TY - JOUR
T1 - Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin
AU - Hossain, Mohammed Akhter
AU - Okamoto, Ryo
AU - Karas, John A.
AU - Praveen, Praveen
AU - Liu, Mengjie
AU - Forbes, Briony E.
AU - Wade, John D.
AU - Kajihara, Yasuhiro
PY - 2020/1/22
Y1 - 2020/1/22
N2 - Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps. Because of the solubilizing and hydration effects of sugars, it was thought that glycosylation of insulin could inhibit fibril formation and lead to a more stable formulation. Since enzymatic glycosylation results in heterogeneous products, we developed a novel chemical strategy to produce a homogeneous glycoinsulin (disialo-glycoinsulin) in excellent yield (∼60%). It showed a near-native binding affinity for insulin receptors A and B in vitro and high glucose-lowering effects in vivo, irrespective of the route of administration (s.c. vs i.p.). The glycoinsulin retained insulin-like helical structure and exhibited improved stability in human serum. Importantly, our disialo-glycoinsulin analogue does not form fibrils at both high concentration and temperature. Therefore, it is an excellent candidate for clinical use in insulin pumps.
AB - Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps. Because of the solubilizing and hydration effects of sugars, it was thought that glycosylation of insulin could inhibit fibril formation and lead to a more stable formulation. Since enzymatic glycosylation results in heterogeneous products, we developed a novel chemical strategy to produce a homogeneous glycoinsulin (disialo-glycoinsulin) in excellent yield (∼60%). It showed a near-native binding affinity for insulin receptors A and B in vitro and high glucose-lowering effects in vivo, irrespective of the route of administration (s.c. vs i.p.). The glycoinsulin retained insulin-like helical structure and exhibited improved stability in human serum. Importantly, our disialo-glycoinsulin analogue does not form fibrils at both high concentration and temperature. Therefore, it is an excellent candidate for clinical use in insulin pumps.
KW - Nanofibers
KW - Peptides and proteins
KW - Carbohydrates
KW - Monomers
KW - Post-translational modification
UR - http://www.scopus.com/inward/record.url?scp=85078332819&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1163310
UR - http://purl.org/au-research/grants/NHMRC/1023321
UR - http://purl.org/au-research/grants/NHMRC/1023078
UR - http://purl.org/au-research/grants/NHMRC/1117483
U2 - 10.1021/jacs.9b11424
DO - 10.1021/jacs.9b11424
M3 - Article
C2 - 31850747
AN - SCOPUS:85078332819
SN - 0002-7863
VL - 142
SP - 1164
EP - 1169
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 3
ER -