Plant-derived Cyclotides in Immunomodulation and their Therapeutic Potential

The incidences of immune-related disorders have drastically increased in recent years across the world population. Treatment and management of these diseases, especially autoimmune disorders, are complex and challenging. Available synthetic drugs are not completely effective and also pose serious side effects for the patients. Cyclotides are a class of plant-derived cyclic peptides (28-37 amino acids) with three conserved disulfide linkages establishing a cyclic cystine knot (CCK) motif that makes them very stable biomolecules. Their inherent stability, bioavailability and membrane-penetrating capabilities render them attractive potential pharmacological agents. Studies have demonstrated that cyclotides can either enhance or suppress immune responses, making them versatile candidates for treating various immune-related disorders. Of more than 1000 cyclotides discovered to date, only up to 15 native cyclotides (e.g. kalata B1, pase and caripe cyclotides) have been screened to demonstrate their immunomodulatory activity. Of special significance is the chemically synthesised lysine mutant of kalata B1 viz. [T20K], where preclinical studies have shown promise in the treatment of the autoimmune disorder, multiple sclerosis. In vivo studies in mice models have demonstrated that daily administration of 1mg/day of [T20K] led to a significant decrease in the level of cytokine secretion, lesser demyelination (<1%) and very low inflammatory index (<0.5), in the immunized mice. Moreover, when compared with other immunosuppressive drugs (azathioprine, prednisolone, and cyclosporine A) there was a notable drop in mortality and morbidity in mice administered with [T20K]. The cyclotides, kalata B1 and MCoTI-I have also been used as scaffolds to graft bioactive peptides with immunomodulatory activity. Subsequent in vitro and in vivo studies of these grafted cyclotides have demonstrated their therapeutic ability. Keeping in view the therapeutic potential of cyclotides as immunomodulatory peptides, the present review discusses its current research scenario and implications for the future in tackling immune-related disorders.