Kissorphin

Kissorphin comprises the N-terminally amidated 45-50 fragment of the Kisspeptin-54 peptide hormone (Milton 2012) and is a ligand for the NPFF receptors (Milton 2012; Gibula-Bruzda et al 2017). The Kissorphin and Kisspeptin-54 peptides are derivatives from the metastasis suppressor KiSS-1 gene. Both Kisspeptin-54 peptide and C-terminal derivatives act via GRP-54 and NPFF receptors, however Kissorphin only acts on the NPFF receptors. The major function of Kisspeptin is as an activator of the Hypothalamic-Pituitary-Gonadal axis, via GPR-54 receptors and stimulation of hypothalamic gonadotrophin-releasing hormone (GnRH) release. The Kisspeptin peptides are also effective suppressors of metastasis of some cancers and were originally termed metastin for this activity.

We have shown that peptides containing residues 45-50 of the Kisspeptin-54 peptide bind to amyloid-ß 25-35, prion protein 106-126 and amylin 1-37 peptides (
Milton et al 2012). This region of the Kisspeptin-54 peptide is part of a sequence with significant similarity to the catalase amyloid-ß binding domain and can displace catalase binding to amyloid peptides. The Kissorphin peptide is itself neuroprotective against amyloid-ß, prion protein and amylin peptides. The peptide also reduces Congo red binding aggregate formation and the neuroprotective action appears to be independent of GPR-54 and NPFF receptor activation (Milton et al 2012).

A UK patent for the use of kissorphin peptides in the treatment of Alzheimer's disease, Creutzfeldt jakob disease and diabetes mellitus (
Milton 2017) has been granted. Aptamers against kissorphin have been generated by the Neuroaptamer group and in silico interactions with other proteins examined by NeuroDelta Ltd.

Cell lines overexpressing the KiSS-1 gene are resistant to amyloid peptide toxicity (
Chilumuri & Milton 2013). The mechanism of resistance to amyloid-ß toxicity involves activation of a pathway that can be inhibited by the oxytocin antagonist atosiban and the cyclo-oxygenase inhibitor SC-560. Kisspeptin immunoreactivity co-localizes with amyloid-ß deposits in the Alzheimer's brain (Chilumuri et al 2013), where there are also deposits staining for catalase and the neuroprotective corticotropin releasing hormone.

Research on Kisspeptin as an Alzheimer's neuroprotective compound was presented at the Alzheimer's Research UK 2013 conference (
Chilumuri 2013). Other groups have confirmed the utility of kisspeptin (Jiang et al 2015) for prevention of amyloid-ß toxicity in vivo and the potential for therapeutic use in Alzheimer's disease.