Peptide drugs to target G protein-coupled receptors

Bellmann‐Sickert, Kathrin; Beck‐Sickinger, Annette G.

doi:10.1016/j.tips.2010.06.003

Cited by 82 publications

(59 citation statements)

References 61 publications

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“…The natural and synthetic therapeutic peptides are often potent receptor agonists, requiring lower concentrations for receptor activation (Hruby, 2002;Lien and Lowman, 2003). Peptides can also be used as replacement therapy when the endogenous peptide system is deficient (Leader et al, 2008;Bellmann-Sickert and Beck-Sickinger, 2010).…”

Section: B Therapeutic Targets Of Peptide Drugsmentioning

confidence: 99%

“…Already more than 100 peptide-based drugs have reached the market, and hundreds of peptidergic compounds are in clinical or preclinical studies (Lien and Lowman, 2003;Bellmann-Sickert and Beck-Sickinger, 2010;Vlieghe et al, 2010;Craik et al, 2013). The advantages and disadvantages of peptides as drugs are summarized in Table 1.…”

Section: Introductionmentioning

confidence: 99%

“…Compared with lowmolecular-weight drugs, peptides can be more potent, more efficient, and more target specific (Vlieghe et al, 2010). Peptides are often better tolerated and may enable efficient replacement treatment; the adverse effects are related to their excessive pharmacodynamics Leader et al, 2008;Bellmann-Sickert and Beck-Sickinger, 2010). With their gentler side effect profile and greater selectivity and efficiency, peptides can easily be used in different pathologic states, including cancer.…”

Section: Introductionmentioning

confidence: 99%

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Novel Delivery Systems for Improving the Clinical Use of Peptides

et al. 2015

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Section: B Therapeutic Targets Of Peptide Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Delivery Systems for Improving the Clinical Use of Peptides

et al. 2015

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“…attachment of fatty acid to peptide through an ester or amide bond leading to an increased stability and halflife in an organism and possible delivery over the BBB (Brasnjevic et al 2009, Bellmann-Sickert & Beck-Sickinger 2010, Malavolta & Cabral 2011. Usually, palmitoylation or myristoylation through amide bond at Lys have been used for this purpose.…”

Section: Introductionmentioning

confidence: 99%

Prolactin-releasing peptide: a new tool for obesity treatment

Kuneš

Pražienková

Popelová

et al. 2016

Journal of Endocrinology

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Obesity is an escalating epidemic, but an effective noninvasive therapy is still scarce. For obesity treatment, anorexigenic neuropeptides are promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. In this review, we summarize results of several studies with our newly designed lipidized analogs of prolactin-releasing peptide (PrRP). PrRP is involved in feeding and energy balance regulation as demonstrated by obesity phenotypes of both PrRP-and PrRP-receptor-knockout mice. Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF (NPFF)-2 receptor. Acute peripheral administration of myristoylated and palmitoylated PrRP analogs to mice and rats induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight, improved metabolic parameters and attenuated lipogenesis in mice with diet-induced obesity. A strong anorexigenic, body weight-reducing and glucose tolerance-improving effect of palmitoylated-PrRP31 was shown also in diet-induced obese rats after its repeated 2-week-long peripheral administration. Thus, the strong anorexigenic and body weight-reducing effects of palmitoylated PrRP31 and myristoylated PrRP20 make these analogs attractive candidates for antiobesity treatment. Moreover, PrRP receptor might be a new target for obesity therapy.

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“…[1] With four Y receptors expressed in humans (hY 1 R, hY 2 R, hY 4 R, hY 5 R) and the three endogenous agonists NPY, peptide YY, and pancreatic polypeptide (PP), [2] this system is involved in many physiological processes, such as food intake. [3] Both hY 1 R and hY 5 R mediate orexigenic effects, whereas activation of hY 2 R and hY 4 R produce anorexigenic signals.…”

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confidence: 99%

Peptide Modifications Differentially Alter G Protein‐Coupled Receptor Internalization and Signaling Bias

et al. 2014

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Although G protein‐coupled receptors (GPCRs) are targeted by more clinically used drugs than any other type of protein, their ligand development is particularly challenging. Humans have four neuropeptide Y receptors: hY1R and hY5R are orexigenic, while hY2R and hY4R are anorexigenic, and represent important anti‐obesity drug targets. We show for the first time that PEGylation and lipidation, chemical modifications that prolong the plasma half‐lives of peptides, confer additional benefits. Both modifications enhance pancreatic polypeptide preference for hY2R/hY4R over hY1R/hY5R. Lipidation biases the ligand towards arrestin recruitment and internalization, whereas PEGylation confers the opposite bias. These effects were independent of the cell system and modified residue. We thus provide novel insights into the mode of action of peptide modifications and open innovative venues for generating peptide agonists with extended therapeutic potential.

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Peptide drugs to target G protein-coupled receptors

Cited by 82 publications

References 61 publications

Novel Delivery Systems for Improving the Clinical Use of Peptides

Novel Delivery Systems for Improving the Clinical Use of Peptides

Prolactin-releasing peptide: a new tool for obesity treatment

Peptide Modifications Differentially Alter G Protein‐Coupled Receptor Internalization and Signaling Bias

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