Abstract
Grafting a bioactive peptide onto a disulfide-rich scaffold is a promising approach to improve its structure and metabolic stability. The ginkgo plant-derived β-ginkgotide β-gB1 is a highly unusual molecule: Small, hyperdisulfide, and found only in selected ancient plants. It also contains a conserved 16-amino-acid core with three interlocking disulfides, as well as a six-amino-acid inter-cysteine loop 2 suitable for grafting peptide epitopes. However, very little is known about this recently-discovered family of molecules. Here, we report the biophysical and functional characterizations of the β-ginkgotide β-gB1 from G. biloba. A circular dichroism spectroscopy analysis at 90 °C and proteolytic treatments of β-gB1 supported that it is hyperstable. Data mining revealed that the β-gB1 loop 2 contains the canonical LC3 interacting region (LIR) motif crucial for selective autophagy. Cell-based assays and pull-down experiments showed that β-gB1 is an adaptogen, able to maintain cellular homeostasis through induced autophagosomes formation and to protect cells by targeting intracellular proteins from stress-mediated damage against hypoxia and the hypoxia-reoxygenation of induced cell death. This is the first report of an LIR-containing peptide natural product. Together, our results suggest that the plant-derived β-ginkgotide is cytoprotective, capable of targeting intracellular proteins, and holds promise as a hyperdisulfide scaffold for engineering peptidyl therapeutics with enhanced structural and metabolic stability.
Highlights
Bioactive peptides, peptide hormones that are small in size and flexible in structure, are useful drug leads
We found that β-ginkgotide is highly resistant to heat and proteolytic degradation, suggesting it is a suitable scaffold for grafting peptide epitopes
This report describes, for the first time, that the hyperdisulfide peptide, the β-ginkgotide β-gB1 derived from the ginkgo plant, is cytoprotective against hypoxia stress
Summary
Peptide hormones that are small in size and flexible in structure, are useful drug leads. Such disulfide-rich peptides would have a high structural and metabolic stability because of multiple cross-braces by disulfides Such peptides would contain, on average, a cysteine in every four or five amino acids in their sequence or about 18–25% cysteine per molecule. Because of their structure and metabolic stability, disulfide-rich peptides have been used successfully as scaffolds to graft bioactive peptides [22,23,24]. We discovered hyperdisulfide peptides from medicinal plants These peptides contain a cysteine in every three amino acids or about 30% cysteine per molecule. We showed that the β-ginkgotide β-gB1 displays cytoprotective and adaptogenic properties to modulate cellular homeostasis and survivability against hypoxia-induced stress
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