GLP-1 analogs containing disulfide bond exhibited prolonged half-life in vivo than GLP-1

Liu, Ying; Zheng, Xiaojiao; Li-da, Tang; Xu, Weifeng; Gong, Min

doi:10.1016/j.peptides.2011.04.001

Cited by 31 publications

(24 citation statements)

References 35 publications

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“…Accordingly, two residues, Ser18 and Lys26, were substituted by cysteine in the GLP-1 peptide, derived from the results of our previous investigation. 35,36 The intrapeptide disulfide bond formed by these two cysteine residues induced a V-shaped conformation.…”

Section: ■ Discussionmentioning

confidence: 99%

Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications

et al. 2014

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Glucagon-like peptide-1 (GLP-1) possesses multiple physiological functions, which make it a potential drug candidate for the treatment of type 2 diabetes. However, its clinical application was limited severely by its short half-life in vivo. Therefore, stabilization of GLP-1 is critical for the use of this peptide in drug development. In this study, a novel GLP-1 derivative, VGLP1K6, processed a significantly prolonged half-life in vivo. Structural analysis using molecular dynamics simulations demonstrated that VGLP1K6 has a rigid V-shaped conformation resulting from the intrapeptide disulfide bond. The C-terminal polylysine residues of VGLP1K6 caused the vulnerable N-terminus of GLP-1 (HA-fragment) to reside within the pocket-like cavity of the peptide due to the intrahydrogen bonds. The structural analysis suggested that this structural alteration contributed to the remarkable prolonged half-life of VGLP1K6, which was approximately 70 h. In addition, VGLP1K6 induced better long-acting glucose tolerance and greater HbA1c reductions than GLP-1 in rodents. Our findings suggest that the GLP-1 derivative VGLP1K6 might be a possible potent antidiabetic drug for the treatment of type 2 diabetes mellitus.

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Section: ■ Discussionmentioning

confidence: 99%

Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications

et al. 2014

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“…Li et al introduced a cysteine-containing glycine tail at the C-terminus of GLP-1, enabling disulfide bond formation between GLP-1 molecules that stabilized the peptide, protected it from proteolysis, and extended its half-life, while maintaining in vivo insulinotropic and glucoregulatory activity out to 5 days following a single s.c. injection[111]. …”

Section: Glucagon-like Peptide-1 Receptor Agonistsmentioning

confidence: 99%

Controlled release of biologics for the treatment of type 2 diabetes

Gilroy

Luginbuhl

Chilkoti

2016

Journal of Controlled Release

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Type 2 diabetes is a rapidly growing disease that poses a significant burden to the United States healthcare system. Despite the many available treatments for the disease, close to half of diagnosed type 2 diabetes cases are not properly managed, largely due to inadequate patient adherence to prescribed treatment regimens. Methods for improving delivery — and thereby easing administration — of type 2 drugs have the potential to greatly improve patient health. This review focuses on two peptide drugs — insulin and glucagon-like peptide 1 (GLP-1) — for treatment of type diabetes. Peptide drugs offer the benefits of high potency and specificity but pose a significant delivery challenge due to their inherent instability and short half-life. The development of insulin and GLP-1 analogs highlights the broad spectrum of drug delivery strategies that have been used to solve these problems. Numerous structural modifications and formulations have been introduced to optimize absorption, residence time, stability, route of delivery and frequency of administration. Continual improvements in delivery methods for insulin and GLP-1 receptor agonists are paving the way towards better patient compliance and improved disease management, and thereby enhanced patient quality of life.

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“…Bioactive peptides have a variety of biological functions such as angiotensin-I-converting enzyme (ACE) inhibitory [1], antioxidant [2], immune modulatory [3], antimicrobial [4], and anti-diabetic properties [5]. In recent decades, an increasing number of bioactive peptides, including peptides that have ACE inhibitory activity, have been identified from various protein hydrolysate sources.…”

Section: Introductionmentioning

confidence: 99%

Characterization of ACE Inhibitory Peptides from Mactra veneriformis Hydrolysate by Nano-Liquid Chromatography Electrospray Ionization Mass Spectrometry (Nano-LC-ESI-MS) and Molecular Docking

et al. 2014

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Food-derived bioactive compounds are gaining increasing significance in life sciences. In the present study, we identified angiotensin I-converting enzyme (ACE)-inhibitory peptides from Mactra veneriformis hydrolysate using a nano-LC-MS/MS method. Mactra veneriformis hydrolysate was first separated into four fractions (F1–F4) based on molecular weight by ultrafiltration. The fraction with molecular weight lower than 1 kDa (F1) showed the highest ACE inhibitory activity. F1 was then analyzed by a high throughput nano-LC-MS/MS method and sequences of peptides in F1 were calculated accordingly. The 27 peptides identified as above were chemically synthesized and tested for ACE-inhibitory activity. The hexapeptide VVCVPW showed the highest potency with an IC50 value of 4.07 μM. We then investigated the interaction mechanism between the six most potent peptides and ACE by molecular docking. Our docking results suggested that the ACE inhibitory peptides bind to ACE via interactions with His383, His387, and Glu411 residues. Particularly, similar to the thiol group of captopril, the cysteine thiol group of the most potent peptide VVCVPW may play a key role in the binding of this peptide to the ACE active site.

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GLP-1 analogs containing disulfide bond exhibited prolonged half-life in vivo than GLP-1

Cited by 31 publications

References 35 publications

Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications

Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications

Controlled release of biologics for the treatment of type 2 diabetes

Characterization of ACE Inhibitory Peptides from Mactra veneriformis Hydrolysate by Nano-Liquid Chromatography Electrospray Ionization Mass Spectrometry (Nano-LC-ESI-MS) and Molecular Docking

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