Biological Activities of Natural and Engineered Cyclotides, a Novel Molecular Scaffold for Peptide-Based Therapeutics

Angie      E. Garcia; Julio      A. Camarero

Abstract

Cyclotides are a growing family of large plant-derived backbone-cyclized polypeptides (≉30 amino acids long) that share a disulfide-stabilized core characterized by an unusual knotted structure. Their unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Currently more than 100 sequences of different cyclotides have been characterized and the number is expected to increase dramatically in the coming years. Considering their stability, biological activities and ability to cross the cell membrane, cyclotides can be exploited to develop new peptide-based drugs with high potential for success. The cyclotide scaffold can be engineered or evolved using molecular evolution to inhibit protein-protein interactions implicated in cancer and other human diseases, or design new antimicrobials. The present review reports the biological diversity and therapeutic potential of natural and engineered cyclotides.

Keywords: Cyclic peptides, Cyclotides, Intein, Kalata B1, MCoTI-I/II, Protein splicing, Protein engineering, Daptomycin, Streptomyces roseo-sporus, Sunflower trypsin inhibitor 1, SFTI-1, Rubiaceae, Violaceae, Cucurbitaceae, anti-HIV, antimicrobial, insecticidal, uterotonic, antitumor, antihelminthic, cyclic cystine knot, CCK, Ecballium elaterium trypsin inhibitor II, Oldenlandia affinis, Psycho-tropia longipes, Bowman-Birk inhibitor SFTI-1, defensins, N-intein, C-intein, vascular en-dothelial growth factor A, VEGF-A, MCoTI-II, trypsin inhibitor, molluscum contagiosum, MCV, FLICE-inhibitory protein, FLIP, Mycobacterium xenopus