RESUMO
Chronic wasting disease (CWD) agents are shed into biological samples, facilitating their horizontal transmission between cervid species. Once prions enter the environment, binding of PrPCWD by soil particles may maintain them near the soil surface, posing a challenge for decontamination. A 2 N sodium hydroxide (NaOH) or 2% sodium hypochlorite (NaClO) solution is traditionally recommended for prion decontamination of equipment and surfaces. Using protein misfolding cyclic amplification with beads and a bioassay with TgElk mice, we compared the effects of these disinfectants in CWD-contaminated soil for 1 or 16 h to those of controls of known infectious titres. Our results suggest that 2 N NaOH in a 1/5 farm soil volume provides a large decrease (>102-fold) in prion infectivity.
Assuntos
Cáusticos/toxicidade , Príons/antagonistas & inibidores , Hidróxido de Sódio/toxicidade , Solo/química , Doença de Emaciação Crônica/prevenção & controle , Animais , Descontaminação/métodos , Cervos/genética , Fazendas , Camundongos , Camundongos Transgênicos , Príons/química , Príons/genética , Doença de Emaciação Crônica/transmissãoRESUMO
Conformational conversion of the normal cellular isoform of the prion protein PrPC into an infectious isoform PrPSc causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrPC binding site, and effectively reduced PrPSc levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies.