Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists

Anderson, Richard K.; Newton, Claire; Millar, Robert P.

doi:10.3389/fendo.2018.00757

Cited by 30 publications

(26 citation statements)

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“…Several FSHR small molecule modulators have been developed in recent years. Although FSHR small molecule modulators have shown promising results in vitro and in vivo, these molecules failed to show desirable results in human clinical trials (18) (30) (31) (32).…”

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confidence: 99%

Identification and in vivo validation of a 9-mer peptide derived from FSHβ with FSHR antagonist activity

et al. 2020

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FSH-FSHR interaction is critical for folliculogenesis as well as progression of several cancers. FSHR peptidic antagonists can circumvent the side effects associated with currently available steroidal contraceptives. The present study aims to identify the shortest peptidic stretch of FSH that can exhibit FSHR antagonistic activity. Based on homology and structural analysis of FSH-FSHR complex (PDB ID: 4AY9), a minimal continuous stretch within FSHβ seat-belt loop (FSHβ (89-97)) was identified to be crucial for FSH-FSHR interaction. Binding affinity and activity of FSHβ (89-97) peptide was evaluated using in silico, in vitro and in vivo methods. The peptide could significantly inhibit binding of [ 125 I] FSH to rat FSHR as well as FSH-induced cAMP production. In vivo administration of this peptide resulted in reduced ovarian weight in immature Holtzman female rats. The peptide inhibited transition of follicles from pre-antral to antral stage as well as progression of granulosa cells beyond G0/G1 phase. Administration of FSHβ (89-97) peptide in adult female rats inhibited conversion of testosterone to estradiol and could significantly retard folliculogenesis. In summary, FSHβ (89-97) peptide is a potential candidate for further optimization for use as fertility regulator or theranostic agent in cancer therapy.

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confidence: 99%

Identification and in vivo validation of a 9-mer peptide derived from FSHβ with FSHR antagonist activity

et al. 2020

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“…(Bis)Sulfonic Acid, (Bis)Benzamides, Tetrahydroquinolines and Benzamide Derivatives have been tested in in vitro and in vivo studies for their efficacy [143 ]. However, although these molecules are promising in their approach of oral administration to obviate the need of multiple injections protocol and reducing the risk of OHSS, can potentially rescue misfolded receptors and could also serve in protection of endangered animal species, more information about the epitopes and domains in FSHR involved in binding and signaling pathways transduced, is needed.…”

Section: Accepted Articlementioning

confidence: 99%

From cell surface to signalling and back: the life of the mammalian FSH receptor

2020

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Follicle stimulating hormone receptor (FSHR) is a class A G-protein coupled receptor that belongs to the subfamily of glycoprotein hormone receptors (GPHRs). The interaction of FSH with FSHR triggers downstream signaling pathways that play a central role in mammalian reproduction, such as folliculogenesis in females and the maintenance of spermatogenesis in males. This warrants a detailed investigation into FSHR, from its genesis, to the post translational modifications that enable it to become functionally competent, followed by its trafficking to the cell membrane. Subsequently, FSH stimulated G s uncoupling and transduction of G-protein mediated signaling pathways takes place, after which the receptor undergoes β-arrestin mediated internalization and may trigger other noncanonical signaling pathways. The majority of the FSH-FSHR complexes are recycled back to the cell surface and only a small proportion are routed to lysosomal degradation pathways, thus, completing the lifecycle of FSH receptor. Information about important epitopes and aspects of FSH receptor function has been gleaned from a number of sources including structure-function studies on naturally occurring as well as induced mutations, single-nucleotide polymorphisms, peptides and antipeptide antibodies corresponding to predicted functional residues, X-ray crystallography analysis and high resolution imaging studies, in addition to the information available for the other GPHRs. In this review, we have traversed through the life cycle of the FSH receptor, along with discussing reproductive pathophysiologies that could result due to impairment in the receptor function, which may arise from defects during its journey from its birth to its degradation .. Moreover, unresolved questions and challenges that need exploration have been highlighted.

