Rational design and selection of next-generation cyclotide drugs using the knotted cyclic peptide scaffold MCoTI-II

Naturally occurring cyclic peptides have emerged as intriguing and relevant scaffolds for next-generation drug design. Especially peptides from the highly constrained cyclotide family provide an exceptional opportunity for drug discovery, given their characteristic head-to-tail cyclic structure and cystine-knotted core that confer favourable pharmaceutical properties. As a result, Momordica cochinchinensis trypsin inhibitor II (MCoTI-II), a cyclic knottin peptide natural product of gấc fruit, has been the centre of various molecular engineering efforts. To target medicinally relevant proteins, surface-exposed loops of the mini-protein have been purposefully modified or entirely selected de novo to install bioactive epitopes. This mini-review aims to provide a succinct overview of recent studies on MCoTI-II-derived structures in inhibitor and diagnostic design. A variety of methods facilitate access to MCoTI-II-based next-generation therapeutics and diagnostics, including rational design, loop grafting and genetically encoded discovery platforms.