High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

Yanofsky, Stephen D.; Baldwin, David N.; Butler, John H.; Holden, Frank; Jacobs, J. W.; Palaniappan, Balasubramanian; Chinn, Jason P.; Cwirla, Steven E.; Peters-Bhatt, Elizabeth; Whitehorn, Erik A.; Tate, Emily H.; Akeson, Ann L.; Bowlin, Terry L.; Dower, William J.; Barrett, Ronald W.

doi:10.1073/pnas.93.14.7381

Cited by 106 publications

(62 citation statements)

References 42 publications

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“…Due to structural stabilization, cyclization of peptide motifs is associated with a higher affinity for the receptors compared with their linear analogues (18,48,50). The design of carrier molecules described in this study may also be applicable for other receptors, such as cytokine or growth factor receptors (48,(51)(52)(53). Studies on drug carriers to the platelet-derived growth factor receptor are in progress.…”

Section: Discussionmentioning

confidence: 99%

Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

Beljaars¹,

Molema²,

Schuppan³

et al. 2000

Journal of Biological Chemistry

134

105

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Section: Discussionmentioning

confidence: 99%

Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

Beljaars¹,

Molema²,

Schuppan³

et al. 2000

Journal of Biological Chemistry

134

105

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“…Detailed structure-function analysis of the IL-5͞IL-5 receptor interaction, by scanning alanine mutagenesis of IL-5, has revealed that the key charged residues important for the formation of the ligand-receptor complex are spatially distinct and are separated across a large surface area (17,19). This topography may provide a molecular explanation for the lack of small molecule IL-5 receptor antagonists that have been reported.The screening of libraries of random recombinant peptides has previously led to the discovery of both agonistic and antagonistic peptides to several other cytokine receptors (20)(21)(22). In this study, we report the identification and characterization of two distinct series of specific antagonists of IL-5 that bind to the ligand-binding ␣ subunit of the receptor.…”

mentioning

confidence: 95%

“…The screening of libraries of random recombinant peptides has previously led to the discovery of both agonistic and antagonistic peptides to several other cytokine receptors (20)(21)(22). In this study, we report the identification and characterization of two distinct series of specific antagonists of IL-5 that bind to the ligand-binding ␣ subunit of the receptor.…”

mentioning

confidence: 95%

A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor α chains

England

Palaniappan

Uings

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Two series of peptides that specifically bind to the extracellular domain of the ␣ chain of the human interleukin-5 receptor (IL-5R␣), but share no primary sequence homology to IL-5, were identified from libraries of random recombinant peptides. Affinity maturation procedures generated a 19-aa peptide that binds to the IL-5 receptor ␣͞␤ heterodimer complex with an affinity equal to that of IL-5 and is a potent and specific antagonist of IL-5 activity in a human eosinophil adhesion assay. The active form of the peptide is a disulfide-crosslinked dimer that forms spontaneously in solution. Gel filtration analysis, receptor-binding studies, and analytical ultracentrifugation reveal that the dimeric peptide binds simultaneously to two receptor ␣ chains in solution. Furthermore, the dimer peptide, but not IL-5, can activate a chimeric receptor consisting of the IL-5R␣ extracellular domain fused to the intracellular domain of the epidermal growth factor receptor, thus demonstrating that the peptide also promotes receptor dimerization in a cellular context. The functional antagonism produced by the bivalent interaction of the dimeric peptide with two IL-5R ␣ chains represents a distinctive mechanism for the antagonism of cytokines that use heteromeric receptors.I nterleukin-5 (IL-5) is a T cell-derived hematopoietic cytokine that acts exclusively on cells of the eosinophil and basophil lineage (1, 2). Although IL-5 can regulate many of the functions of mature, terminally differentiated eosinophils such as cell survival (3), adhesion (4), and activation (5), its primary function is to promote the differentiation and expansion of eosinophil precursors in the bone marrow (6).Transgenic mice that constitutively overexpress IL-5 in their lungs exhibit systemic and airway eosinophilia, bronchial hyperreactivity, and histopathological features characteristic of human asthma (7). Administration of recombinant IL-5 into the airways of either guinea pigs (8) or mildly asthmatic individuals (9) promotes a lung eosinophilia and bronchial hyperreactivity. Moreover, blocking the activity of IL-5 through administration of neutralizing anti-IL-5 antibodies (10-12), or through IL-5 gene deletion (13), prevents allergen-induced airway eosinophilia and bronchial hyperreactivity. Together, these data demonstrate that IL-5 plays a central role in the development of allergen-induced eosinophilia in animals and suggest that an anti-IL-5 therapeutic could provide an alternative approach to the treatment of human asthma perhaps more specific than current anti-inf lammatory therapies such as inhaled corticosteroids.The IL-5 receptor is a heterodimer consisting of an ␣ chain that specifically binds IL-5 and a signal-transducing ␤ c chain shared with the receptors for two structurally related cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF) and . A number of protein-based IL-5 antagonists have been reported, including soluble IL-5 receptor ␣ chains (IL5R␣s) that sequester the ligand in solution (15), single point mutants of IL...

