Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans
| Autor: | Peter Madsen, Thomas Kjeldsen, Claus Bekker Jeppesen, Hanne H. F. Refsgaard, Trine Porsgaard, Helle Naver, Sanne Gram-Nielsen, Frantisek Hubalek, Lone Pridal, Tina Møller Tagmose, Erica Nishimura, Inger Lautrup-Larsen, Carsten Enggaard Stidsen, Valentina Manfè, Thomas Hoeg-Jensen, Claudia Ulrich Hjørringgaard, Svend Ludvigsen, Christian Fledelius |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Injections Subcutaneous Insulin analog Type 2 diabetes 01 natural sciences Drug Administration Schedule Rats Sprague-Dawley 03 medical and health sciences Dogs Internal medicine Diabetes mellitus Drug Discovery medicine Animals Humans Hypoglycemic Agents Insulin 030304 developmental biology Glycemic 0303 health sciences biology Insulin glargine Chemistry Albumin medicine.disease 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Insulin receptor Endocrinology Diabetes Mellitus Type 2 Injections Intravenous biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 64(13) |
| ISSN: | 1520-4804 |
| Popis: | Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure-activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure-activity relationship study leading to insulin icodec is presented here. |
| Databáze: | OpenAIRE |
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