The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells

Pagadala, Nataraj Sekhar; Bjorndahl, Trent C.; Joyce, Michael; Wishart, David S.; Syed, Khajamohiddin; Landi, Abdolamir

doi:10.1016/j.bmc.2017.09.024

Cited by 2 publications

(1 citation statement)

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“…A previous study examining anti-prion mechanism of a positively charged poly-(amino acid), poly-L-Lys, indicated that a negatively charged surface of the Helix 2-Helix 3 region of PrP C (residues 169-230) is the specific site for poly-L-Lys binding [8]. In fact, the Helix 2-Helix 3 region has been suggested as an initiation site for the structural conversion of PrP toward PrP Sc [23][24][25][26] and is a major target for many anti-prion compounds [14,[27][28][29][30]. Given that the major population of poly-L-His is positively charged in acidic environments, in which the pathogenic conversion is believed to occur [31,32], the same mechanism can be applied to the case of poly-L-His.…”

Section: Poly-l-his Directly Binds To Cellular Prion Proteinmentioning

confidence: 99%

Poly-L-histidine inhibits prion propagation in a prion-infected cell line

Honda

Yamaguchi

Elhelaly

et al. 2018

Prion

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Transmissible spongiform encephalopathies (TSEs) are a group of lethal neurodegenerative diseases involving the structural conversion of cellular prion protein (PrP) into the pathogenic isoform (PrP) for which no effective treatment is currently available. Previous studies have implicated that a polymeric molecule with a repeating unit, such as pentosane polysulfate and polyamidoamide dendrimers, exhibits a potent anti-prion activity, suggesting that poly-(amino acid)s could be a candidate molecule for inhibiting prion propagation. Here, by screening a series of poly-(amino acid)s in a prion-infected neuroblastoma cell line (GT), we identified poly-L-His as a novel anti-prion compound with an IC value of 1.8 µg/mL (0.18 µM). This potent anti-prion activity was specific to a high-molecular-weight poly-L-His and absent in monomeric histidine or low-molecular-weight poly-L-His. Solution NMR data indicated that poly-L-His directly binds to the loop region connecting Helix 2 and Helix 3 of PrP and sterically blocks the structural conversion toward PrP. Poly-L-His, however, did not inhibit prion propagation in a prion-infected mouse when administered intraperitoneally, suggesting that the penetration of blood-brain barrier and/or the chemical stability of this polypeptide must be addressed before its application in vivo. Taken together, this study revealed the potential use of poly-L-His as a novel treatment against TSEs. (203 words).

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