Natural and grafted cyclotides in cancer therapy: An insight

• Published in: Journal of peptide science 2020-04, Vol.26 (4-5), p.e3246-n/a
• Main Authors: Mehta, Lovekesh, Dhankhar, Rakhi, Gulati, Pooja, Kapoor, Rajeev Kumar, Mohanty, Aparajita, Kumar, Sanjay
• Format: Article
• Language: English
• Subjects: Amino acid substitution; Amino acids; Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - therapeutic use; bioactive peptides; Bioavailability; Biocompatibility; Biological activity; Biological Products - chemistry; Biological Products - therapeutic use; Cancer; Cancer therapies; Cell membranes; Cell permeability; cyclotides; Cyclotides - chemistry; Cyclotides - therapeutic use; Cytotoxicity; Drug delivery; Drug delivery systems; epitope; Epitopes; Fabaceae; Grafting; Humans; Immunological tolerance; knotted topology; Landscape studies; Membrane permeability; Neoplasms - drug therapy; Peptides; Pharmacokinetics; Proteolysis; Rubiaceae; Therapy; Topology; Toxicity; Tumor cell lines; Violaceae
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/psc.3246

Cyclotides is a rapidly growing class of plant‐derived cyclic peptides exhibiting several bioactivities with potential applications in the agricultural and pharmaceutical sectors. Both natural and grafted cyclotides have shown promise in cancer therapy. Approximately 70 natural cyclotides belonging to three plant families (Fabaceae, Rubiaceae, and Violaceae) have shown cytotoxicity against several cancer cell lines. Cyclotides exhibit considerable stability against thermal and enzymatic proteolysis, owing to their unique structure with knotted topology and head to tail cyclization. Further, their small size, high stability, oral bioavailability, and tolerance to amino acid substitution in structural loops make them an ideal platform for designing peptide‐based drugs for cancer. Thus, cyclotides provide ideal scaffolds for bioactive epitope grafting and facilitating drug delivery in cancer treatment. Many anticancer linear peptides have been grafted in cysteine knotted cyclic framework of cyclotide for enhancing their cell permeability across cellular membranes, thereby improving their delivery and pharmacokinetics. The present review comprehensively discusses the distribution, toxicity, and anticancer bioactivity of natural cyclotides. Further, it systematically elaborates on the role and action of epitopes' into grafted cyclotides in targeting cancer. The review also encompasses related patents landscape study and future challenges in peptide‐based cancer therapy. Anticancer linear peptides have been useful in cancer therapy. However, their use in cancer treatment is limited due to their susceptibility to protease degradation. The same anticancer peptides, when grafted as “peptide epitopes” into the framework of cyclotides (plant‐based cyclic peptides with cystine knot topology, conferring resistance to heat and enzymatic degradation), can resist protease degradation. Thus, cyclotides serve as an efficient scaffold for grafting “peptide epitope” and facilitate peptide‐based drug delivery in cancer treatment.