Bulletin of the American Physical Society
APS March Meeting 2024
Monday–Friday, March 4–8, 2024; Minneapolis & Virtual
Session N00: Poster Session II (11:30am-2:30pm CST)
11:30 AM,
Wednesday, March 6, 2024
Room: Hall BC
Sponsoring
Unit:
APS/SPS
Abstract: N00.00323 : Computational cyclic peptide design against prion-induced toxicity*
Presenter:
Ioana M Ilie
(University of Amsterdam)
Author:
Ioana M Ilie
(University of Amsterdam)
A proposed therapeutic approach to prevent the toxic transformation is to develop monoclonal antibodies that bind to PrPC 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 PrPC 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 PrPC-peptide interactions and offers the molecular basis for the development of new therapeutics against neurodegenerative diseases.
[1] D. de Raffele, I.M. Ilie, submitted
*Synapsis Foundation Switzerland
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