Gonadotropin-Releasing Hormone Analog Design. Structure-Function Studies Toward the Development of Agonists and Antagonists: Rationale and Perspective

Karten, Marvin J.; Rivier, Jean

doi:10.1210/edrv-7-1-44

Cited by 528 publications

(293 citation statements)

References 143 publications

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“…It was revealed many years ago that substitution of the Gly amino acid residue at position 6 of LHRH (pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ) by various D-amino acids results in very potent analogs of LHRH with high binding affinity (46 ,D-Mel 6 and D-Ala 10 substitutions were also produced (19). Interestingly, the analog containing D-Trp showed very high binding affinity (19).…”

Section: Design and Synthesis Of Targeted Cytotoxic Analogs Of Lhrhmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to ]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesinlike peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.

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Section: Design and Synthesis Of Targeted Cytotoxic Analogs Of Lhrhmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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“…The first observation of a GnRH partial agonist ([Gly 2 ]-GnRH) led to the design of the first GnRH antagonist, des-His 2 -GnRH (Vale et al 1972). Interestingly, substitutions other than Gly at position 2 of GnRH (such as -amino acids) led to low potency full agonists whereas substitutions by a -amino acid led to full antagonists (Karten & Rivier 1986). It is only with the synthesis of cyclic GnRH analogues that a new family of GnRH partial agonists was discovered.…”

Section: Introductionmentioning

confidence: 99%

Identification of new gonadotrophin-releasing hormone partial agonists

Leaños‐Miranda

Ulloa‐Aguirre²,

Cervini³

et al. 2006

Journal of Endocrinology

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GnRH agonists or antagonists are currently utilized as therapeutic agents in a number of diseases. A side-effect of prolonged treatment with GnRH analogues is hypoestrogenism. In this study, we tested the in vitro potency of different GnRH analogues originally found to be partial agonists (i.e. analogues with decreased efficacy for activating or stimulating their cognate receptor) as well as novel analogues, to identify compounds that might potentially be useful for partial blockade of gonadotrophin release.

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“…The majority of clinically used GnRH agonists (including triptorelin), contain a D-amino in place of glycine at position 6 (Beyer et al, 2011). This replacement leads to a greater metabolic stability of the compound (Karten and Rivier, 1986). Furthermore, the D-amino acid in this position enhances receptor binding by stabilizing the type II ß-turn conformation that has been shown to be important for interaction with the receptor (Laimou et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

Varamini

Mansfeld

Giddam

et al. 2017

International Journal of Pharmaceutics

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Graphical abstractGonadotropin-releasing hormone (GnRH) is an endogenous peptide with a short biological half-life. Although GnRH analogs (eg. triptorelin) are developed with enhanced stability compared to the native peptide, they still suffer from poor biological stability and pharmacokinetic properties. Furthermore, they are only effective in the treatment of hormone-dependent reproductive cancers. In this study we applied lipidation and glycosylation along with D-amino acid substitution at position 6 (D-Trp 6 ) to improve the stability, permeability, and consequently the potency of the GnRH peptide and triptorelin. We showed that the conjugation of GnRH with a lipid moiety and carbohydrates made all modified constructs (1-8) more stable than the parent peptide against enzymatic degradation (5.5 to 6.5 times). Two of the lactose-modified glycolipopeptides, 3 and 6, showed 27 and 16 times higher membrane permeability than the parent GnRH, respectively. All analogs with D-Trp 6 -substitution (4-6) exerted GnRH receptor-mediated antiproliferative activity in prostate and ovarian GnRH-receptor positive cell lines. They were more potent than triptorelin in the hormone-independent prostate cancer cell line: DU145. Compound 6 (lactose-modified) was the most potent analog for stimulating the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) gonadotropins from rat pituitary cells in vitro. The same glycolipopeptide exhibited a higher efficacy and duration of action in stimulating the release of LH than triptorelin in a preclinical mouse model. The superior activity 2 of lipid-and carbohydrate-substituted triptorelin analog 6 made it a promising candidate for the development of new GnRH agonists to treat both hormone-dependent and hormone-refractory prostate cancer..LIST OF ABBREVIATIONS

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Gonadotropin-Releasing Hormone Analog Design. Structure-Function Studies Toward the Development of Agonists and Antagonists: Rationale and Perspective

Cited by 528 publications

References 143 publications

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Identification of new gonadotrophin-releasing hormone partial agonists

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

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