Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22330%2F21%3A43934148" target="_blank" >RIV/60461373:22330/21:43934148 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388963:_____/21:00546413

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01388" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01388</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c01388" target="_blank" >10.1021/acs.jmedchem.1c01388</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities

Popis výsledku v původním jazyce

Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the &quot;metabolic&quot;IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [AlaB29,GluB31,amideB31]-insulin may be interesting for further clinical evaluation. © 2021 American Chemical Society.

Název v anglickém jazyce

Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities

Popis výsledku anglicky

Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the &quot;metabolic&quot;IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [AlaB29,GluB31,amideB31]-insulin may be interesting for further clinical evaluation. © 2021 American Chemical Society.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30100 - Basic medicine

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JOURNAL OF MEDICINAL CHEMISTRY

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

64

Číslo periodika v rámci svazku

19

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

14848-14859

Kód UT WoS článku

000709633100048

EID výsledku v databázi Scopus

2-s2.0-85117073608