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Cysteine-rich circular Peptide Drug Discovery from Nature. Phytochemistry and Ethnopharmacology.

cysteine-rich peptides have been shown to be stable to chemical and heat treatment. Interestingly, cysteine-rich peptides have been reported to maintain their native state after several steps of purification and are more readily amenable to chemical synthesis due to their shorter peptide length (~20 to 40 residues). Even of great scientific interest is the discovery of naturally occurring cysteine-rich circular miniproteins known as cyclotides some three decades back. These peptides are of low molecular weight ranging from 2 000 to 4 000 daltons. Their circular nature and knotted arrangement of disulfide bonds makes cysteine–rich circular peptides ultrastable. The cysteine knot and circular backbone present in this class of circular peptides is known as Cyclic Cystine Knot (CCK) motif. Cyclotides have been reported to orally stable and active.Thus it may be hypothesized that cysteine rich low molecular weight peptides fulfill the basic drug delivery criteria (Stability and bioavailability). Unlike plant secondary compounds (such as alkaloids, glycosides, flavonoids, saponins, terpenes, etc) several cysteine rich mini-proteins (including cyclotides, defensins, PA1b) are not intermediary products of metabolism but specific gene directed molecules whose sequences are encoded by DNA.This makes these peptides important candidates for genetic engineering and “Pharming” efforts. Hundreds of thousands of peptides have been isolated from plants, animals and microorganisms whose occurrence may be constitutive or induced in the host plant, to defeat fungal invasion or to fight insect pests. According to literature, cyclotides possess varying bioactivities including antimicrobial, antithrombotic, antihypertensive, opioid, immunomodulatory, mineral binding, anti-oxidative, uterotonic, hemolytic, anti-HIV, neurotensin antagonism, cytotoxic, antifouling, anti-viral, insecticidal. Sadly, less than 1% of the World flora has been screened for cyclotide drug discovery.