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“…Successful examples of protein minimization projects [4] include the minimization of protein A [5] and atrial natriuretic peptide [6], both to peptides of nearly half the size the original proteins. Even more substantial reductions were recently published by Yanofsky and co-workers [7] who obtained a 15-residue peptide antagonist of the interleukin-1 receptor that may mimic the binding motif of its natural 153-residue antagonist. Wrighton and co-workers [8] reported the discovery of a 20-residue peptide dimer that binds and activates the erythropoietin receptor.…”

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confidence: 99%

Towards minimized gonadotropins with full bioactivity

Heikoop

Winkel

Grootenhuis

1999

European Journal of Biochemistry

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Gonadotropins are highly complex glycoprotein hormones consisting of two noncovalently associated subunits, which are heavily glycosylated. Using the X-ray structure of human choriogonadotropin and structure/activity relationships we aimed to design`minimized' gonadotropins of reduced complexity. Our results show that it is possible to reduce the size of natural human choriogonadotropin by one-third of its molecular weight while retaining its wild-type biopotency. To our knowledge, such`mini'-human choriogonadotropins represent the smallest gonadotropins described so far with an lutropin/choriogonadotropin receptor affinity and in vitro biological activity comparable with that of natural human choriogonadotropin. It provides an important step towards the structure/ function-based design of small molecule drugs to the human gonadotropin receptors.Keywords: gonadotropin; human choriogonadotropin; protein minimization; single-chain.Choriogonadotropin, lutropin and follitropin form the family of gonadotropins that play a key role in fertility [1]. They are heterodimeric glycoproteins composed of an a-subunit and a b-subunit, which are noncovalently linked. Both subunits are glycosylated and contain N-linked oligosaccharides, and in the case of the choriogonadotropin b-subunit, O-linked oligosaccharides. Assembly of the common a-subunit with one of the three b-subunits results in the unique properties of each hormone leading to its specific biological activity.The elucidation of the crystal structure of human choriogonadotropin [2,3] has been a major step forward in the understanding of gonadotropin structure/function relationships. However, the mechanism of gonadotropin receptor interactions is poorly understood at present. The reduction of the highly complex heterodimeric glycoprotein hormones to small structured polypeptides or`mini-proteins' that retain their biological activity would be a major step towards achieving the structure/ function-based design of small molecule drugs for the treatment of infertility. Reducing the size and complexity of protein drugs may also open the way for other routes of administration, e.g. nasal rather than by injection. Successful examples of protein minimization projects [4] include the minimization of protein A [5] and atrial natriuretic peptide [6], both to peptides of nearly half the size the original proteins. Even more substantial reductions were recently published by Yanofsky and co-workers [7] who obtained a 15-residue peptide antagonist of the interleukin-1 receptor that may mimic the binding motif of its natural 153-residue antagonist. Wrighton and co-workers [8] reported the discovery of a 20-residue peptide dimer that binds and activates the erythropoietin receptor.In an attempt to reduce the structural complexity of gonadotropins we have engineered a mini-choriogonadotropin in which the two subunits are truncated by a total of 17 amino acid residues and which, in addition, lacks the C-terminal peptide of the b-subunit and its four O-glycosylation sites [9]. Although ...

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High affinity type I interleukin 1 receptor antagonists discovered by screening recombinant peptide libraries.

Cited by 106 publications

References 42 publications

Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor α chains

Towards minimized gonadotropins with full bioactivity

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