Introduction ON JUNE 24, 1971, Andrew V. Schally announced the determination of the primary structure of porcine GnRH at The Endocrine Society Meeting in San Francisco. This announcement was followed by publications by Matsuo et al. (1, 2) and Baba et al. (3) on the proposed amino acid sequence for porcine GnRH and its synthesis and by Burgus et al. (4) who characterized ovine GnRH and found the sequence to be identical with that of porcine GnRH. The physiological and therapeutic importance attributed to the discovery of the new substance was greatly increased by the prospect of the design of potent and long acting GnRH agonists and antagonists. Since that time more than 2000 analogs of GnRH have been synthesized. The impact of research of GnRH and its analogs on clinical medicine recently led Ziporyn (5) to note, “There's almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogs.” It is the intent of this article to provide a historical ...

Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective.

I. Introduction II. Amino Acid Sequences of GnRH Receptors A. GnRH receptor cDNAs B. General structural features C. Covalent modifications D. Gene structure III. Structure-Activity Relations of GnRH Peptides A. Overview B. Comparative structures and activities of vertebrate GnRHs C. Roles of individual amino acids in GnRH activity at the mammalian receptor D. Conclusions from peptide structure-activity data IV. Structure and Conformation of GnRH and Its Analogs A. Early studies of GnRH conformation B. Integrated computational and experimental studies C. Exploration of the entire conformation space of GnRH analogs V. Functional Structure of the Receptor and Ligand-Receptor Complex A. Extracellular domains B. Helix domains C. Intracellular loop domains D. Computational modeling of three-dimensional receptor structure VI. Conclusions

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Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor

https://science.sciencemag.org/content/sci/144/3622/1100.full.pdf

Tarichatoxin--tetrodotoxin: a potent neurotoxin.

The renal acid protease renin selectively cleaves its plasma substrate angiotensinogen to release the decapeptide angiotensin I, which in turn is cleaved by a carboxydipeptidase converting enzyme to yield the pressor octapeptide angiotensin II1. It is generally accepted that the renin–angiotensin system has a physiological role in blood pressure and electrolyte homeostasis2, and that abnormalities of the system contribute to certain forms of hypertension3. We previously showed that reduction of the Leu10–Leu11 scissile peptide bond in the (6–13) octapeptide sequence 2 of equine angiotensinogen produced potent and selective inhibitors of canine plasma renin5. We have now used the same approach to modify the recently elucidated N-terminal sequence6 of human angiotensinogen and report here the production of highly active and species-specific in vitro inhibitors of endogenous human renin cleaving renin substrate in human plasma. Whereas the (6–13) octapeptide H-112 of human angiotensinogen is only a weak inhibitor of human plasma renin (IC50 = 313 µM), the analogue H-113, in which the scissile Leu–Val bond has been reduced, has IC50 = 0.19 µM. Extension of H-113 with Pro at the N-terminus and with Lys at the C-terminus7, giving the decapeptide derivative H-142, increases inhibitory potency further (IC50 = 10 nM). We believe that the high in vitro inhibitory potencies of H-113 and H-142 are due to the ability of the reduced moiety —CH2—NH— to act as a non-hydrolysable analogue of the tetrahedral transition state formed during hydrolysis of the (10–11) peptide bond. H-113 and H-142 are strongly species specific, and are highly specific for renin among acid proteases: H-142 has no inhibitory effect in vitro on human cathepsin D or renal acid protease at a concentration of 712 µM.

Potent new inhibitors of human renin

Methods of enhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis

Benzyloxycarbonyl (Cbz)-amino acid esters were reduced to the corresponding α-aminoaldehydes with diisobutylaluminum hydride. Comparison of specific rotation of the Cbz-aminoalcohols, which were derived from the aldehydes by sodium borohydride reduction, with that of the optically pure material showed that chromatography on a silica gel caused marked racemization in the Cbz-α-aminoaldehyde through keto-enol tautomerism. Cbz-S-Bzl-cysteinal was liable to racemize to a great extent. On the other hand, little racemization occurred in Cbz-NG-nitroargininal. This fact might be accounted for the characteristic cyclic carbinolamine structure of the argininal derivative. The semicarbazones prepared from the crude Cbz-α-aminoaldehydes could be reproduced to the initial aldehydes without racemization. These semicarbazones might be used as good starting materials in peptide aldehyde synthesis.

A New Method to synthesize α-Aminoaldehydes

Some of the leupeptin Ac-LL analogs, in which the argininal moiety was replaced by aromatic aminoaldehydes, were synthesized starting from benzyloxycarbonyl-α-amino-aldehyde semicarbazones derived from benzyloxycarbonyl amino acid esters by the reduction with diisobutylaluminum hydride. The racemization of the aldehyde part of the purified analogs was examined using the analytical ion exchange chromatography of diastereomers produced by the condensation of L-aspartic acid with aminoalcohols, which were obtained by the sodium borohydride reduction of the synthesized peptide aldehydes followed by acid hydrolysis. The results demonstrate that racemization occurs only to a limited extent, when these starting materials are used and careful purifications of the products are carried out.

Synthetic Study of Peptide Aldehydes

Six analogues of LH-RH, in which the tryptophan residue in position 3 was replaced by nonprotein amino acids, were synthesized and evaluated for their LH-RH activity. The analogues substituted by amino acids having the fused aromatic ring structure in the side-chain retained relatively high biological activity. In particular, the potency of [3- (1-naphthyl)-L-alanine]3-LH-RH was 187.1% of that of synthetic LH-RH. The results demonstrate that the fused aromatic ring structure of the side-chain in position 3 is a favorable factor, and that the indolyl NH group in the Trp residue is not essential.

Analogues of luteinizing hormone-releasing hormone with modification in position 3.

Three analogues of tetragastrin, in which the tryptophan residue was substituted by 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine or 1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid, were synthesized and evaluated for their gastric juice stimulating activity. The results suggest that the indolyl NH function in the tryptophan residue plays an important role and that the role of the tryptophan residue in an interaction between tetragastrin and its receptor is different from that in the case of luteinizing hormonereleasing hormone.

Yoshihiko Baba

Papers

A New Method to synthesize α-Aminoaldehydes

Synthetic Study of Peptide Aldehydes

Analogues of luteinizing hormone-releasing hormone with modification in position 3.

Synthesis and biological activity of tetragastrin analogues modifying the tryptophan residue.

Catalytic properties of cytochrome c heme peptides.