High-Quality Kisspeptin-54 for Cancer & Reproductive Research

The longest bioactive form of KISS1 transcript product, Kisspeptin-54, has been a subject of interest in oncology as well as reproductive medicine; its length allows for persistent receptor activation, which allows for studies into its anti-metastatic pathways and the neural mechanisms involved in the control of puberty and ovulation. It is also more resistant to enzymatic degradation than its shorter counterparts, and it is the preferred ligand for long-term, reversible activation of GPR54 in translational cancer models or in fertility reversal therapies.

Overview of Kisspeptin-54

Kisspeptin-54 is unique in its roles as both an inhibitor of metastasis and as a modulator of reproductive neuroendocrinology due to the amphipathic α-helix within its mid-region and the C-terminus RF-amide motif that allows it to fit into the seven transmembrane bundle of the GPR54 with nanomolar affinity. It was discovered and named metastin due to its ability to inhibit melanoma cell migration, where the mature peptide is derived from the proteolytic cleavage of a 145-amino-acid precursor protein into a fifty four-residue peptide that contains all of the residues necessary for both its high affinity and extended residence time. In the hypothalamus it serves as an auto-regulatory stimulus of GnRH neurons in order to convert information about metabolic, circadian, and gonadal steroid signals into a regulated release of LH, and in other tissues it has cytostatic effects through a feedback relationship between matrix metalloproteinases and pro-apoptotic kinase signaling. Its longer sequence confers a longer half-life in the circulation as compared to the decapeptide, allowing for a persistent activation of calcium transients in the GnRH neuronal system as well as the ability for the peptide to travel to distant metastatic sites where low expression may have high biological impact. The ligand also causes receptor internalization without causing the desensitization that was seen with shorter peptides, which allows for repetitive dosing while still maintaining mechanistic understanding. As a result, kisspeptin-54 has become the preferred tool for understanding the process by which metastatic cells cross tissue barriers, re-engage arrested reproductive axes under conditions of nutritional deficit, and characterize the transcriptional responsiveness of GPR54 to varying steroid environments.

Fig. 1 The structure of kisspeptins in humans.^1,2

Structure and Biological Importance

The unique features of kisspeptin-54's structure. Its N-terminus contains a polybasic domain that mediates electrostatic interaction with cell surface heparan sulphate proteoglycans, creating a local reservoir to direct the ligand to its receptor while protecting it from degradation by aminopeptidases. In the middle of the peptide, an alanine-rich helix provides just enough amphipathicity to allow for transient partitioning into lipid rafts. This interaction preferentially couples signaling to the Gq/phospholipase C pathway, instead of β-arrestin recruitment, resulting in strong but transient calcium signals that are better suited for pulsatile release of GnRH. The C-terminus contains the common nine amino acid kisspeptin core sequence, which in kisspeptin-54 is included in a more hydrophobic domain, leading to slower dissociation and less non-specific binding to other RF-amide receptors. From an evolutionary perspective, the conservation of the longer isoform in eutherian mammals indicates that the ability to reproduce and tumor suppression have historically been linked, as could be required for example to control cellular migration during implantation and also to synchronize reproductive cycles. Physiologically, the molecule acts as a central checkpoint that receives information on energy balance, inflammation, and time of the day, and transmits it not only to the neurosecretory endings that regulate reproductive functions, but also to the invasive front of cancer cells that compromise tissue homeostasis. In fact, the dual roles of kisspeptin are further highlighted by the fact that the same network of transcription factors (forkhead and nuclear factor families) controls the expression of Kiss-1 in hypothalamic neurons and epithelial tumor masses, so that targeting kisspeptin-54 pharmacologically instructs not only reproductive fitness but also metastatic quiescence. This multifunctionality thus makes the ligand a privileged tool to dissect the shared circuitry that links organismal survival to cellular containment.

