Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1863, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbamem.2020.183480
Keywords
Cell-penetrating peptide; Host-defense peptide; Cellular uptake; Peptide-lipid interaction; Drug delivery; Mode-of-action
Categories
Funding
- Australian Research Council (ARC) [FT150100398]
- ARC Australian Laureate Fellow [FL150100146]
- National Health Medical Research Council (NHMRC) [APP1084965]
- ARC [FT150100398]
- Australian Government
- Marie Sklodowska-Curie Research and Innovation Staff Exchange grant (RISE) [644167-H2020-MSCA-RISE-2014]
- ACRF
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Peptides are gaining traction as promising anticancer therapeutics, with Gomesin and its analogues showing potential for targeted disruption of cancer cell membranes and internalization. By incorporating D-amino acids, an improved non-toxic peptide analogue has been designed to maintain internalization ability while decreasing toxicity, expanding the possibilities for peptide-based drug delivery.
Anticancer chemo- and targeted therapies are limited in some cases due to strong side effects and/or drug resistance. Peptides have received renascent interest as anticancer therapeutics and are currently being considered as alternatives and/or as complementary to biologics and small-molecule drugs. Gomesin, a disulfide-rich host defense peptide expressed in the Brazilian spider Acanthoscurria gomesiana selectively targets and disrupts cancer cell membranes. In the current study, we employed a range of biophysical methodologies with model membranes and bioassays to investigate the use of a cyclic analogue of gomesin as a drug scaffold to internalize cancer cells. We found that cyclic gomesin can internalize cancer cells via endocytosis and direct membrane permeation. In addition, we designed an improved non-disruptive and non-toxic cyclic gomesin analogue by incorporating D-amino acids within the scaffold. This improved analogue retained the ability to enter cancer cells and can be used as a scaffold to deliver drugs. Efforts to investigate the internalization mechanism used by host defense peptides, and to improve their stability, potency, selectivity and ability to permeate cancer cell membranes will increase the opportunities to repurpose peptides as templates for designing alternative anticancer therapeutic leads.
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