The inhibition of prions through blocking prion conversion by permanently charged branched polyamines of low cytotoxicity

Yong beom Lim, Charles E. Mays, Younghwan Kim, William B. Titlow, Chongsuk Ryou

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2025-2033
Number of pages9
JournalBiomaterials
Volume31
Issue number8
DOIs
Publication statusPublished - 2010 Mar 1

Fingerprint

Prions
Polyamines
Cytotoxicity
Polyethyleneimine
Toxicity
Dendrimers
Prion Diseases
Neuroblastoma
Surface charge
Charge density
Amines
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Lim, Yong beom ; Mays, Charles E. ; Kim, Younghwan ; Titlow, William B. ; Ryou, Chongsuk. / The inhibition of prions through blocking prion conversion by permanently charged branched polyamines of low cytotoxicity. In: Biomaterials. 2010 ; Vol. 31, No. 8. pp. 2025-2033.
@article{36aed91e51a54d338ac42857d179b869,
title = "The inhibition of prions through blocking prion conversion by permanently charged branched polyamines of low cytotoxicity",
abstract = "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.",
author = "Lim, {Yong beom} and Mays, {Charles E.} and Younghwan Kim and Titlow, {William B.} and Chongsuk Ryou",
year = "2010",
month = "3",
day = "1",
doi = "10.1016/j.biomaterials.2009.11.085",
language = "English",
volume = "31",
pages = "2025--2033",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
number = "8",

}

The inhibition of prions through blocking prion conversion by permanently charged branched polyamines of low cytotoxicity. / Lim, Yong beom; Mays, Charles E.; Kim, Younghwan; Titlow, William B.; Ryou, Chongsuk.

In: Biomaterials, Vol. 31, No. 8, 01.03.2010, p. 2025-2033.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The inhibition of prions through blocking prion conversion by permanently charged branched polyamines of low cytotoxicity

AU - Lim, Yong beom

AU - Mays, Charles E.

AU - Kim, Younghwan

AU - Titlow, William B.

AU - Ryou, Chongsuk

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=74449085875&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74449085875&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2009.11.085

DO - 10.1016/j.biomaterials.2009.11.085

M3 - Article

C2 - 20022103

AN - SCOPUS:74449085875

VL - 31

SP - 2025

EP - 2033

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 8

ER -