Structure−Activity Relationship Studies of Gonadotropin-Releasing Hormone Antagonists Containing<i>S</i>-Aryl/Alkyl Norcysteines and Their Oxidized Derivatives

Samant, Manoj; White, Richard; Hong, Doley J.; Croston, Glenn; Conn, P. Michael; Rivier, Jean

doi:10.1021/jm0613931

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…Along with these intriguing data regarding the molecular changes associated with early follicle selection, the present study provided novel results concerning the molecular changes caused by acute inhibition of LH near the time of follicle selection by treatment with acyline, a long-acting, potent GnRH receptor antagonist of the azaline B family [40,41]. The GnRH antagonist actions of acyline have been demonstrated previously in dogs [42], horses [43], cattle [44], rodents [45], monkeys [46], and humans [47].…”

Section: Discussionmentioning

confidence: 72%

The Role of Luteinizing Hormone in Regulating Gene Expression During Selection of a Dominant Follicle in Cattle

Luo¹,

Gümen²,

Haughian³

et al. 2010

Biology of Reproduction

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At approximately 8.5 mm in diameter, the future dominant follicle is "selected" for continued growth in cattle. In the present study, cows were treated with a gonadotropin-releasing hormone receptor antagonist, acyline, just before follicle selection (near 7.8 mm) to investigate the role of LH in changing mRNA concentrations during selection of a dominant follicle. The ovaries containing the expected dominant follicle (EDF; first largest follicle) and expected largest subordinate follicle (ESF) were removed after 12 or 24 h of treatment. Real-time PCR was used to determine mRNA concentrations. ELISA was used to measure testosterone and 17beta-estradiol (E(2)) and radioimmunoassay to measure androstenedione (A(4)) in follicular fluid. Concentrations of E(2) were greater in EDF than in ESF of untreated cows near the time of follicle selection (12 h) or at 12 h after selection (24 h). Testosterone, E(2), and A(4) were all dramatically decreased by acyline treatment at both times. In theca cells, acyline treatment reduced CYP17A1 (P450 17alpha) in EDF and STAR (steroidogenic acute regulatory protein) in both EDF and ESF but did not alter CYP11A1 (P450scc). In granulosa cells (GCs), LHCGR (luteinizing hormone [LH] receptor) was much greater in EDF than in ESF at both time of selection (739% greater) and 12 h after selection (2837% greater) and was decreased by acyline in EDF (87% decrease). The mRNA for CYP19A1 (cytochrome P450 aromatase) and PAPPA (pregnancy-associated plasma protein-A) tended to be greater in EDF than in ESF at follicle selection, and both mRNAs were much greater at 12 h after selection, with acyline significantly decreasing PAPPA mRNA after 24 h of treatment. The mRNA for FSHR (follicle-stimulating hormone receptor) was not different in EDF versus ESF and was not altered by acyline. Thus, induction of LHCGR mRNA in GCs is an early event during the follicle selection process, and surprisingly, expression of LHCGR mRNA is dependent on circulating LH. Production of follicular A(4), testosterone, and E(2) are also acutely related to LH but due to changes in expression of STAR and CYP17A1 in TC.

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Section: Discussionmentioning

confidence: 72%

The Role of Luteinizing Hormone in Regulating Gene Expression During Selection of a Dominant Follicle in Cattle

Luo¹,

Gümen²,

Haughian³

et al. 2010

Biology of Reproduction

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“…This antagonist blocks GnRH and inhibits LH production, which in turn causes a suppression of testosterone and DHT [41,68]. In addition, other antagonistic peptide analogues such as Antide [N-Ac-DNal 1 , DpClPhe 2 , DPal 3 , Lys(Nic) 5 , DLys(Nic) 6 , Lys(iPr) 8 Rivier et al have designed and synthesized a large number of modified GnRH analogues, both agonistic [69] and antagonistic [70][71][72][73], using unnatural amino acids [74,75], cyclization and in some cases dicyclization [76][77][78][79]. Variable substitutions were involved in almost all positions, especially in the N-terminal, leading to the synthesis of antagonists [80][81][82].…”

Section: Nhmentioning

confidence: 99%

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Mantzourani¹,

Laimou²,

Matsoukas³

et al. 2008

AIAAMC

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Peptides regulate most physiological processes, mainly by binding to specific receptors located on the cell surface and inducing a series of signals, neurotransmissions or the release of growth factors. There has been a rapid expansion in the use of peptides as therapeutic agents after the 1960s, but a series of unfortunate side effects present in Phase I and II clinical studies combined with their low bioavailability, led to the introduction of the idea of peptidomimetics as alternative compounds that mimic the biological activity of peptides, while offering the advantages of increased bioavailability, biostability, bioefficiency, and bioselectivity. Since then new peptides with promising in vitro results, involving the monoclonal antibody expansion, as well as the newly launched research field for novel formulations for increasing peptides' bioavailability, redirected the interest on the peptide market. In this report we will highlight three areas where the use of peptides has shown promising results, with products that are either currently used as drugs or included into Phase III clinical studies.

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“…Hemiaminal S1. S1 was prepared on multi-gram scale according to the procedure reported by Rivier and co-workers 30 . An oven-dried 250 mL round-bottom flask was charged with glyoxylic acid monohydrate (3.6 g, 39 mmol, 1.1 equiv) and tert-butyl carbamate (4.1 g, 35 mmol, 1.0 equiv).…”

Section: General Procedures For Chemical Synthesismentioning

confidence: 99%

Catalytic Use of a Leader Peptide in the Biosynthesis of 3-Thiaglutamate

Donk

Funk

Ting

2018

Preprint

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Small molecule natural products are key modulators of many types of intra-and interspecies communication. The availability of genome sequences allows the discovery of pathways to previously unknown natural products. We describe here a pathway in which a ribosomally synthesized small peptide serves as a catalytic scaffold on which a small-molecule anti-metabolite is biosynthesized in Pseudomonas syringae. First, a cysteine residue is transferred from Cys-tRNA to the C-terminus of the peptide, a reaction that replaces ribosomal protein synthesis. Then, a translocation of the cysteine thiol from the β-carbon to the α-carbon is catalyzed by an oxidase that removes the βcarbon as formate. The resulting thiol is carboxymethylated and proteolysis releases 3thiaglutamate, in the process regenerating the peptide scaffold. This pathway features three previously unknown biochemical processes.

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Structure−Activity Relationship Studies of Gonadotropin-Releasing Hormone Antagonists ContainingS-Aryl/Alkyl Norcysteines and Their Oxidized Derivatives

Cited by 14 publications

References 62 publications

The Role of Luteinizing Hormone in Regulating Gene Expression During Selection of a Dominant Follicle in Cattle

The Role of Luteinizing Hormone in Regulating Gene Expression During Selection of a Dominant Follicle in Cattle

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

Catalytic Use of a Leader Peptide in the Biosynthesis of 3-Thiaglutamate

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