Albumin-binding DARPins as scaffold improve the hypoglycemic and anti-obesity effects of exendin-4 in vivo

Xia, Jun; Gao, Guosheng; Zhang, Changzhen; Ying, Jingjing; Li, Jianhui

doi:10.1016/j.ejps.2023.106422

Cited by 7 publications

(2 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their results demonstrated that Ex-DARPin fusion proteins were substantially stable, resulting in incomplete denaturation even at 80 °C. The in vitro bioactivity results showed that Ex-DARPin fusion proteins could bind to HSA, activate GLP-1R, and have a longer half-life than native Ex 57 .…”

Section: Discussionmentioning

confidence: 99%

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Ehsasatvatan,

Baghban Kohnehrouz

2023

Sci Rep

View full text Add to dashboard Cite

Glucagon-like peptide-1 (GLP-1) is an intestinally derived incretin that plays a vital role in engineering the biological circuit involved in treating type 2 diabetes. Exceedingly short half-life (1–2 min) of GLP-1 limits its therapeutic applicability, and the implication of its new variants is under question. Since albumin-binding DARPin as a mimetic molecule has been reported to increase the serum half-life of therapeutic compounds, the interaction of new variants of GLP-1 in fusion with DARPin needs to be examined against the GLP-1 receptor. This study was aimed to design stable and functional fusion proteins consisting of new protease-resistant GLP-1 mutants (mGLP1) genetically fused to DARPin as a critical step toward developing long-acting GLP-1 receptor agonists. The stability and solubility of the engineered fusion proteins were analyzed, and their secondary and tertiary structures were predicted and satisfactorily validated. Molecular dynamics simulation studies revealed that the predicted structures of engineered fusion proteins remained stable throughout the simulation. The relative binding affinity of the engineered fusion proteins' complex with human serum albumin and the GLP-1 receptor individually was assessed using molecular docking analyses. It revealed a higher affinity compared to the interaction of the individual GLP-1 and HSA-binding DARPin with the GLP-1 receptor and human serum albumin, respectively. The present study suggests that engineered fusion proteins can be used as a potential molecule in the treatment of type 2 diabetes, and this study provides insight into further experimental use of mimetic complexes as alternative molecules to be evaluated as new bio-breaks in the engineering of biological circuits in the treatment of type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Ehsasatvatan,

Baghban Kohnehrouz

2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These findings demonstrate that enzyme-resistant GLP-1 analogs could cross the BBB. The half-life of exendin-4 is 2.4-4 h, allowing it to penetrate into the brain after intravenous administration [66,67]. It was found that exendin-4 is soluble in water but exhibits moderate lipophilicity, allowing it to quickly penetrate into the brain after intravenous injection regardless of circumventricular organs which are devoid of the BBB [68].…”

Section: Permeability Of the Blood-brain Barrier Of Glucagon-like Pep...mentioning

confidence: 99%

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists

Boshchenko,

Maslov,

Mukhomedzyanov

et al. 2024

IJMS

View full text Add to dashboard Cite

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

show abstract

Human serum albumin binders: A piggyback ride for long-acting therapeutics

Ullah

Lim

2023

Drug Discovery Today

View full text Add to dashboard Cite

Albumin-binding DARPins as scaffold improve the hypoglycemic and anti-obesity effects of exendin-4 in vivo

Cited by 7 publications

References 56 publications

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists

Human serum albumin binders: A piggyback ride for long-acting therapeutics

Contact Info

Product

Resources

About