Synthesis and Characterization of Glucose Responsive Insulins
Lin Yan
Principal Scientist, Merck & Co., Inc.
Insulin therapy is the mainstay of treatment of type I diabetes and some advanced type II diabetes. Both fast-acting insulin, e.g., insulin lispro/aspart, and basal insulin, e.g., insulin glargine/degludec, have been developed to control patient blood glucose after meals and between meals/during sleep, respectively, to mimic endogenous insulin action. Insulin, however, has a narrow therapeutic window — overdosing insulin could lead to severe and sometimes fatal hypoglycemia. The clearance of exogenous insulin, once administrated, is independent upon the blood glucose concentration in patient, and the fear of hypoglycemia, especially nocturnal hypoglycemia, prevents a strict control of blood glucose using insulin. A smart insulin or a glucose-responsive insulin, which adjusts insulin action upward or downward in response to changing blood glucose levels, can allow for tighter glucose control in diabetic patient. Our study demonstrates that insulin conjugated with carbohydate ligands, e.g., mannose and its derivatives, which bind to endogenous mannose receptor C-type 1, acquires a novel blood glucose-dependent clearance pathway in addition to clearance through insulin receptor. Subsequent glycoengineering led to the identification of our clinical candidate MK-2640 with glucose lowering capability sensitive to blood glucose concentrations within physiologically relevant range in preclinical animals. Moreover, the presentation will describe the synthetic chemistry challenges associated with site selective functionalization of insulin and discuss the chemistry approach that was adopted to prepare MK-2640 and analogs.
Lin obtained his BS in Polymer Physics from University of Science and Technology of China (USTC) and did his PhD study in Chemistry under the guidance of Professor Dan Kahne at Princeton. After a postdoctoral study with Professor George Whitesides at Harvard, he joined Bristol-Myers Squibb at Princeton in 1998, working in cardiovascular disease area. Since joined Merck Research Lab in 2001, he has worked on therapeutic areas related to immunology, hematology, obesity, diabetes, hypertension, anti-infectious and cancer, spanning from small molecule to large proteins, in the field of bioconjugation, peptide chemistry, chemical and enzymatic ligation, and targeted delivery of lipid nanoparticles.