Drug Development-targeted Screening of Leptin Agonist Glycopeptides

Knappe, Daniel; Ötvös, László; Pascali, Francesco De; Cassone, Marco; Scolaro, Laura; Abbadessa, Giovanni; Carrillo-Infante, Cynthia; Kiani, Mohammad F.; Donelson, Fred; Hoffmann, Ralf; Surmacz, Eva

doi:10.1007/s10989-008-9139-y

Cited by 6 publications

(8 citation statements)

References 17 publications

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“…Consideration of the site III sequence within the Thr121‐Arg128 ObR‐inhibitor limits led to the design of a potential antagonist called Nva3 (Table I). Peptide Nva3 bound ObR on our medium‐throughput solid‐phase assay16 and interfered with leptin‐induced proliferation of MCF‐7 breast cancer cells in a concentration‐dependent manner. It was a full antagonist at 1 μ M but had no agonistic activity.…”

Section: Resultsmentioning

confidence: 95%

“…Upon intraperitoneal administration to Balb/c mice, N‐terminally Alexa 680‐labeled peptide Allo‐Aca was distributed into the usual peptide elimination organs17: the kidneys, the urinary bladder, the liver, and the rectum (Figure 3A). In addition, the labeled peptide migrated into the same tissues as our earlier leptin site III agonist peptide (termed E1): the tail, limbs and the brain 12–16. Leptin crosses the blood‐brain barrier (BBB) by a saturable system,18 presumably through some ObR forms residing at the brain side of the barrier and in the lumen of cerebral arteries 19.…”

Section: Resultsmentioning

confidence: 98%

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Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

et al. 2011

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Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Because of the presence of multiple leptin/receptor (ObR) interaction sites and diverse leptin activities, the literature lacks truly monofunctional leptin protein derivatives or fragments. To date, selective ObR antagonists have not been reported. We developed short, pharmacologically advantageous peptide analogs of ObR-binding site III of leptin that acted as selective ObR inhibitors without any partial agonistic activity. These reduced leptin-dependent growth and signaling in cancer cell lines at picomolar and low nanomolar concentrations. In immunocompromised mice the peptides suppressed the growth of rapidly proliferating orthotopic human breast cancer xenografts by 50% when administered either intraperitoneally (i.p.) or subcutaneously (s.c.) for 38 days at a 0.1 mg/kg/day dose. The peptides were distributed to the brain, and when added to growing C57BL/6 normal mice i.p., s.c., or orally, the lead antagonist accelerated normal weight increase without producing any toxic effects. Weight gain increases could not be observed after 10-12 days of treatment indicating that the mice became resistant to the central nervous system activity of leptin antagonists. However, in normal growing rats the intranasal administration at 0.1 mg/kg/day for 20 days resulted in a 2% net total body weight gain without signs of resistance induction. In addition to the potential of these peptides in drug development against primary and metastatic tumors and cachexia, our data confirm that resistance to leptin resides at the blood-brain barrier.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 98%

Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

et al. 2011

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“…When injected ip into Balb/c mice, E1/Aca was distributed into the usual peptide elimination organs [18]: the kidneys, the liver and the spleen in about 1 h ( figure 3). In addition, the peptide migrated into the same tissues as E1Free, the tail, limbs and the brain [7,8]. The presence of the peptide in the brain was more apparent when the mice were photographed from their dorsal side, indicating that E1/Aca perhaps concentrated in the hypothalamic regions ( figure 3).…”

Section: In Vitro Activity In Vivo Biodistributionmentioning

confidence: 95%

“…Peptide E1Free selectively stimulates proliferation and initiates leptin signalling at nanomolar concentrations in ObR-positive cells. In mouse models, E1Free penetrates the BBB more efficiently than leptin protein itself [8]. When injected into the brain of sheep, peptide E1Free reduces voluntary food intake of program-fed animals by 25% and increases postprandial thermogenesis in muscle by 3 • C without effects on core body temperature in summer and winter.…”

Section: Namementioning

confidence: 99%

“…E1Free is a selective and full agonist of ObR, that is, it stimulates the growth of ObR-positive cells when added alone, but neither antagonizes leptin actions on the same cells, nor interferes with ObR-negative cells [7]. Leptin site II and site III peptides, including E1Free and its acetylated derivative bind the extracellular domain of ObR on solid-phase assays, although it needs to be mentioned that removal of the carbohydrate hydroxyl protecting groups significantly decreases the ability of the peptide to attach to cellulose and plastic surfaces, and the ObR preparation itself has unfavourable physical properties for quantitative measurement of ligand binding [7,8]. In the current study, E1/Aca bound ObR on our enzyme-linked immunosorbent assay -type assay [8] identically to the positive control leptin site II combined construct (data not shown).…”

Section: In Vitro Activity In Vivo Biodistributionmentioning

confidence: 99%

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Leptin‐based glycopeptide induces weight loss and simultaneously restores fertility in animal models

Kovalszky

Surmacz

Scolaro

et al. 2010

Diabetes Obesity Metabolism

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No resistance induction to peptide E1/Aca or toxicity in either obese or healthy rodents was observed, indicating the potential for widespread utility of the peptidomimetic in the treatment of leptin-deficiency disorders. We provide additional proof for the hypothesis that difficulties in current leptin therapies reside at the BBB penetration stage, and we document that by either glycosylation or intranasal peptide administration we can overcome this limitation.

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In‐house standards derived from doping peptides: Enzymatic and serum stability and degradation profile of GHRP and GHRH‐related peptides

González‐López,

Guerra‐Acero‐Turizo,

Blanco‐Medina

et al. 2023

Biomedical Chromatography

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Matrix effect and sample pretreatment significantly affect the percentage recovery of peptides in biological matrices, affecting the method robustness and accuracy. To counteract this effect, an internal standard (IS) is used; however, in most cases this is not available, which limits the analytical method. It is important to identify short peptides that can be used as ISs in the quantification of peptides in biological matrices. In this study, doping peptides GHRP‐4, GHRP‐5, GHRP‐6, Sermorelin (1–11), Sermorelin (13–20) and Sermorelin (22–29) were synthesized using solid‐phase peptide synthesis. Treatment with human blood, trypsin and chymotrypsin was used to determine the stability of the peptides. Products were evaluated using the high‐performance liquid chromatography‐diode array detector (HPLC‐DAD) method. The analytical methodology and sample pretreatment were effective for the analysis of these molecules. A unique profile related to protein binding and enzymatic stability of each peptide was established. GHRP‐4, GHRP‐6 and Sermorelin (22–29) can be considered as in‐house ISs as they were stable to enzyme and blood treatment and can be used for the quantification of peptides in biological samples. Peptides GHRP‐6 and Sermorelin (22–29) were used to analyse a dimeric peptide (26[F] LfcinB (20–30)2) in four different matrices to test these peptides as in‐house IS.

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Drug Development-targeted Screening of Leptin Agonist Glycopeptides

Cited by 6 publications

References 17 publications

Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

Peptide‐based leptin receptor antagonists for cancer treatment and appetite regulation

Leptin‐based glycopeptide induces weight loss and simultaneously restores fertility in animal models

In‐house standards derived from doping peptides: Enzymatic and serum stability and degradation profile of GHRP and GHRH‐related peptides

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