Hexapeptide and Cyclic Pentapeptide Endothelin Antagonists Directly Activate Pituitary Gonadotropin-Releasing Hormone Receptors

Yahalom, Dror; Koch, Yitzhak; Ben-Aroya, Nurit; Fridkin, Mati

doi:10.1124/mol.57.4.718

Cited by 4 publications

(2 citation statements)

References 41 publications

(45 reference statements)

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“…Nevertheless, we have previously demonstrated that peptide I can activate the pituitary GnRH receptor and induce LH secretion. 6 Peptide I, derived from the sequence of the C-terminal domain of ET, binds specifically to pituitary GnRH receptors with a moderate affinity (K i ) 1.9 µM), whereas ET itself does not bind to the GnRH receptor. 6 We have also found that removal of the acetyl group of the peptide I results in a hexapeptide (D-Trp-Leu-Asp-Ile-Ile-Trp, peptide II) (Table 1) with similar properties with respect to the GnRH receptor, but with a diminished affinity toward the ET receptor.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

et al. 2000

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We have previously determined that Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide I), an endothelin antagonist, binds specifically (Ki = 1.9 microM) to the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Moreover, peptide I exhibits a GnRH agonistic activity, mediated directly by the GnRH receptor. We now report structure-activity studies of peptide I in respect to its interactions with the GnRH receptor. Our studies suggest that the bioactive conformation of peptide I, recognized by the GnRH receptor, is of a cyclic nature. Thus cyclic analogues of peptide I exhibit higher affinity to the GnRH receptor and increased agonistic potencies as compared to peptide I itself. A linear peptide, Ile-Ile-Trp-D-Trp-Leu-Asp, which presumably forms a similar cyclic conformation, was also shown to be a GnRH agonist. Intraperitoneal administration of Ac-Ile-Ile-Trp-D-Trp-Leu-Cys-OH (Ki = 0.32 microM), one of the cyclic hexapeptides that we have synthesized, to rats induces secretion of luteinizing hormone (LH) with a potency which is only 1 order of magnitude less than that of GnRH itself. Moreover, plasma levels of LH remained elevated for a longer period of time following the administration of the cyclic hexapeptide. This novel class of GnRH agonists may prove useful in the development of new therapeutics.

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Section: Introductionmentioning

confidence: 99%

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

et al. 2000

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“…41 Furthermore, cyclic tetrapeptides have been found that inhibit histone deacetylases, 42 and cyclic pentapeptide antagonsists have been discovered for endothelin. 43 Considering their high affinity, target specificity, and metabolic stability, it seems likely that cyclic peptides will continue to gain attention as powerful biological tools.…”

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confidence: 99%

Cyclic Peptides, A Chemical Genetics Tool for Biologists

Horswill¹,

Benkovic²

2005

Cell Cycle

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The genomics era has presented scientists with an overwhelming amount of sequence information that encodes for a continuously expanding array of metabolic pathways and regulatory networks. In order to unravel this elaborate maze, effective approaches need to be pioneered, and cyclic peptides represent an exciting new tool that can aid this challenging task. There are considerable benefits to cyclic peptides including enhanced protein binding affinity and metabolic stability, but perhaps most important is the ability to biologically synthesize them using intein chemistry. This capacity for genetic encoding allows biologists access to diverse, intracellular small-molecule libraries that can be tailored for numerous chemical genetics approaches. An increasing number of molecular strategies are being developed to aid in the implementation of cyclic peptides in forward and reverse genetics experiments, which will provide researchers with a powerful toolbox to complement existing genomic methodologies.

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Peptidology: short amino acid modules in cell biology and immunology

et al. 2006

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Short amino acid motifs, either linear sequences or discontinuous amino acid groupings, can interact with specific protein domains, so exerting a central role in cell adhesion, signal transduction, hormone activity, regulation of transcript expression, enzyme activity, and antigen-antibody interaction. Here, we analyze the literature for such critical short amino acid motifs to determine the minimal peptide length involved in biologically important interactions. We report the pentapeptide unit as a common minimal amino acid sequence critically involved in peptide-protein interaction and immune recognition. The present survey may have implications in defining the dimensional module for peptide-based therapeutical approaches such as the development of novel antibiotics, enzyme inhibitors/activators, mimetic agonists/antagonists of neuropeptides, thrombolitic agents, specific anti-viral agents, etc. In such a therapeutical context, it is of considerable interest that low molecular weight peptides can easily cross biological barriers, are less susceptible to protease attacks, and can be administered at high concentrations. In addition, small peptides are a rational target for strategies aimed at antigen-specific immunotherapeutical intervention. As an example, specific short peptide fragments might be used to elicit antibodies capable of reacting with the full-length proteins containing the peptide fragment's amino acid sequence, so abolishing the risk of cross-reactivity.

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Hexapeptide and Cyclic Pentapeptide Endothelin Antagonists Directly Activate Pituitary Gonadotropin-Releasing Hormone Receptors

Cited by 4 publications

References 41 publications

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

Cyclic Peptides, A Chemical Genetics Tool for Biologists

Peptidology: short amino acid modules in cell biology and immunology

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