Herein, we report novel neuroprotective activity of the neurohypophyseal hormone analogue desmopressin (DDAVP) against toxic conformations of human prion protein. Systematic analysis using biophysical techniques in conjunction with surface plasmon resonance, high-end microscopy, conformational antibodies, and cell-based assays demonstrated DDAVP's specific binding and potent antiaggregating effects on prion protein (rPrPres). In addition to subjugating conformational conversion of rPrPres into oligomeric forms, DDAVP also exhibits potent fibril modulatory effects. It eventually ameliorated neuronal toxicity of rPrPres oligomers by significantly reducing their cellular internalization. Molecular dynamics simulations showed that DDAVP prevents β-sheet transitions in the N-terminal amyloidogenic region of prion and induces antagonistic mobilities in its α2-α3 and β2-α2 loop regions. Collectively, our data proposes DDAVP as a new structural motif for rational drug discovery against prion diseases.
Keywords: Prion; amyloid; desmopressin; microscopy; oligomer; toxicity.