Computer-aided engineering of stabilized fibroblast growth
factor 21

J 2024

Computer-aided engineering of stabilized fibroblast growth factor 21

DE LA BOURDONNAYE, Gabin; Tereza GHAZALOVÁ; Petr FOJTÍK; Katerina KUTALKOVA; David BEDNÁŘ et al.

Základní údaje

Originální název

Computer-aided engineering of stabilized fibroblast growth factor 21

Autoři

DE LA BOURDONNAYE, Gabin; Tereza GHAZALOVÁ; Petr FOJTÍK; Katerina KUTALKOVA; David BEDNÁŘ; Jiří DAMBORSKÝ; Vladimír ROTREKL; Veronika STEPANKOVA a Radka CHALOUPKOVÁ

Vydání

Computational and Structural Biotechnology Journal, Elsevier, 2024, 2001-0370

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Nizozemské království

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.100

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/24:00135651

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

Fibroblast growth factor 21; Protein engineering; Protein stabilization

Štítky

14110513, 14314010, 143180, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 4. 2025 12:43, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

FGF21 is an endocrine signaling protein belonging to the family of fibroblast growth factors (FGFs). It has emerged as a molecule of interest for treating various metabolic diseases due to its role in regulating glucogenesis and ketogenesis in the liver. However, FGF21 is prone to heat, proteolytic, and acid-mediated degradation, and its low molecular weight makes it susceptible to kidney clearance, significantly reducing its therapeutic potential. Protein engineering studies addressing these challenges have generally shown that increasing the thermostability of FGF21 led to improved pharmacokinetics. Here, we describe the computer-aided design and experimental characterization of FGF21 variants with enhanced melting temperature up to 15 ◦C, uncompromised efficacy at activation of MAPK/ERK signaling in Hep G2 cell culture, and ability to stimulate proliferation of Hep G2 and NIH 3T3 fibroblasts cells comparable with FGF21-WT. We propose that stabilizing the FGF21 molecule by rational design should be combined with other reported stabilization strategies to maximize the pharmaceutical potential of FGF21.

Návaznosti

LM2023055, projekt VaV

Název: Česká národní infrastruktura pro biologická data

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, ELIXIR-CZ: Česká národní infrastruktura pro biologická data

LX22NPO5107, projekt VaV

Název: Národní ústav pro neurologický výzkum

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní ústav pro neurologický výzkum, 5.1 EXCELES

90269, velká výzkumná infrastruktura

Název: RECETOX RI II

Přiložené soubory

2383957.pdf

Citovat

DE LA BOURDONNAYE, Gabin; Tereza GHAZALOVÁ; Petr FOJTÍK; Katerina KUTALKOVA; David BEDNÁŘ; Jiří DAMBORSKÝ; Vladimír ROTREKL; Veronika STEPANKOVA a Radka CHALOUPKOVÁ. Computer-aided engineering of stabilized fibroblast growth factor 21. Computational and Structural Biotechnology Journal. Elsevier, 2024, roč. 23, December 2024, s. 942-951. ISSN 2001-0370. Dostupné z: https://doi.org/10.1016/j.csbj.2024.02.001.

@article{2383957,
   author = {de La Bourdonnaye, Gabin and Ghazalová, Tereza and Fojtík, Petr and Kutalkova, Katerina and Bednář, David and Damborský, Jiří and Rotrekl, Vladimír and Stepankova, Veronika and Chaloupková, Radka},
   article_number = {December 2024},
   doi = {https://doi.org/10.1016/j.csbj.2024.02.001},
   keywords = {Fibroblast growth factor 21; Protein engineering; Protein stabilization},
   language = {eng},
   issn = {2001-0370},
   journal = {Computational and Structural Biotechnology Journal},
   title = {Computer-aided engineering of stabilized fibroblast growth factor 21},
   url = {https://www.sciencedirect.com/science/article/pii/S2001037024000254?via%3Dihub},
   volume = {23},
   year = {2024}
}

TY  - JOUR
ID  - 2383957
AU  - de La Bourdonnaye, Gabin - Ghazalová, Tereza - Fojtík, Petr - Kutalkova, Katerina - Bednář, David - Damborský, Jiří - Rotrekl, Vladimír - Stepankova, Veronika - Chaloupková, Radka
PY  - 2024
TI  - Computer-aided engineering of stabilized fibroblast growth factor 21
JF  - Computational and Structural Biotechnology Journal
VL  - 23
IS  - December 2024
SP  - 942-951
EP  - 942-951
PB  - Elsevier
SN  - 20010370
KW  - Fibroblast growth factor 21
KW  - Protein engineering
KW  - Protein stabilization
UR  - https://www.sciencedirect.com/science/article/pii/S2001037024000254?via%3Dihub
N2  - FGF21 is an endocrine signaling protein belonging to the family of fibroblast growth factors (FGFs). It has emerged as a molecule of interest for treating various metabolic diseases due to its role in regulating glucogenesis and ketogenesis in the liver. However, FGF21 is prone to heat, proteolytic, and acid-mediated degradation, and its low molecular weight makes it susceptible to kidney clearance, significantly reducing its therapeutic potential. Protein engineering studies addressing these challenges have generally shown that increasing the thermostability of FGF21 led to improved pharmacokinetics. Here, we describe the computer-aided design and experimental characterization of FGF21 variants with enhanced melting temperature up to 15 ◦C, uncompromised efficacy at activation of MAPK/ERK signaling in Hep G2 cell culture, and ability to stimulate proliferation of Hep G2 and NIH 3T3 fibroblasts cells comparable with FGF21-WT. We propose that stabilizing the FGF21 molecule by rational design should be combined with other reported stabilization strategies to maximize the pharmaceutical potential of FGF21.
ER  -

DE LA BOURDONNAYE, Gabin; Tereza GHAZALOVÁ; Petr FOJTÍK; Katerina KUTALKOVA; David BEDNÁŘ; Jiří DAMBORSKÝ; Vladimír ROTREKL; Veronika STEPANKOVA a Radka CHALOUPKOVÁ. Computer-aided engineering of stabilized fibroblast growth factor 21. \textit{Computational and Structural Biotechnology Journal}. Elsevier, 2024, roč.~23, December 2024, s.~942-951. ISSN~2001-0370. Dostupné z: https://doi.org/10.1016/j.csbj.2024.02.001.

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