The calcitonin receptor is the main mediator of LAAMA's body weight lowering effects in male mice

Gamakharia, Salome; Foll, Christelle Le; Rist, Wolfgang; Baader-Pagler, Tamara; Baljuls, Angela; Lutz, Thomas

doi:10.1016/j.ejphar.2021.174352

Cited by 6 publications

(8 citation statements)

References 36 publications

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“…These results suggest that the activation of CTR itself is involved in those metabolic processes and that CTR may be a valid player for the efficacy of the dual agonists. In addition, a long-acting amylin analog (LAAMA) was reported to decrease body weight gain in RAMP1 or RAMP3 knockout mice given a high fat diet [9]. These results indicate that CTR alone activated by LAAMA was enough to prevent body weight gain in mice.…”

Section: Discussionmentioning

confidence: 85%

“…Mass spectrometry was performed at Genscript to confirm the molecular weight of the synthesized peptides. Fluorescein isothiocyanate (FITC)-labeled sCT (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), FITC-labeled AC413 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), and FITC-labeled AC413(6-25) with Y25P mutation were used as peptide probes for peptide binding assay. The extinction coefficient of FITC (63,000 M −1 •cm −1 at 495 nm, pH 7.0) was used to determine the concentration of the FITC-labeled peptide probes.…”

Section: Synthetic Peptidesmentioning

confidence: 99%

“…Background (reaction buffer only) was subtracted for anisotropy calculation. For the SpectraiD5, G factor (0.38 for FITC-sCT(22-32) and 0.41 for FITC-AC413 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and FITC-AC413(6-25) Y25P) was used to correct the instrumental bias for anisotropy calculation. The polarization (mP) of the FITC-peptide probes only (No receptor ECD) was set close to 50 mP.…”

Section: Fluorescence Polarization/anisotropy (Fp) Peptide Binding Assaymentioning

confidence: 99%

“…A rat amylin analog pramlintide was developed and is available in clinics to treat diabetes as co-therapy with insulin [8]. In addition, lots of effort has been focused on developing next-generation peptide drugs targeting AMY receptors as exemplified with dual amylin calcitonin receptor agonists (DACRA) and long-acting amylin/calcitonin receptor agonists [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

Lee

2021

Biomolecules

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The calcitonin and amylin receptors (CTR and AMY receptors) are the drug targets for osteoporosis and diabetes treatment, respectively. Salmon calcitonin (sCT) and pramlintide were developed as peptide drugs that activate these receptors. However, next-generation drugs with improved receptor binding profiles are desirable for more effective pharmacotherapy. The extracellular domain (ECD) of CTR was reported as the critical binding site for the C-terminal half of sCT. For the screening of high-affinity sCT analog fragments, purified CTR ECD was used for fluorescence polarization/anisotropy peptide binding assay. When three mutations (N26D, S29P, and P32HYP) were introduced to the sCT(22–32) fragment, sCT(22–32) affinity for the CTR ECD was increased by 21-fold. CTR was reported to form a complex with receptor activity-modifying protein (RAMP), and the CTR:RAMP complexes function as amylin receptors with increased binding for the peptide hormone amylin. All three types of functional AMY receptor ECDs were prepared and tested for the binding of the mutated sCT(22–32). Interestingly, the mutated sCT(22–32) also retained its high affinity for all three types of the AMY receptor ECDs. In summary, the mutated sCT(22–32) showing high affinity for CTR and AMY receptor ECDs could be considered for developing the next-generation peptide agonists.

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Section: Discussionmentioning

confidence: 85%

Section: Synthetic Peptidesmentioning

confidence: 99%

Section: Fluorescence Polarization/anisotropy (Fp) Peptide Binding Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

Lee

2021

Biomolecules

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“…Thus, there are species differences with regards to the effect of salmon calcitonin on body weight that are yet to be understood fully. In another study, the effect of once daily injections with an unnamed longacting amylin receptor analogue or saline for one week was evaluated in mice maintained on a high-fat diet (198). Here, chronic amylin receptor agonism reduced body weight in both WT and in RAMP1 and 3 knockout mice, but not in CTR knockout mice, highlighting the importance of the CTR rather than specific RAMPS in modulating the weight-lowering effects of long-acting amylin analogues.…”

Section: Long-acting Amylin Analogues and Dual Agonistsmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin – physiology and pharmacology

Mathiesen

Lund

Holst

et al. 2022

European Journal of Endocrinology

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Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged, and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and it also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the three amylin receptors, which have partial identity to the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce gastric emptying rate and promote satiation. Pre-clinical trials with agents targeting the calcitonin receptor and the amylin receptors, which are based on the calcitonin core receptor, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.

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NN1213 – A Potent, Long-Acting, and Selective Analog of Human Amylin

Dahl,

Raun,

Hansen

et al. 2024

J. Med. Chem.

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Amylin, a member of the calcitonin family, acts via amylin receptors in the hindbrain and hypothalamus to suppress appetite. Native ligands of these receptors are peptides with short halflives. Conjugating fatty acids to these peptides can increase their halflives. The long-acting human amylin analog, NN1213, was generated from structure−activity efforts optimizing solubility, stability, receptor affinity, and selectivity, as well as in vivo potency and clearance. In both rats and dogs, a single dose of NN1213 reduced appetite in a dosedependent manner and with a long duration of action. Consistent with the effect on appetite, studies in obese rats demonstrated that daily NN1213 dosing resulted in a dose-dependent reduction in body weight over a 21-day period. Magnetic resonance imaging indicated that this was primarily driven by loss of fat mass. Based on these data, NN1213 could be considered an attractive option for weight management in the clinical setting.

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The calcitonin receptor is the main mediator of LAAMA's body weight lowering effects in male mice

Cited by 6 publications

References 36 publications

Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin – physiology and pharmacology

NN1213 – A Potent, Long-Acting, and Selective Analog of Human Amylin

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