Speaker:
Title:
Engineering a Knottin Inhibitor of Tumor Necrosis Factor
Abstract:
Knottins are small, disulfide-rich peptides that exhibit exceptional stability to extremes of pH, heat, and protease concentration. Their solvent-exposed loops are amenable to mutation, raising the possibility of engineering them into orally available mini binders. Such binders could be used as protein-protein interaction inhibitors for gastrointestinal indications – similar to how the antibody drug Humira can block autoimmune activity by blocking tumor necrosis factor (TNF) from binding its receptor on immune cells. We aimed to create a yeast surface display platform to accelerate knottin binder development to any target protein, focusing first on TNF. We have isolated a knottin TNF-binder, affinity-matured it, and characterized its protease-resistance, activity, and unique conformational characteristics.