A designer molecular chaperone against transmissible spongiform encephalopathy slows disease progression in mice and macaques

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that lack therapeutic solutions. Here, we show that the molecular chaperone ( N , N ′-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide)), designed via docking simulations, molecular dynamics simulations and quantum chemical calculations, slows down the progress of TSEs. In vitro, the designer molecular chaperone stabilizes the normal cellular prion protein, eradicates prions in infected cells, prevents the formation of drug-resistant strains and directly inhibits the interaction between prions and abnormal aggregates, as shown via real-time quaking-induced conversion and in vitro conversion NMR. Weekly intraperitoneal injection of the chaperone in prion-infected mice prolonged their survival, and weekly intravenous administration of the compound in macaques infected with bovine TSE slowed down the development of neurological and psychological symptoms and reduced the concentration of disease-associated biomarkers in the animals’ cerebrospinal fluid. The de novo rational design of chaperone compounds could lead to therapeutics that can bind to different prion protein strains to ameliorate the pathology of TSEs. A computationally designed molecular chaperone inhibits the interaction of normal prions with abnormal isoforms associated with transmissible spongiform encephalopathy, prolongs survival in infected mice and limits symptoms in infected macaques.