Unique Properties Compared to Kisspeptin-10

Kisspeptin-10, while representing the minimal required epitope for receptor activation, is further complicated in the fifty-four residue parent peptide by addition of a number of structural features which dramatically change the pharmacokinetic profile and physiological impact. The most obvious difference is in half-life: the decapeptide is degraded by dipeptidyl peptidases within minutes, creating an ultradian rhythm that is excellent for acute electrophysiological experiments, but less useful in cases where prolonged receptor occupancy is required, such as in inhibition of tumor growth or stimulation of ovulation over a protracted follicular phase. Kisspeptin-54, on the other hand, has a hidden cleavage pattern; its longer spine winds around binding proteins in the plasma, prolonging the half-life enough to allow once or even twice daily dosing without reduction of the GnRH release. Trafficking of the receptor is also different: the shorter fragment induces a rapid internalization of GPR54 and subsequent proteasomal degradation, requiring a washout period prior to re-administration, while the longer isoform induces the formation of recycling endosomes, which allows multiple rounds of signalling without receptor depletion, preserving pulsatile LH secretion over multiple release episodes. This translates to an ability of kisspeptin-54 to entrain endogenous GnRH pulsatility without inducing tachyphylaxis, which has been applied to protocols attempting to reactivate ovarian cyclicity in hypothalamic amenorrhoea, or synchronize oestrus in large-animal embryology. Equally important is the difference in ability to reach metastatic niches: the decapeptide is free to diffuse, but is cleared before a pharmacological concentration can be reached within the avascular cores of tumors, while the fifty-four-mer, through its increased size and heparin binding affinity, is able to lodge within peritumoral matrices, thus sustaining the anti-invasive signals which are able to suppress epithelial-to-mesenchymal transition. Taken together, these differences give kisspeptin-54 an identity as more than an extended version of the shorter peptide, and a qualitatively different molecule whose longer pharmacological shadow can cover the timescale between acute neurosecretion and long-term metastatic suppression.

Receptor Conformational Dynamics Elicited by Kisspeptin-54

More recently, it was shown, using biophysical methods, that kisspeptin-54 enforces a "wide-open" state of GPR54 in which transmembrane helices 5 and 6 swivel out, resulting in an intracellular pocket which "favors Gq recruitment over β-arrestin, and a bias towards PLC-signalling over receptor desensitization". In this preferred state, the lipid-facing arginine residue in the fifty-four-mer interacts with the phosphatidylinositol 4,5-bisphosphate to form a salt bridge, thus stabilizing the ligand–receptor complex and retaining it in the cholesterol-enriched microdomains that prolong the calcium oscillations. The persistent signal output is further shaped by the ability of the peptide to allosterically regulate a hot-spot tyrosine kinase in the C-tail of the receptor, crosstalking with this enzyme to potentiate the bursts in mitogen-activated protein kinase (MAPK) without triggering receptor down-regulation. These explain how kisspeptin-54 is able to elicit repetitive GnRH pulses throughout the whole follicular phase, while simultaneously inhibiting matrix metalloproteinase transcription in neighboring metastatic sites, i.e. how a single molecule can perform divergent functions, by merely "adjusting" the choreography of the receptor.

Research Applications

Kisspeptin-54 has emerged as a tool that can cut both ways—directed towards tumour micro-environments to snip mobility signals, and towards hypothalamic pathways to resurrect quiescent reproductive activity. Its long half-life allows the researcher to track the progress of metastatic cells through multiple phases of cell detachment, vascular navigation and extravascular engraftment, while the same pharmacodynamic property allows sustained delivery of GnRH pulses necessary to recapitulate ovulatory events in vivo or in an organotypic slice culture preparation. In addition, since both the disease and the reproductive endocrinology spheres are mediated by the same receptor, similar experiments can be carried out side by side, so that the same sample preparation can serve as its own positive control to gain clearer mechanistic insight without introducing the batch-to-batch variability that is inherent in multi-reagent assays.

Oncology Studies (Metastasis Suppression)

In the context of cancer, kisspeptin-54 has been found to play a greater role in homeostatic guardian than that of an executioner. The ligand binds to GPR54 on the leading edge of tumor-derived circulating clusters, initiating a signaling cascade that phosphorylates FAKs towards enhancing cell-substrate adhesion and inhibiting lamellipodia formation. In addition, the peptide suppresses MMP transcription by sequestering activators bound to the MMP promoter to inactive nuclear domains, thus increasing the density of ECM that tumor cells need to penetrate. These cytostatic signals are reliant on transient changes in the cytoplasm and not dependent on cytotoxic genomic mutations; thus, researchers can reversibly turn on/off tumor cell invasion and witness the transcriptional changes that take place after ligand removal. Metastasis assays have used this reversibility to determine the time frame in which disseminated cells are still receptive to repositioning. In orthotopic breast or melanoma tumors, infusion of kisspeptin-54 leads to reduced pulmonary metastases without affecting the size of the primary tumor, indicating a point of intervention that is downstream of oncogenesis but before the formation of macro metastases. The same approach has been applied in the context of dormancy, in which residual micro metastatic cells are forced into a dormant state and yet maintain proliferative ability after peptide removal, creating a pre-clinical model in which to test secondary inhibitors of awakening. As the ligand is endogenously amidated and without exogenous sequences, immune reactivity is avoided even after long-term administration, and thus long-term intravital imaging studies that follow single-cell dynamics over weeks are possible without inflammation-induced interference. Overall, these properties make kisspeptin-54 a useful tool to parse the timeline of metastasis, each step of which can be inhibited without destroying the cell population for further mechanistic interrogation.

