Antiprion activity of DB772 and related monothiophene- and furan-based analogs in a persistently infected ovine microglia culture system

Kelcey D. Dinkel, James B. Stanton, David W. Boykin, Chad E. Stephens, Sally A. Madsen-Bouterse, David A. Schneider

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the misfolding of the native cellular prion protein (PrPC) into the accumulating, disease-associated isoform (PrPSc). Despite extensive research into the inhibition of prion accumulation, no effective treatment exists. Previously, we demonstrated the inhibitory activity of DB772, a monocationic phenyl-furan-benzimidazole, against PrPSc accumulation in sheep microglial cells. In an effort to determine the effect of structural substitutions on the antiprion activity of DB772, we employed an in vitro strategy to survey a library of structurally related, monothiophene- and furan-based compounds for improved inhibitory activity. Eighty-nine compounds were screened at 1 μM for effects on cell viability and prion accumulation in a persistently infected ovine microglia culture system. Eleven compounds with activity equivalent to or higher than that of DB772 were identified as preliminary hit compounds. For the preliminary hits, cytotoxicities and antiprion activities were compared to calculate the tissue culture selectivity index. A structure-activity relationship (SAR) analysis was performed to determine molecular components contributing to antiprion activity. To investigate potential mechanisms of inhibition, effects on PrPC and PrPSc were examined. While inhibition of total PrPC was not observed, the results suggest that a potential target for inhibition at biologically relevant concentrations is through PrPC misfolding to PrPSc. Further, SAR analysis suggests that two structural elements were associated with micromolar antiprion activity. Taken together, the described data provide a foundation for deeper investigation into untested DB compounds and in the design of effective therapeutics.

Original languageEnglish (US)
Pages (from-to)5467-5482
Number of pages16
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Microglia
Sheep
Prions
Structure-Activity Relationship
Library Surveys
Prion Diseases
Neurodegenerative Diseases
Cell Survival
Protein Isoforms
Research
2-(2-benzimidazolyl)-5-(4-(2-imidazolino)phenyl)furan
furan
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Antiprion activity of DB772 and related monothiophene- and furan-based analogs in a persistently infected ovine microglia culture system. / Dinkel, Kelcey D.; Stanton, James B.; Boykin, David W.; Stephens, Chad E.; Madsen-Bouterse, Sally A.; Schneider, David A.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 9, 01.09.2016, p. 5467-5482.

Research output: Contribution to journalArticle

Dinkel, Kelcey D. ; Stanton, James B. ; Boykin, David W. ; Stephens, Chad E. ; Madsen-Bouterse, Sally A. ; Schneider, David A. / Antiprion activity of DB772 and related monothiophene- and furan-based analogs in a persistently infected ovine microglia culture system. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 9. pp. 5467-5482.
@article{e0e5decea98c4e5eaa8c99203bc855be,
title = "Antiprion activity of DB772 and related monothiophene- and furan-based analogs in a persistently infected ovine microglia culture system",
abstract = "The transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the misfolding of the native cellular prion protein (PrPC) into the accumulating, disease-associated isoform (PrPSc). Despite extensive research into the inhibition of prion accumulation, no effective treatment exists. Previously, we demonstrated the inhibitory activity of DB772, a monocationic phenyl-furan-benzimidazole, against PrPSc accumulation in sheep microglial cells. In an effort to determine the effect of structural substitutions on the antiprion activity of DB772, we employed an in vitro strategy to survey a library of structurally related, monothiophene- and furan-based compounds for improved inhibitory activity. Eighty-nine compounds were screened at 1 μM for effects on cell viability and prion accumulation in a persistently infected ovine microglia culture system. Eleven compounds with activity equivalent to or higher than that of DB772 were identified as preliminary hit compounds. For the preliminary hits, cytotoxicities and antiprion activities were compared to calculate the tissue culture selectivity index. A structure-activity relationship (SAR) analysis was performed to determine molecular components contributing to antiprion activity. To investigate potential mechanisms of inhibition, effects on PrPC and PrPSc were examined. While inhibition of total PrPC was not observed, the results suggest that a potential target for inhibition at biologically relevant concentrations is through PrPC misfolding to PrPSc. Further, SAR analysis suggests that two structural elements were associated with micromolar antiprion activity. Taken together, the described data provide a foundation for deeper investigation into untested DB compounds and in the design of effective therapeutics.",
author = "Dinkel, {Kelcey D.} and Stanton, {James B.} and Boykin, {David W.} and Stephens, {Chad E.} and Madsen-Bouterse, {Sally A.} and Schneider, {David A.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1128/AAC.00811-16",
language = "English (US)",
volume = "60",
pages = "5467--5482",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "9",

