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.