Role in Reproductive Health Studies

The primary use of kisspeptin-54 in reproductive medicine and research is to provide an external physiological pacemaker, which can restore the normal pattern of GnRH secretion where the internal factors fail. In women with functional hypothalamic amenorrhoea, subcutaneous administration of a single dose re-induces a recognizable pattern of LH surge whose pattern is similar to that in spontaneously cycling women, thus demonstrating that the pulse generator at the hypothalamus is intact, but temporarily suppressed by metabolic and/or psychogenic inhibitions. The long circulating half-life of kisspeptin-54 compared to smaller fragments make it possible for the researcher to continuously provide an oscillatory signal throughout an entire follicular phase, without the need for surgically implantable pumps, a logistical consideration when using large animal models and human volunteers where repeated venepuncture is limited. Similarly in older males, administration of kisspeptin-54 restores LH pulsatility to the normal circadian rhythm and re-establishes testicular steroidogenesis without inducing the refractoriness that comes with injection of external gonadotropin cocktails. Furthermore, the ligand does not override the normal steroid feedback mechanism, it only enhances the normal negative and positive feedback, which is essential to retain the necessary dynamic range for hypothesis testing. This has been used to establish the molecular basis for polycystic ovary syndrome where an exaggerated LH plateau in response to kisspeptin-54 administration has demonstrated the hypothesis that GnRH pulse generator is intrinsically faster in affected patients. In both males and females, administration of the peptide can act as a non-surgical stress test to assess ovarian or testicular reserve, and determine if behavior, nutritional or hormonal intervention is required. As receptor occupancy will be time limited as the ligand is degraded and the receptors are recycled, the subsequent experimental cycles can be assessed from the same cohort providing a longitudinal perspective of reproductive function which would not be possible with irreversible interventions.

Cardio-Endocrine Axis as an Emerging investigative Frontier

Lineage tracing has also recently indicated GPR54 to be expressed at the mRNA level in ventricular cardiomyocytes and on the endothelial cells of coronary microvasculature suggesting kisspeptin-54 as a possible messenger linking cardiac metabolism and reproductive function. The infusion of the peptide into isolated hearts ex vivo has been shown to decrease diastolic stiffness without interfering with maximum systolic tension; this was not seen in GPR54 knockout samples, but was restored with the re-expression of the receptor using adenoviral delivery. The data thus far has suggested that the ligand acts to engage a Gq-linked phospholipase C, which then phosphorylates a sarcoplasmic reticulum calcium handling phosphoprotein, ultimately leading to a more rapid calcium re-uptake and a shorter twitch duration. These cardiac functional effects have been translated into in vivo testing, where chronic administration of kisspeptin-54 was paired with chronic reproductive hormone level maintenance; the initial histological studies show a decrease in interstitial fibrosis and a more 'normal' capillary density, which suggest a possible role of the peptide in protecting the heart from the adverse changes seen in prolonged hypo-oestrogenaemia. This same pathway has also been investigated in oncology, as cardiac output is the major determinant of the shear stress that tumour emboli are exposed to during circulation. By affecting both the vasculature and the length of the cardiac cycle, kisspeptin-54 is seen to have an indirect effect on the ability of disseminated cells to adhere to the endothelium, tying together the seemingly unrelated fields of metastasis suppression and cardio-protection.

Product Specifications

Kisspeptin-54 is provided as a sterile, pyrogen-free lyophilizate, the physical appearance of which is described as a transparent, tan, brittle solid that breaks with a smooth edge when force is applied horizontally (which is indicative of low residual moisture content and quick dissolution). The certificate of quality for each batch eschews specific values and rather indicates that a single major symmetrical peak is seen when shallow-gradient reversed-phase chromatography is performed, that no hydrophilic deletion species are seen leading up to the main peak, and that no hydrophobic aggregates are seen trailing down from the baseline after long equilibration. Mass verification is defined as agreement between theoretical and observed protonated mass envelopes, the range being wide enough to include isotopic variants yet narrow enough to exclude oxidized and truncated species.

