Development of therapeutic strategies

Rational Drug Design

Rational Design of PrP Conversion Inhibitors: a new structure-based approach toward anti-prion chemotherapeutics

2007: 2 years / Grant: 95 000 euros

Project: Even if the structure of PrPC is well known, the conversion process and early events associated to the process, are far to be understood. In pathologies, due to protein misfolidng, most rational drug-design strategies target the misfolded state of proteins involved. By admitting that amyloid assemblies once formed are by far the most stable structure that could exist, the aim of the project “PMARDD” was to identify precisely PrP regions involved in prion replication and develop by rational design selective anti-prion molecules that could prevent the conformational conversion by stabilizing the native PrPC state instead of targeting PrPSc assemblies.

Main results and related published data: The region of PrP, comprising the hairpin formed by the helices H2 and H3 was shown to be an independent and stable folded unit that could retain its secondary and tertiary structure independently from the rest of the protein. Being highly amyloidogenic, this region could be considered as a seed for the PrP misfolding through a “bananapeeling” mechanism. More recently this study was completed and a displacement of the H1 helix promoted the uncovering of the H2H3 domain, and thusthe formation of persistent -sheets between H2 and H3 residues.From thisresult, a putative model of fibrillization could be constructed and used to target the H2/H3 region to design new anti-prion drugs.