}

TY - JOUR

T1 - Antiprion activity of DB772 and related monothiophene- and furan-based analogs in a persistently infected ovine microglia culture system

AU - Dinkel, Kelcey D.

AU - Stanton, James B.

AU - Boykin, David W.

AU - Stephens, Chad E.

AU - Madsen-Bouterse, Sally A.

AU - Schneider, David A.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - The transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the misfolding of the native cellular prion protein (PrPC) into the accumulating, disease-associated isoform (PrPSc). Despite extensive research into the inhibition of prion accumulation, no effective treatment exists. Previously, we demonstrated the inhibitory activity of DB772, a monocationic phenyl-furan-benzimidazole, against PrPSc accumulation in sheep microglial cells. In an effort to determine the effect of structural substitutions on the antiprion activity of DB772, we employed an in vitro strategy to survey a library of structurally related, monothiophene- and furan-based compounds for improved inhibitory activity. Eighty-nine compounds were screened at 1 μM for effects on cell viability and prion accumulation in a persistently infected ovine microglia culture system. Eleven compounds with activity equivalent to or higher than that of DB772 were identified as preliminary hit compounds. For the preliminary hits, cytotoxicities and antiprion activities were compared to calculate the tissue culture selectivity index. A structure-activity relationship (SAR) analysis was performed to determine molecular components contributing to antiprion activity. To investigate potential mechanisms of inhibition, effects on PrPC and PrPSc were examined. While inhibition of total PrPC was not observed, the results suggest that a potential target for inhibition at biologically relevant concentrations is through PrPC misfolding to PrPSc. Further, SAR analysis suggests that two structural elements were associated with micromolar antiprion activity. Taken together, the described data provide a foundation for deeper investigation into untested DB compounds and in the design of effective therapeutics.

AB - The transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the misfolding of the native cellular prion protein (PrPC) into the accumulating, disease-associated isoform (PrPSc). Despite extensive research into the inhibition of prion accumulation, no effective treatment exists. Previously, we demonstrated the inhibitory activity of DB772, a monocationic phenyl-furan-benzimidazole, against PrPSc accumulation in sheep microglial cells. In an effort to determine the effect of structural substitutions on the antiprion activity of DB772, we employed an in vitro strategy to survey a library of structurally related, monothiophene- and furan-based compounds for improved inhibitory activity. Eighty-nine compounds were screened at 1 μM for effects on cell viability and prion accumulation in a persistently infected ovine microglia culture system. Eleven compounds with activity equivalent to or higher than that of DB772 were identified as preliminary hit compounds. For the preliminary hits, cytotoxicities and antiprion activities were compared to calculate the tissue culture selectivity index. A structure-activity relationship (SAR) analysis was performed to determine molecular components contributing to antiprion activity. To investigate potential mechanisms of inhibition, effects on PrPC and PrPSc were examined. While inhibition of total PrPC was not observed, the results suggest that a potential target for inhibition at biologically relevant concentrations is through PrPC misfolding to PrPSc. Further, SAR analysis suggests that two structural elements were associated with micromolar antiprion activity. Taken together, the described data provide a foundation for deeper investigation into untested DB compounds and in the design of effective therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=84983667056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983667056&partnerID=8YFLogxK

U2 - 10.1128/AAC.00811-16

DO - 10.1128/AAC.00811-16

M3 - Article

C2 - 27381401

AN - SCOPUS:84983667056

VL - 60

SP - 5467

EP - 5482

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

ER -