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X Fact
January 18, 2021
Complexity Rating

Intrinsically Motivated

Vitamin B12 (B12), also known as cobalamin, is a water-soluble vitamin essential for human health and development. Only naturally produced by bacteria and archaea, B12 must be consumed through diet. To see the structure and read more on B12 uptake, see our earlier X Facts (b12-is-the-biggest-and-most-complex-vitamin-by-far and how-does-a-big-molecule-like-vitamin-b12-get-absorbed-from-the-intestine). Given the specific dietary uptake pathway evolved to protect, transport and target B12 where it is needed, it is an ideal candidate to be used as a drug modifier, transporter or targeting vehicle. Successful chemical modification or conjugation of B12 and subsequent exploitation of its dietary uptake and systemic pathway for the development of new pharmaceuticals has been undergoing considerable recent research. We now understand and have access to critical information necessary for the medicinal chemist in terms of B12 sites of conjugation to facilitate specific binding, access to dietary proteins to explore binding affinity and selectivity, and effects on the tethered drug, etc.

One area in particular focuses on using the gastrically produced B12 binding protein Intrinsic Factor (IF) (how-scientists-discovered-intrinsic-factor-and-its-vital-role-in-vitamin-b12-absorption) and the fact that IF, when bound with B12, will only bind to a receptor called cubilin, a receptor found primarily in the intestines and kidneys.  Cubilin is a multi-purpose receptor that can bind several ligands beyond IF-B12 but has a specific region for such in so called ‘CUB’ domains 5–8.

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Who Wrote This X Fact
Robert P. Doyle PhD
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Prof. Robert Doyle is a medicinal chemist with an interest in pharmaceutical drug and probe development for the study and treatment of obesity and type 2 diabetes. He has a broad background in peptide and protein design and expression, synthetic bio-conjugate chemistry, drug delivery, protein biochemistry and assay development. In 2005, he was appointed Assistant Professor of Chemistry at Syracuse University and promoted, with tenure, to Associate Professor in 2009 and then full Professor in 2014. He is also adjunct Associate Professor of Medicine at SUNY, Upstate Medical University (UMU). In 2016, He was named the Laura J. and L. Douglas Meredith Professor, Syracuse University.  As a Principal Investigator (PI), he has focused on the  chemistry of vitamin B12 and its dietary pathway and components to modify drug pharmacodynamics and/or pharmacokinetics. He has been funded by the NIH and DoD, as well as multiple societies, foundations and pharmaceutical companies.  He has published over 100 research papers (35+ in the vitamin B12 space) and is the holder of over a dozen patents.

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