TY - JOUR
T1 - Engineering of a Biologically Active Insulin Dimer
AU - Liu, Mengjie
AU - White, Barbara F.
AU - Praveen, Praveen
AU - Li, Wenyi
AU - Lin, Feng
AU - Wu, Hongkang
AU - Li, Rong
AU - Delaine, Carlie
AU - Forbes, Briony E.
AU - Wade, John D.
AU - Hossain, Mohammed Akhter
PY - 2021/12/9
Y1 - 2021/12/9
N2 - The growing epidemic of diabetes means that there is a need for therapies that are more efficacious, safe, and convenient. Here, we report the efficient synthesis of a novel disulfide dimer of human insulin tethered at the N-terminus of its B-chain through placement of a cysteine residue. The resulting peptide was shown to bind to both the insulin receptor isoform B and insulin-like growth factor-1 receptor with comparable affinity to native insulin. In in vivo insulin tolerance tests, the dimer was equipotent to Actrapid insulin and possessed a sustained duration of action greater than that of Actrapid and Glargine. While the secondary structure of our dimeric insulin was similar to that of insulin, it was more resistant to proteolysis. More importantly, our analogue was produced in quantitative yield from a monomeric thiol insulin scaffold. Our results suggest that this dimer has significant potential to address the clinical needs in the treatment of diabetes.
AB - The growing epidemic of diabetes means that there is a need for therapies that are more efficacious, safe, and convenient. Here, we report the efficient synthesis of a novel disulfide dimer of human insulin tethered at the N-terminus of its B-chain through placement of a cysteine residue. The resulting peptide was shown to bind to both the insulin receptor isoform B and insulin-like growth factor-1 receptor with comparable affinity to native insulin. In in vivo insulin tolerance tests, the dimer was equipotent to Actrapid insulin and possessed a sustained duration of action greater than that of Actrapid and Glargine. While the secondary structure of our dimeric insulin was similar to that of insulin, it was more resistant to proteolysis. More importantly, our analogue was produced in quantitative yield from a monomeric thiol insulin scaffold. Our results suggest that this dimer has significant potential to address the clinical needs in the treatment of diabetes.
KW - Thiols
KW - Peptides and proteins
KW - Carbohydrates
KW - Oligomers
KW - Receptors
UR - http://www.scopus.com/inward/record.url?scp=85120378344&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
U2 - 10.1021/acs.jmedchem.1c01594
DO - 10.1021/acs.jmedchem.1c01594
M3 - Article
AN - SCOPUS:85120378344
SN - 0022-2623
VL - 64
SP - 17448
EP - 17454
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -