Peptides can be potent and specific therapeutics, yet their small size leads to their rapid removal from the bloodstream by the kidneys, which severely limits their therapeutic potential. Although conjugation of small proteins to large polymers typically results in longer residence times, peptide-polymer conjugates often have a significant loss of biological activity due to steric hindrance. Here, we improve the pharmacokinetics of peptide therapeutics by harnessing the biology of vitamin D. We show that attachment of a vitamin D-based “carrier” molecule (D-VITylation<sup>™</sup>) protects the conjugated peptide or protein from renal clearance by virtue of reversible binding to the serum-circulating vitamin D binding protein (DBP), without compromising bioactivity. By varying the conjugation site on vitamin D, the binding to DBP varies, with higher affinity constructs corresponding to a longer plasma half-life <i>in vivo</i>. We demonstrated the half-life extending potential of D-VITylation on two natural peptide hormones, ghrelin and insulin, and one small protein, FGF21. We observed increases in plasma half-life and decreases in clearance ranging from 10-100 fold copared to that of unmodified peptide. As proof-of-principle, we demonstrate that a vitamin D-insulin conjugate lowers blood glucose levels for nearly 24 hours in a type 1 diabetic rat model.

D-VITylation: Harnessing the biology of vitamin D to improve the pharmacokinetic properties of peptides and small proteins

255th National Meeting (2018)

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