Blogging a blog post recently blogged here in a post, with a zoom-in below because no decent-sized version of the same can be found on the MedChemComm site, all pertaining to the "Examining the effects of vitamin B12 conjugation on the biological activity of insulin: a molecular dynamic and in vivo oral uptake investigation" article from Susan Clardy-James, myself, Timothy J. Fairchild and Robert P. Doyle in ChemMedComm (available at pubs.rsc.org/en/Content/ArticleLanding/2012/MD/C2MD20040F).
The MedChemComm post also provides the caption for the cover (below), which I reproduce below for context:
Oral delivery of drugs aims to open up new areas of peptide/protein therapeutics associated with the removal for a need for injections. The major problems facing oral delivery of peptides/proteins is hydrolysis/proteolysis in the gastrointestinal tract and an inefficient uptake mechanism for peptides/proteins from the tract. Robert P. Doyle et al. are interested in the use of the vitamin B12 dietary uptake pathway to address these hurdles. In this paper Doyle et al. report the synthesis, purification and characterisation of a new B12-insulin conjugate attached between the B12 ribose hydroxyl group and insulin PheB1.
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.