Author:

Keywords:

Structure-activity relationship, OSIP108, apoptosis, copper

Abstract:

Apoptosis is an essential process in development. However, excessive cell death is linked to several degenerative diseases, such as Parkinson’s and Alzheimer’s. We previously discovered the plant-derived decapeptide OSIP108, which increases tolerance of yeast and human cells to death-inducing agents, like copper and cisplatin. Moreover, treatment with OSIP108 also increases survival in eukaryotic cell models for Wilson’s disease, which is characterized by excessive hepatic copper accumulation, resulting in apoptosis of hepatocytes, but also neurodegeneration. Here, using a whole amino acid scan of OSIP108, we conducted structure-activity relationship studies on its potential to induce cisplatin tolerance (CT) in yeast. We found that positively-charged residues (R, H or K) on positions 2, 4-8 or 10, or a P on positions 4-7, improved OSIP108’s CT-promoting activity by 10% or more. Treatment with the variant OSIP108* showed the most pronounced increased tolerance of yeast and human cells to toxic concentrations of copper or cisplatin. Furthermore, OSIP108 and OSIP108* internalized into HeLa cells equally, in contrast to an inactive variant OSIP108[E10A], suggesting that differences in CT-promoting activity are only partly dependent on altered internalization. In conclusion, we demonstrated improved activity of OSIP108* compared to OSIP108, suggesting its potential as a lead peptide in development of a novel peptide-based therapy for degenerative diseases, such as Wilson’s disease.