Analytical Testing Results

Its identity is confirmed by independent chromatographic behavior, not by some arbitrary purity number that can be misleadingly precise. RP chromatography under ion-pair conditions should yield a single symmetrical peak with a tail free of early-eluting hydrophilic truncation mutants and a shoulder free of late-eluting oxidized species. Capillary zone electrophoresis at a slightly basic pH should show a single spot, indicating that all molecules are of uniform charge. Mass spectrometry, both reducing and non-reducing, should produce a single monoisotopic envelope corresponding to the expected protonated molecule. MS/MS should yield a fragmentation spectrum containing the y- and b-ions expected for the 54 amino acid sequence and no other product ions that would indicate a chemical modification. Its endotoxin level is determined by a limulus amoebocyte lysate assay, the result of which should be less than some unmentioned value (EU/mg) that is nevertheless universally recognized as non-pyrogenic for subcutaneous administration to even the most endotoxin-sensitive mouse strain. Its sterility is determined by inoculating a reconstituted sample into both broth cultures with and without oxygen and incubating at both room and elevated temperatures for an extended period of time. The presence of any cloudiness in either of these cultures would be grounds for rejecting the sample. This list of characteristics is a living document, one that can be appended with each lot but that is never reduced to a fixed set of numbers.

Packaging & Handling Recommendations

The lyophilized cake is packed into an amber, Type-I borosilicate vial whose opening is over-sealed with a halobutyl stopper that has been laminated on the underside with a fluoropolymer film, a moisture barrier with minimal vapor transmission that is also unreactive during extended frozen storage. The headspace is back-flushed with dry nitrogen before crimping, displacing the residual oxygen that might otherwise promote methionyl oxidation during extended storage. The vial is sealed inside a secondary foil pouch with a colorimetric desiccant tablet that will change color if the internal dew-point should ever exceed a pre-set level, providing a built-in visual early-warning system without the need for more intrusive sampling.

Lyophilization Matrix & Reconstitution Rheology

In addition to chemical considerations, the physical form of the kisspeptin-54 lyophilized powder affects the reproducibility with which it can be used to prepare solutions. Kisspeptin-54's eutectic behavior is more amenable to glass formation, which is shear-stable but hygroscopic. If the collapse temperature during lyophilization is exceeded even for a short time (leading to a viscoelastic flow of the material), the cake is susceptible to trapping residual water and potential phase separation within the vial, which appears later as a sticky pellet at the bottom of the vial upon reconstitution. Reconstitution behavior is thus not only for convenience but an implicit specification: a good cake readily falls apart within 10 s upon gentle mixing in a vortex, leaving a meniscus that rises up the glass in a sheet, instead of forming droplets that might indicate surface hydrophobicity. Choice of solvent affects wetting kinetics; a buffered isotonic saline solution with a small amount of volatile cosolvent will reduce the surface tension without changing osmolality, allowing immediate solubility without the foaming that may result from over-agitation. The solution should have Newtonian flow at shear rates used for syringe injection; if the solution exhibits nonlinear thickening, it may be an early indication of self-association into higher-order oligomeric β-sheet structures that could non-specifically sequester active monomeric species. To avoid such aggregation, the pre-cooled solvent should be added to the wall of the vial rather than directly onto the cake, to avoid high local concentrations that may nucleate fibrillation. Visual inspection under cross-polarized light provides a qualitative check as well: birefringent flashes would indicate early β-sheet structures long before turbidity becomes visible, allowing investigators to discard such aliquots before use in live tissue.

Get Kisspeptin-54 & Custom Peptide Synthesis Services

Our Kisspeptin-54 peptide is manufactured under stringent quality control to deliver high purity, validated by HPLC and MS analysis. As a longer active form of Kisspeptin, it is widely used in oncology studies focusing on metastasis suppression and in reproductive biology research investigating hormone regulation. For labs with specific project requirements, we also provide custom peptide synthesis services. Whether you need Kisspeptin-54 in bulk quantities, modified formats, or tailored peptide sequences, our expert team can deliver reliable solutions designed to fit your research protocols. Empower your cancer and reproductive research with premium Kisspeptin-54 peptides trusted by scientists worldwide. Reach out today to request a quote, bulk order details, or discuss custom synthesis options. We ensure high purity, secure global delivery, and dedicated technical support to meet your laboratory's needs.

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Frequently Asked Questions (FAQs)

1. Is Kisspeptin-54 intended for therapeutic use?

No. Our Kisspeptin-54 is strictly for laboratory research only and is not approved for human or veterinary applications.

2. What makes Kisspeptin-54 different from Kisspeptin-10?

Kisspeptin-54 is a longer peptide chain that may have distinct biological properties, making it especially relevant for oncology and reproductive system studies.

3. Do you offer Kisspeptin-54 in bulk supply?

Yes. We provide bulk ordering options for universities, pharmaceutical companies, and biotech labs conducting long-term studies.

4. Can I request custom modifications to Kisspeptin-54?

Absolutely. Our custom peptide synthesis service can adjust peptide length, labeling, or sequence modifications to suit your specific research requirements.