Computational cyclic peptide design against prion-induced toxicity

Prion diseases are neurodegenerative disorders associated with the conversion of the cellular prion protein (PrP^C) into a pathologic conformer (PrP^Sc).

A proposed therapeutic approach to prevent the toxic transformation is to develop monoclonal antibodies that bind to PrP^C and stabilize its structure. Over the past years, peptide-based therapeutics are taking over the global market due to their high bioavailability, good efficiency, and specificity. In particular, cyclic peptides have a long in vivo stability, while maintaining a robust antibody-like binding affinity, reduced accumulation propensities, cross the brain-blood-barrier, and work on their targets very selectively [1].

Here, we introduce and computationally validate a novel approach toward the de novo design of cyclic peptides against prion-induced toxicity by combining rational design with molecular dynamics simulations. First, we rationally design cyclic peptides starting from the crystal structures of PrP^C in complex with monoclonal antibodies. Next, we employ molecular dynamics simulations to probe the structural stabilities of the individual peptides and to determine their binding affinities to the cellular prion protein. The results compare favorably to experimental findings.

This work sheds light on the physical and structural mechanisms of PrP^C-peptide interactions and offers the molecular basis for the development of new therapeutics against neurodegenerative diseases.

[1] D. de Raffele, I.M. Ilie, submitted