!). I'm still awaiting the journal's posting of the article content but wanted to get something up in March. For related content, see the discussion on the "MedChemComm September 2012 Front Cover Image For The 'Examining The Effects Of Vitamin B12 Conjugation…' Paper" post or any of the B12-related posts on this site (www.somewhereville.com/index.php?s=b12). This work is similar in scope to the B12-insulin bioconjugate work in the previous studies, but now includes a different peptide (glucagon-like peptide-1) with similar properties.
Published in MedChemComm (direct link: xlink.rsc.org/?doi=C2MD20040F). And Happy Belated New Year. After the methodological work that went into the Molecular Biosystems paper, this was a remarkably simple molecular dynamics study of the changes to vitamin B12 binding in transcobalamin II (TCII) with the B12 conjugated to the first amino acid side chain in the B-Chain of insulin. The structure of the B12-insulin conjugate is shown below in a molecular dynamics snapshot, which reveals that the binding of B12 to its TCII transport protein is negligibly affected.
And apparently the experiments went well, too. Cover hopefully to follow.
Susan Clardy-James, Damian G. Allis, Timothy J. Fairchild and Robert P. Doyle
Abstract: The practical use of the vitamin B12 uptake pathway to orally deliver peptides and proteins is much debated. To understand the full potential of the pathway however, a deeper understanding of the impact B12 conjugation has on peptides and proteins is needed. We previously reported an orally active B12 based insulin conjugate attached at LysB29 with hypoglycaemic properties in STZ diabetic rats. We are exploring an alternative attachment for B12 on insulin in an attempt to determine the effect B12 has on the protein biological activity. We describe herein the synthesis, characterization, and purification of a new B12-insulin conjugate, which is attached between the B12 ribose hydroxyl group and insulin PheB1. The hypoglycemic properties resulting from oral administration (gavage) of such a conjugate in STZ diabetic rats was similar to that noted in a conjugate covalently linked at insulin LysB2911, demonstrating the availability of both position on insulin for B12 attachment. A possible rationale for this result is put forward from MD simulations. We also conclude that there is a dose dependent response that can be observed for B12-insulin conjugates, with doses of conjugate greater than 10-9 M necessary to observe even low levels of glucose drop.