Novel anti-prion compounds screening in prion-infected cell culture model combined with surface plasmon resonance analysis

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Abstract
Prions are misfolded proteins (PrPSc) capable of inducing the same conformational change in normal prion proteins (PrPC). These aberrant proteins are responsible for neurodegenerative diseases in animals and humans, for which no effective treatments currently exist. At present, preventive diagnostic screening remains the only viable intervention. Our research has focused on screening compound libraries to identify small molecules capable of blocking PrPSc formation using a prion-infected cell culture model. Over the past several years, we have identified and assembled a set of compounds with diverse chemotypes that inhibit prion activity in human prion-infected cells while maintaining acceptable toxicity profiles, without affecting cell proliferation and morphological change. In this study, we combined the prion-infected cell culture model with surface plasmon resonance (SPR) analysis to screen for novel anti-prion compounds. A previously identified compound set with diverse chemical scaffolds was used as a training set for two-dimensional substructure searches, leading to the discovery of new chemical scaffolds. Representative compounds were selected and evaluated for anti-prion activity, resulting in the identification of two distinct subsets: one that simultaneously suppressed both PrPSc and PrPC levels, and another that selectively inhibited PrPSc without affecting PrPC expression. Correlation analysis between binding affinity parameters (Kd) obtained from SPR and in vitro anti-prion activity demonstrated that concentration-dependent interaction profiles could predict the inhibitory potential of each compound. This integrated approach provides a practical screening strategy to accelerate the elucidation of mechanisms of action and facilitate the discovery of anti-prion agents. All compounds identified in this study are novel and possess favorable chemical features suitable for further structural optimization and rational drug design.
Funding Information
  • Japan Society for the Promotion of Science (22K19497)
  • Japan Society for the Promotion of Science (22H02989)

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