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“…It stimulated the AC activity in the CHO cells expressing the FSH receptor (EC 50 , 3.9 nM) but was not active in the in vivo conditions [55]. A search for new LMW ligands of FSH receptor revealed a large number of the compounds with different pharmacological activity [39,[56][57][58]. They belong to different classes of the organic compounds, such as the thiazolidines [59][60][61][62], substituted γ-lactams [63], diketopiperazines [64,65], N-alkylated sulfonyl piperazines [66], tetrahydroquinolines [67], hexahydroquinolines [68,69], thienopyrimidines [70], and benzamides [69].…”

Section: The Low-molecular-weight Ligands Of the Follicle-stimulatingmentioning

confidence: 99%

“…In conclusion, it should be noted that despite the large number of the investigated allosteric ligands of FSH receptor, they are not yet used in the clinic due to the many unresolved problems with their bioavailability, the mechanisms of action, and possible undesirable effects [57,58]. However, the limitations with the use of commercial FSH drugs in the clinic and the need to develop the selective FSH receptor inhibitors are a good stimulus to further development of the LMW ligands of FSH receptor and their implementation into clinical practice.…”

Section: The Chaperone-like Properties Of the Lmw Allosteric Agonistsmentioning

confidence: 99%

The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

Шпаков¹,

Derkach²,

Bakhtyukov³

et al. 2020

Innovations in Assisted Reproduction Technology

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In clinic, the luteinizing (LH) and follicle-stimulating (FSH) hormones and human chorionic gonadotropin (hCG) are used to treat reproductive dysfunctions and in assisted reproductive technology. They are the αβ-heterodimeric complexes and specifically bind to ectodomain of G protein-coupled LH and FSH receptors. This leads to activation of many signaling cascades; some of which are responsible for steroidogenesis, folliculogenesis, and spermatogenesis, while the others, such as β-arrestin pathways, trigger the downregulation of gonadotropin receptors. A low selectivity of the intracellular signaling of gonadotropins and a large number of their isoforms are the main causes of undesirable effects of gonadotropins, limiting their clinical applications. Unlike gonadotropins, the low-molecular-weight (LMW) ligands interact with an allosteric site located in the transmembrane domain of the LH and FSH receptors and selectively activate the certain signaling pathway, preventing a number of side effects of gonadotropins. The LMW ligands are characterized by activity of the full and inverse agonists and neutral antagonists, as well as the positive and negative modulators, and they have the in vivo activity, including when administered orally. This review focuses on the advances in the development of LMW allosteric ligands of the LH and FSH receptors and the prospects for their use in reproductive medicine.Innovations in Assisted Reproduction Technology 2 folliculogenesis, and spermatogenesis in patients with the dysfunctions in the hypothalamo-pituitary-gonadal axis, (ii) the induction of ovulation in the assisted reproductive technologies, and (iii) the treatment of sex hormone-dependent tumors [1][2][3][4]. The gonadotropins with LH activity are isolated from the urine of pregnant women (the urinary forms of hCG) or produced in the specialized cellular cultures (the recombinant forms of LH and hCG), while FSH is isolated from the urine of postmenopausal women (the urinary forms of FSH) or produced by genetic engineering approaches (the recombinant forms of FSH) [1,5,6]. Despite the fact that these forms of gonadotropins are widely used in the clinic, they have the significant side effects. In the case of urinary forms of hCG and FSH, the main disadvantages are the presence of biologically active impurities in the gonadotropin preparations and a low degree of its standardization [2,7]. The placental hCG differs significantly in both the structure and functions from the LH and sulfated hCG which are secreted by the pituitary gonadotrophs and circulate in the blood of adult men and women [2,8]. Furthermore, the placental hCG is produced only during pregnancy and regulates the growth and development of the embryo [9]. The urinary FSH contains mainly highly glycosylated forms of this gonadotropin with the reduced activity, which associated with the impaired reproductive functions and infertility at the postmenopausal period [10]. At the same time, the recombinant forms of gonadotropins differ from their natural forms in the ...

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Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists

Cited by 30 publications

References 65 publications

Identification and in vivo validation of a 9-mer peptide derived from FSHβ with FSHR antagonist activity

Identification and in vivo validation of a 9-mer peptide derived from FSHβ with FSHR antagonist activity

From cell surface to signalling and back: the life of the mammalian FSH receptor

The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

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