The KNOTTIN database

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].
  • Main efforts along this way are outlined below.
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Cell internalization

Circular permutations

Computer simulations

Homology modeling



Protein engineering

Cell internalization

The knottin scaffold is considered as a useful stabilizing framework to deliver bioactive peptide drugs. For intracellular targets, it may be necessary for the knottin-based drug to enter cells.

Internalization of MCoTI-II

It has been shown that the cyclic knottin MCoTI-II is internalized into mammalian cells by macropynocytose. [Grenwood et al., 2007]. As a consequence MCoTI-II may have the potential to transport bioactivities to intracellular targets.

Internalization of PA1b

The toxin PA1b from pea is lethal for certain insects. It has been shown that PA1b is internalized into insect cells sf9 by binding to a high-affinity site. The mecanisms leading to cell death remain to be determined. Mammalian cells are insensitive to the toxin. [Rahioui et al., 2007].