期刊
BIOMATERIALS
卷 31, 期 8, 页码 2025-2033出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2009.11.085
关键词
Prion; Branched polyamines; Quaternization; Cytotoxicity; Prion protein conversion; Therapy
资金
- Sanders-Brown Center on Aging
- College of Medicine, University of Kentucky
- National Research Foundation of Korea [2009-0066736, 2009-0076516, 2009-0082617]
- Translational Research Center for Protein Function Control [20090092971]
- Priority Research Center [2009-0093823]
- Yonsei University
- National Research Foundation of Korea [2009-0076516, 2009-0066736, 2009-0082617] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Branched polyamines are effective in inhibiting prions in a cationic surface charge density dependent manner. However, toxicity associated with branched polyamines, in general, often hampers the successful application of the compounds to treat prion diseases. Here, we report that constitutively maintained cationic properties in branched polyamines reduced the intrinsic toxicity of the compounds while retaining the anti-prion activities. In prion-infected neuroblastoma cells, quaternization of amines in polyethyleneimine (PEI) and polyamidoamine (PAMAM) dendrimers markedly increased the nontoxic concentration ranges of the compounds and still supported, albeit reduced, an appreciable level of anti-prion activity in clearing prions from the infected cells. Furthermore, quaternized PEI was able to degrade prions at acidic pH conditions and inhibit the in vitro prion propagation facilitated by conversion of the normal prion protein isoform to its misfolded counterpart, although such activities were decreased by quaternization. Quaternized PAMAM was least effective in degrading prions but efficiently inhibited prion conversion with the same efficacy as unmodified PAMAM. Our results suggest that quaternization represents an effective strategy for developing nontoxic branched polyamines with potent anti-prion activity. This study highlights the importance of polyamine structural control for developing polyamine-based anti-prion agents and understanding of an action mechanism of quaternized branched polyamines. (C) 2009 Elsevier Ltd. All rights reserved.
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