Knottins provide useful scaffolds or leads for drug design


  • ‣ Knottins are exceptional in that they are very small proteins yet with particularly well-defined scaffolds and remarkably high stability.
  • ‣ Also remarkable is the fact that knottins with very similar 3D structures have virtually no sequence identity except for cysteines. This observation has led to the conclusion that the knottin scaffold is very sequence tolerant.
  • ‣ These remarkable features suggest that knottins can provide excellent lead molecules or elementary scaffold in drug design studies [Chiche et al., 2004; Craik et al., 2006; Werle et al., 2006; Moore et al., 2012], and in biotechnological applications [Cox et al., 2016; Moore et al., 2013; Glotzbach et al., 2013; Barba et al., 2012].
  • ‣ Main efforts along this way are outlined below.
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Cell internalization

Circular permutations

Computer simulations

Homology modeling

Libraries

Mutations

Protein engineering

Homology modeling

Homology modeling of two cyclotides

The three-dimensional structures of two cyclotides from Viola odorata were modeled by homology using the NMR structure of kalata B1 as template. The models displayed amphipathic structures with considerable surface hydrophobicity [Svangard et al., 2003].


Homology modeling of several squash inhibitors has been reported

Several squash inhibitors were modeled from the X-ray structure of MCTI-II either free or complexed to trypsin [Chakraborty et al., 2000]. Analysis of the structures indicate that sequence variations allow fine tune of the specific biological functions without destabilizing the structural scaffold.