Pharmacological chaperone for the structured domain of human prion protein

A.J Nicoll, C.R Trevitt, M Howard Tattum, E Risse, E Quarterman, A Avila Ibarra, C Wright, G.S Jackson, R.B Sessions, M Farrow, J.P Waltho, A.R Clarke, J Collinge

Research output: Contribution to journalArticle (Academic Journal)peer-review

66 Citations (Scopus)


In prion diseases, the misfolded protein aggregates are derived from cellular prion protein (PrPC). Numerous ligands have been reported to bind to human PrPC (huPrP), but none to the structured region with the affinity required for a pharmacological chaperone. Using equilibrium dialysis, we screened molecules previously suggested to interact with PrP to discriminate between those which did not interact with PrP, behaved as nonspecific polyionic aggregates or formed a genuine interaction. Those that bind could potentially act as pharmacological chaperones. Here we report that a cationic tetrapyrrole [Fe(III)-TMPyP], which displays potent antiprion activity, binds to the structured region of huPrP. Using a battery of biophysical techniques, we demonstrate that Fe(III)-TMPyP forms a 1∶1 complex via the structured C terminus of huPrP with a Kd of 4.5 ± 2 μM, which is in the range of its IC50 for curing prion-infected cells of 1.6 ± 0.4 μM and the concentration required to inhibit protein-misfolding cyclic amplification. Therefore, this molecule tests the hypothesis that stabilization of huPrPC, as a principle, could be used in the treatment of human prion disease. The identification of a binding site with a defined 3D structure opens up the possibility of designing small molecules that stabilize huPrP and prevent its conversion into the disease-associated form.
Translated title of the contributionPharmacological chaperone for the structured domain of human prion protein
Original languageEnglish
Pages (from-to)17610 - 17615
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
Publication statusPublished - Oct 2010


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