Molecular Engineering of Efficacious Mono-Valent Ultra-Long Acting Two-Chain Insulin-Fc Conjugates

Autor:	Tina M. Tagmose, Karen-Margrethe Pedersen, Lone Pridal, Carsten E. Stidsen, Marie Ø. Pedersen, Zhaosheng Lin, Yuanyuan Zhang, Zhe Wan, Mercedes Ferreras, Helle Naver, Peter K. Nielsen, Zheng Cao, Yi Wang, Lennart Lykke, Josefine L. Christensen, Victoria S. Jensen, Valentina Manfè, Thomas Å. Pedersen, Eva Johansson, Peter Madsen, János T. Kodra, Martin Münzel, Leonardo De Maria, Erica Nishimura, Thomas B. Kjeldsen
Rok vydání:	2022
Předmět:	Male Immunoconjugates Mesocricetus Protein Engineering Cell Line Diabetes Mellitus Experimental Immunoglobulin Fc Fragments Insulin Long-Acting Rats Sprague-Dawley Drug Discovery Animals Humans Hypoglycemic Agents Molecular Medicine Amino Acid Sequence
Zdroj:	Journal of Medicinal Chemistry. 65:2633-2645
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.1c02039
Popis:	Here, we describe molecular engineering of monovalent ultra-long acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were synthesized using trifunctional linkers with one amino reactive group for reaction with a lysine residue of insulin and two thiol reactive groups used for re-bridging of a disulfide bond within the Fc molecule. The ultra-long pharmacokinetic profile of the insulin-Fc conjugates was the result of concertedly slowing insulin receptor-mediated clearance by (1) introduction of amino acid substitutions that lowered the insulin receptor affinity and (2) conjugating insulin to the Fc element. Fc conjugation leads to recycling by the neonatal Fc receptor and increase in the molecular size, both contributing to the ultra-long pharmacokinetic and pharmacodynamic profiles.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b517e3f0eea1d2de015b33913626c34 https://doi.org/10.1021/acs.jmedchem.1c02039 Zobrazit plný text záznamu