Indiana University

Merck Sharp + Dohme Corp.

Pengyun Li

Richard Dennis DiMarchi

Jie Han

Michael A Meehl

Todd Parody

Alexei Kharitonenkov

Archita S Agrawal

Richard D Dimarchi

Disclosed herein are modified C-terminal fragments of FGF21 optimized for binding to Klotho &#x3b2; or antagonizing FGF21 activity. FGF21 peptides modified to comprise modifications to the C-terminal amino acid sequence are disclosed that have enhanced activity at the FGF21 receptor. Additionally, conjugates formed between the optimized FGF21 peptide fragments and insulin like peptides or nuclear hormone receptor ligands are provided.

FGF21 C-terminal peptide optimization

Disclosed herein are insulin agonist peptides conjugated to a glucagon analog wherein the insulin/glucagon conjugate is targeted to liver tissues upon administration to a patient.

Insulin-incretin conjugates

Compositions and formulations comprising insulin or insulin analogs comprising a carboxy terminal portion (CTP) peptide comprising amino acids 112-118 to 145 of the beta subunit of human chorionic gonadotropin (hCG&#x3b2;) or a partial variant thereof that includes at least one O-glycosylation site of the CTP peptide, wherein the CTP peptide of the CTP peptide-based insulin or insulin analog is O-glycosylated are described. In particular embodiments, the O-glycosylated insulin analogs are produced in vivo and in further embodiments, the O-glycosylated CTP-based insulin analogs comprise predominantly mannotriose and mannotetrose O-glycans or predominantly mannose O-glycans.

O-glycosylated carboxy terminal portion (CTP) peptide-based insulin and insulin analogues

Insulin analogs comprising a non-native glycosylation site sequence are provided having high potency and specificity for the insulin receptor. In one embodiment a peptide sequence of greater than 18 amino acids is used as a linking moiety to link human insulin A and B chains, or analogs or derivatives thereof, to provide high potency single chain insulin analogs. In one embodiment the linking moiety comprises one or more glycosylation sites. Also disclosed are prodrug and conjugate derivatives of the insulin analogs.

Growing community of inventors

Bloomington, IN, United States of America

Pengyun Li