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Disulfide-rich Cyclic Peptides and Their Therapeutic Potentials
A group of different disulfide-rich cyclic peptides has become a new focus of study in drug discovery and development field in recent years. These cyclic peptides provide an ideal scaffold for potential therapeutics.
Cyclotides are fascinating naturally occurring micro-proteins (≈30 residues long) present in several plant families (See Figure1, MCoTI-II). Cyclotides share a unique motif: cystine knot topology (CCK). CCK gives the cyclotides exceptional rigidity, resistance to thermal and chemical denaturation, and enzymatic stability against degradation. Its rigid structure makes these peptides potentially orally bioavailable. Some cyclotides have been shown the ability to cross the cell membranes. Moreover, studies have also shown that engineered cyclotides showed different bioactivity based on the sequences incorporated into the peptide-based scaffold. Therefore these peptides provide us with ideal tools for drug development.
Defensins are cysteine-rich antimicrobial peptides that are important in the innate immune defense of mammals. They are known for their antimicrobial activities, as well as wound healing, immune modulation, neutralization of endotoxin, anti-HIV activities and anti-cancer activities. θ-defensins are backbone cyclized peptides (See Figure1, RTD-1). They present a high resistance to proteolytic degradation in serum and plasma due to its network of disulfide bonds and cyclic topology. They also have been shown to possess anti-inflammatory properties in animal models, thus makes θ-defensin an ideal molecular framework for the development of novel peptide-based therapeutics.
Sunflower trypsin inhibitor 1 (See Figure1, SFTI-1) is a 14 amino acid backbone-cyclized peptide containing a single disulfide bond that is naturally found in the seeds of the sunflower. Due to its relatively rigid backbone conformation, SFTI-1 possesses an exceptional stability to thermal or enzymatic degradation as a consequence of the backbone cyclization combined with the presence of an internal disulfide bond and an extensive hydrogen-bonding network. In addition, SFTI-1 has been shown to be non-toxic to mammalian cells and great cell membrane permeability. Moreover, the SFTI-1 molecular framework can be also readily re-engineered by incorporating foreign biological active peptide sequences into one the loops to produce SFTI-analogs with novel biological activities. These characteristics make SFTI-1 an ideal molecular scaffold for drug development.
The disintegrins are a family of disulfide-rich mini-proteins isolated from snake venoms. Disintegrins block platelet aggregation, which prevents fibrinogen binding. Several cyclic peptides such as eptifibatide have been discovered from the snake venom have shown great potentials as therapeutics.
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 Li Y, Gould A, Aboye T, Camarero JA, Full sequence amino acid scanning of θ-defensin RTD-1 yields a potent anthrax lethal factor protease inhibitor J Med Chem. 2017 Mar 9; 60(5): 1916–1927.
 Li Y1, Aboye T, Breindel, Shekhtman, Camarero JA. Efficient recombinant expression of SFTI-1 in bacterial cells using intein-mediated protein trans-splicing. Biopolymers. 2016 Nov;106(6):818-824. doi: 10.1002/bip.22875.
 Pennington MW, Czerwinski, Norton. Peptide therapeutics from venom: Current status and potential. Bioorg Med Chem. 2018 Jun 1;26(10):2738-2758.