Development and testing of new selective insulin analogs

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00641782" target="_blank" >RIV/61388963:_____/25:00641782 - isvavai.cz</a>

Výsledek na webu

<a href="https://hdl.handle.net/11104/0371817" target="_blank" >https://hdl.handle.net/11104/0371817</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Development and testing of new selective insulin analogs

Popis výsledku v původním jazyce

In this lecture, we summarize key results of the project. By targeted mutagenesis, we identified Arg717 in the insulin receptor and Arg704 in IGF-1R as critical for hormone transfer between binding sites. We developed new computational methods for in silico modeling and analog design. Several novel ligand classes were prepared: insulin dimers, mimetics with alternative bridges, and IGF-1 dimers. Particularly valuable were combinatorial libraries of D-peptide insulin mimetics on trivalent scaffolds. We synthesized insulin analogs with B26 proline derivatives, showing up to 100-fold differences in receptor affinities. One analog displayed 9-fold higher IR-B potency and 3-fold IR-A selectivity compared to insulin. Structural studies (X-ray, cryo-EM, modeling) explained these differences, a manuscript is in preparation. Two octapeptide-based mimetics attached to adamantane or trimesic acid scaffolds were discovered as full IR antagonists, useful against hypoglycemia. Cryo-EM revealed the first structures of fully inhibited IR, demonstrating unexpected conformational plasticity, this work is under peer review. Further, CEITEC Brno prepared functional IR ectodomains in insect systems. In collaboration with Prof. M. Webber (Notre Dame, USA), we helped develop glucose-responsive insulin derivatives based on dendritic nanoparticles that release modified insulin only under high glucose, showing strong efficacy in rats and pigs. With Prof. E. Altindis (Boston College, USA), we studied viral insulin- and IGF-1–like hormones that activate mammalian receptors, in some cases inhibit IGF-1R, and may play roles in diseases such as cancer or type 1. A highlight is discovery of analog IN-ML-15, a potent dual agonist of IR-A, IR-B, and IGF-1R, with 10× higher IR-B affinity than insulin. IN-ML-15 strongly activates IR-A/B and IGF-1R, promotes neuronal growth and recovery, and shows distinct signaling signatures. Cryo-EM revealed the basis of its high affinity, underscoring its potential for neuroprotection and cell culture. In collaboration with Dr. M. Rossmeisl (IPHYS) and Dr. J. Procházka (CCP), we studied the IR-B–selective analog LZ-162. In mice, it activated hepatic IRs more efficiently than insulin, correlating higher affinity with improved function. The project achieved its objectives, delivering major progress in developing new insulin receptor ligands. The discovery of IR antagonists and their complex structures marks a key milestone, offering new insight into the IR apo-form. We also clarified structural requirements of isoform B and identified a strategy for highly potent and selective ligands, paving the way for future therapeutic analogs.

Název v anglickém jazyce

Development and testing of new selective insulin analogs

Popis výsledku anglicky

In this lecture, we summarize key results of the project. By targeted mutagenesis, we identified Arg717 in the insulin receptor and Arg704 in IGF-1R as critical for hormone transfer between binding sites. We developed new computational methods for in silico modeling and analog design. Several novel ligand classes were prepared: insulin dimers, mimetics with alternative bridges, and IGF-1 dimers. Particularly valuable were combinatorial libraries of D-peptide insulin mimetics on trivalent scaffolds. We synthesized insulin analogs with B26 proline derivatives, showing up to 100-fold differences in receptor affinities. One analog displayed 9-fold higher IR-B potency and 3-fold IR-A selectivity compared to insulin. Structural studies (X-ray, cryo-EM, modeling) explained these differences, a manuscript is in preparation. Two octapeptide-based mimetics attached to adamantane or trimesic acid scaffolds were discovered as full IR antagonists, useful against hypoglycemia. Cryo-EM revealed the first structures of fully inhibited IR, demonstrating unexpected conformational plasticity, this work is under peer review. Further, CEITEC Brno prepared functional IR ectodomains in insect systems. In collaboration with Prof. M. Webber (Notre Dame, USA), we helped develop glucose-responsive insulin derivatives based on dendritic nanoparticles that release modified insulin only under high glucose, showing strong efficacy in rats and pigs. With Prof. E. Altindis (Boston College, USA), we studied viral insulin- and IGF-1–like hormones that activate mammalian receptors, in some cases inhibit IGF-1R, and may play roles in diseases such as cancer or type 1. A highlight is discovery of analog IN-ML-15, a potent dual agonist of IR-A, IR-B, and IGF-1R, with 10× higher IR-B affinity than insulin. IN-ML-15 strongly activates IR-A/B and IGF-1R, promotes neuronal growth and recovery, and shows distinct signaling signatures. Cryo-EM revealed the basis of its high affinity, underscoring its potential for neuroprotection and cell culture. In collaboration with Dr. M. Rossmeisl (IPHYS) and Dr. J. Procházka (CCP), we studied the IR-B–selective analog LZ-162. In mice, it activated hepatic IRs more efficiently than insulin, correlating higher affinity with improved function. The project achieved its objectives, delivering major progress in developing new insulin receptor ligands. The discovery of IR antagonists and their complex structures marks a key milestone, offering new insight into the IR apo-form. We also clarified structural requirements of isoform B and identified a strategy for highly potent and selective ligands, paving the way for future therapeutic analogs.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5104" target="_blank" >LX22NPO5104: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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