Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

Novakovic, Zachary M.; Anderson, Brian; Grasso, Patricia

doi:10.1016/j.peptides.2014.10.007

Cited by 14 publications

(4 citation statements)

References 25 publications

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“…MA-[D-Leu-4]-OB3, the myristic acid (MA) conjugate of [D-Leu-4]-OB3 (Ser-Cys-Ser-dLeu-Pro-Gln-Thr), 19 was prepared commercially at >97% purity as a C-terminal amide by Atlantic Peptides (Lewisburg, PA, USA). MA-[D-Leu-4]-OB3 was dissolved in vehicle (.3% dodecyl maltoside, DDM, trade name Intravail®, Aegis Therapeutics, San Diego, CA, USA, reconstituted in sterile deionized water), and delivered by oral gavage (100 μL) once daily between 16:00 and 17:00 h. This time-frame was chosen based on the active feeding time of the mice (after lights out at 19:00 h), and the pharmacokinetics of MA-[D-Leu-4]-OB3: the maximum concentration (C max ) following oral delivery is reached at 4 h (T max ), and the half-life (T 1/2 ) is 29 h. 16…”

Section: Ma-[d-leu-4]-ob3 Administrationmentioning

confidence: 99%

“…12 This peptide has been modified over the years to improve its efficacy, pharmacokinetics, and method of delivery in a number of mouse models of human disease. [13][14][15][16][17][18][19][20] Most worthy of special note is the proven ability of these leptin mimetics to cross the BBB and to localize in the hypothalamus in all mouse models tested, 17 thus overcoming the central resistance associated with common obesity.…”

Section: Introductionmentioning

confidence: 99%

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Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

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Although the regulatory influence of leptin on energy balance, glycemic control, immunity, reproduction, and cognition is well established, its clinical application to common obesity and its co-morbidities has been limited by impaired transport across the blood-brain barrier, and tendencies to induce adverse side effects. To circumvent these drawbacks, MA-[D-Leu-4]-OB3, a leptin-related synthetic peptide that mimics the metabolic and neurotrophic effects of leptin in mouse models of genetic and non-genetic obesity, diabetes, and cognitive dysfunction, has been developed. This report presents the results of our initial efforts to assess the safety of orally delivered MA-[D-Leu-4]-OB3. Two pre-clinical studies were done in male and female C57BL/6 mice: a short-term study with a high dose of MA-[D-Leu-4]-OB3 (50 mg/kg/100 μL/day) and a dose-response study with 3 increasing concentrations of MA-[D-Leu-4]-OB3 (16.6, 50, and 150 mg/kg/100 μL/day). Body weight, food and water intake, glucose tolerance, and episodic memory were evaluated. Once-daily cage-side clinical observations were conducted to detect any physical or behavioral indicators of toxicity. Our results indicate that all metabolic and neurologic endpoints tested were either unaffected or improved by MA-[D-Leu-4]-OB3, and no clinical indicators of toxicity were evident. Together with our previously reported efficacy data, these results provide additional evidence supporting further development of this novel synthetic peptide leptin mimetic as a first-in-class peptide drug candidate for the treatment of a number of metabolic and/or cognitive dysfunctions in humans.

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Section: Ma-[d-leu-4]-ob3 Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

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“…In an effort to address these issues, myristic (tetradecanoic) acid, known to increase membrane solubility, was conjugated to the N-terminal of [D-Leu-4]-OB3 (Novakovic et al, 2014). Myristoylation is the approach that was used to develop detemir insulin (Levemir R , Novo Nordisk), an analog of human insulin with a half-life of 7-8 h, which is commonly used in the management of T2DM in the clinic.…”

Section: Improving the Pharmacokinetics And Efficacy Of The Mimeticmentioning

confidence: 99%

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Grasso

2022

Front. Aging Neurosci.

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In this review, the current understanding of leptin’s role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic “harmony” of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.

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“…The t max values (5-15min) observed here were comparable with published results of pharmacokinetics of various pharmaceutical peptides in rodents after i.p. injection (Cao, Gao, & Jusko, 2012;Novakovic, Anderson, & Grasso, 2014;Yamamoto et al, 2015).…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

LR12‐peptide quantitation in whole blood by RP‐HPLC and intrinsic fluorescence detection: Validation and pharmacokinetic study

Parent

Boudier

Maincent

et al. 2017

Biomedical Chromatography

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A simple, sensitive, selective and robust HPLC method based on intrinsic fluorescence detection was developed for the quantitation of a dodecapeptide (designated as LR12), inhibitor of Triggering Receptor Expressed on Myeloid cells-1, in rat whole blood. Sample treatment was optimized using protein precipitation and solid-phase extraction. Chromatographic separation was carried out in a gradient mode using a core-shell C column (150 × 4.6 mm, 3.6 μm) with mobile phases of acetonitrile and water containing trifluoroacetic acid at 1.0 mL/min. The method was validated using methodology described by the US Food and Drug Administration guidelines for bioanalytical methods. Linearity was demonstrated within the 50-500 ng/mL range and the lower limit of quantitation was 50 ng/mL. Finally, a preliminary pharmacokinetic study after intraperitoneal injection of LR12 in rats was conducted to evaluate both LR12 monomer and its corresponding disulfide dimer, the main product of degradation. Beyond the fact that this paper describes the first fully validated method for LR12 analysis in blood samples, the approach followed here to optimize pre-analytical steps could be beneficial to develop HPLC and/or MS methods for other pharmaceutical peptides.

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Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

Cited by 14 publications

References 25 publications

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

LR12‐peptide quantitation in whole blood by RP‐HPLC and intrinsic fluorescence detection: Validation and pharmacokinetic study

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