Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH₂ (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility

Abstract

Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days.

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

“…Recently, KISS1R agonists have been developed through modification of KP10 to have increased potency and stability in order to advance kisspeptin-targeted therapeutics through the translational pathway (20)(21)(22). MVT-602 (previously known as TAK-448) is a KISS1R agonist with a longer duration of action than native KP54 (8,23).…”

“…MVT-602 is a nanopeptide KISS1R agonist developed to have increased stability, potency, and water solubility (20). To our knowledge, this is the first study to determine its PD and PK profiles in healthy women, and to directly compare these properties with those of native KP54, and with those in women with the 2 minutes after MVT-602 as compared with 55 minutes after KP54 (P = 0.0012) ( Figure 4D).…”

“…However, the onset of the firing response following both ligands was similarly rapid during electrophysiological GnRH neuron studies, indicating that factors preceding receptor occupancy, such as the time needed for gaining access across the bloodbrain barrier (BBB), are more likely to underlie this delay than deferred activation after binding to KISS1R. Indeed, MVT-602 was selected for its hydrophilic properties (20), which could conceivably alter its ability to cross the BBB, whereas KP54 is…”

Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction

“…TAK-448 and TAK 683 are two kisspeptin analogs designed bymodifying KP10 with nine amino acids [ 90 , 98 ]. Compared with KP10, the two analogs show comparable KISS1R-binding affinity and potency with increased water solubility and half-life in vivo [ 92 ].…”

Synthesis of aryl-thioglycopeptides through chemoselective Pd-mediated conjugation

“…We chose the Tyr1 residue (KP10 numbering), that as has been shown by Ala-scanning to be tolerant to modifications, to incorporate a model β-thioglucosyl analogue 32,33. Note that, as many lipopeptides, 6a shows very limited solubility under aqueous conditions, and is prone to hydrogel formation such as the parent KP10 34. Our choice of this peptide as a model compound was in part driven by our curiosity to see if glycoconjugation could improve its physicochemical properties.…”