Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2401-6.

Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

Chou DH¹, Webber MJ², Tang BC², Lin AB², Thapa LS², Deng D², Truong JV², Cortinas AB³, Langer R⁴, Anderson DG⁴.

¹David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;

²David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112;

³Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

⁴David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Anesthesiology, Boston Children's Hospital, Boston, MA 02112; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139 rlanger@mit.edu dgander@mit.edu.

Abstract

Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.