Novel Peptide Antagonists of Adrenomedullin and Calcitonin Gene-Related Peptide Receptors: Identification, Pharmacological Characterization, and Interactions with Position 74 in Receptor Activity-Modifying Protein 1/3

Robinson, Samuel D.; Aitken, Jacqueline F.; Bailey, Richard J.; Poyner, David R.; Hay, Debbie L.

doi:10.1124/jpet.109.156448

Cited by 29 publications

(42 citation statements)

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“…Circular dichroism analyses of AM demonstrated that the peptide structure is composed of 28% a-helix and 18% b-sheet. Interestingly, the antagonist AM(22-52) shares these structural features (14). However, the ring structure composed of 6 residues linked by a disulfide bridge is a characteristic common to all calcitonin peptide family members, despite their low sequence homology, and it has been shown to be important for proper binding and subsequent signaling (13,26).…”

Section: Discussionmentioning

confidence: 99%

“…AM is an antagonist that has 10 times less affinity for its receptors than AM(13-52) in competition displacement experiments but that has higher selectivity for AM1 than for AM2 (CRLR/ RAMP3) (6,14). Thus, this peptide appeared to be a good starting point for generating new AM antagonists suitable for lung nuclear imaging.…”

mentioning

confidence: 99%

“…Previous structureactivity relationship studies demonstrated that truncating the Nterminal stretch while maintaining the cyclic structure formed by a disulfide bridge between residues 16 and 21 generated agonists, such as AM with residues 13-52 [AM ] and AM , with affinities similar to that of the full-length peptide (13). Further truncation at the N terminus to remove the ring structure yielded the only fully characterized human AM antagonist, that is, AM ; in contrast, removal of the C-terminal amino acid greatly diminished binding affinity and peptide activity (13,14). Interestingly, analogs composed only of the ring structure, that is, AM (15)(16)(17)(18)(19)(20)(21)(22) and AM (16)(17)(18)(19)(20)(21), increased systemic arterial blood pressure (15), but AM and AM(1-40) were unable to displace 125 I-AM in a dog lung homogenate binding experiment (6).…”

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confidence: 99%

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PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

et al. 2013

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Previous studies showed that adrenomedullin (AM) could be a promising agent for molecular imaging of the pulmonary circulation, with abundant specific binding sites at the pulmonary vascular endothelium. The purpose of this work was to design an AM-based compound that encompasses the desired imaging properties without posing safety issues for clinical applications. Methods: AM analogs were synthesized through solid-phase peptide synthesis. They were evaluated for 99m Tc labeling efficiency and in vivo lung uptake. Biodistribution and hemodynamic characteristics of the lead compound were determined in anesthetized dogs as well as by a dosimetric analysis. Lung perfusion was evaluated in the monocrotaline model of pulmonary arterial hypertension in rats. Results: A cyclic AM (residues 22-52) analog encompassing a polyethylene glycol spacer and a tetrapeptide chelating moiety was found to possess the desired characteristics, with 90.7% 6 0.3% (mean 6 SD) labeling efficiency, 40% lung uptake at 10 min after injection, and a favorable safety profile. Lung uptake of the 99m Tc-labeled compound was markedly reduced in rats with pulmonary arterial hypertension. Conclusion: This lead compound could be a suitable clinical imaging agent for the molecular diagnosis of disorders of the pulmonary circulation.

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Section: Discussionmentioning

confidence: 99%

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PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

et al. 2013

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“…Truncation of the N-terminal ring structure produces antagonist peptides in all family members. (16) Significantly, removal of N-terminal and C-terminal regions of IMD yields the IMD antagonist peptide IMD 17-47aa , which has been shown to block biological function of IMD through a receptor-mediated mechanism. (10,17,18) Relatively little is known about how IMD might influence cancer development.…”

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Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

et al. 2012

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Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma. (Cancer Sci 2012; 103: 1474-1480 H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and the third leading cause of cancer death.(1) The majority (>80%) of liver cancers are HCC.Conventional chemotherapy and hormonal therapies have minimal response rates. (3) Therapeutic agents targeting angiogenesis, which is required for tumor growth and metastasis, are currently in development. (4,5) Of the known angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is secreted by nearly all solid cancers.(5) Sorafenib, an inhibitor targeting the VEGF and platelet-derived growth factor receptors, is the standard of care in patients with advanced HCC.(6) Promising novel inhibitors are under investigation.(7) The key to targeting angiogenesis successfully in the future may be to use a combination of multiple inhibitors against multiple targets. Intermedin (IMD, adrenomedullin-2), is a secreted peptide that belongs to the calcitonin/calcitonin gene-related peptide family.(9) IMD regulates diverse physiological processes. For example, IMD is required for rat normal fetoplacental growth, (10) functions as a vasodilator and reduces blood pressure in both normal and hypertensive rats.(11) IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor, calcitonin receptor-like receptor (CRLR). (12) The signaling of IMD is mediated by the interaction of CRLR in association with receptor activity modifying protein 3 (RAMP3).(13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal leve...

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“…Antagonists that block the AM 1 , AM 2 and CGRP receptors simultaneously may also prove useful as cancer therapies. Peptide antagonists of this nature have been developed (Robinson et al 2009). Such antagonists are also likely to block any action of AM2.…”

Section: Future Perspectivesmentioning

confidence: 99%

Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges

Hay

Walker²,

Poyner³

2010

Endocrine Related Cancer

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Adrenomedullin (AM), adrenomedullin 2 (AM2/intermedin) and calcitonin gene-related peptide (CGRP) are members of the calcitonin family of peptides. They can act as growth or survival factors for a number of tumours, including those that are endocrine-related. One mechanism through which this occurs is stimulating angiogenesis and lymphangiogenesis. AM is expressed by numerous tumour types and for some cancers, plasma AM levels can be correlated with the severity of the disease. In cancer models, lowering AM content or blocking AM receptors can reduce tumour mass. AM receptors are complexes formed between a seven transmembrane protein, calcitonin receptor-like receptor and one of the two accessory proteins, receptor activity-modifying proteins (RAMPs) 2 or 3 to give the AM 1 and AM 2 receptors respectively. AM also has affinity at the CGRP receptor, which uses RAMP1. Unfortunately, due to a lack of selective pharmacological tools or antibodies to distinguish AM and CGRP receptors, the precise receptors and signal transduction pathways used by the peptides are often uncertain. Two other membrane proteins, RDC1 and L1/G10D (the 'ADMR'), are not currently considered to be genuine CGRP or AM receptors. In order to properly evaluate whether AM or CGRP receptor inhibition has a role in cancer therapy, it is important to identify which receptors mediate the effects of these peptides. To effectively distinguish AM 1 and AM 2 receptors, selective receptor antagonists need to be developed. The development of specific CGRP receptor antagonists suggests that this is now feasible.

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Novel Peptide Antagonists of Adrenomedullin and Calcitonin Gene-Related Peptide Receptors: Identification, Pharmacological Characterization, and Interactions with Position 74 in Receptor Activity-Modifying Protein 1/3

Cited by 29 publications

References 20 publications

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges

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