Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties

Mariana Figuera-Losada, Marigo Stathis, Joelle M. Dorskind, Ajit G. Thomas, Veera Venkata Ratnam Bandaru, Seung Wan Yoo, Nicholas J. Westwood, Graeme W. Rogers, Justin C. McArthur, Norman J. Haughey, Barbara S. Slusher, Camilo Rojas

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β- induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.

Original languageEnglish (US)
Article number0124481
JournalPLoS One
Volume10
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

Fingerprint

Sphingomyelin Phosphodiesterase
neuroprotective effect
ceramides
Ceramides
sphingomyelins
neurons
cell death
assays
Assays
Sphingomyelins
Cell death
tumor necrosis factors
Human immunodeficiency virus
interleukin-1
sclerosis
Alzheimer disease
in vivo studies
Human immunodeficiency virus 1
Neurons
HIV-1

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Figuera-Losada, M., Stathis, M., Dorskind, J. M., Thomas, A. G., Ratnam Bandaru, V. V., Yoo, S. W., ... Rojas, C. (2015). Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. PLoS One, 10(5), [0124481]. https://doi.org/10.1371/journal.pone.0124481

Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. / Figuera-Losada, Mariana; Stathis, Marigo; Dorskind, Joelle M.; Thomas, Ajit G.; Ratnam Bandaru, Veera Venkata; Yoo, Seung Wan; Westwood, Nicholas J.; Rogers, Graeme W.; McArthur, Justin C.; Haughey, Norman J.; Slusher, Barbara S.; Rojas, Camilo.

In: PLoS One, Vol. 10, No. 5, 0124481, 01.05.2015.

Research output: Contribution to journalArticle

Figuera-Losada, M, Stathis, M, Dorskind, JM, Thomas, AG, Ratnam Bandaru, VV, Yoo, SW, Westwood, NJ, Rogers, GW, McArthur, JC, Haughey, NJ, Slusher, BS & Rojas, C 2015, 'Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties', PLoS One, vol. 10, no. 5, 0124481. https://doi.org/10.1371/journal.pone.0124481
Figuera-Losada M, Stathis M, Dorskind JM, Thomas AG, Ratnam Bandaru VV, Yoo SW et al. Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. PLoS One. 2015 May 1;10(5). 0124481. https://doi.org/10.1371/journal.pone.0124481
Figuera-Losada, Mariana ; Stathis, Marigo ; Dorskind, Joelle M. ; Thomas, Ajit G. ; Ratnam Bandaru, Veera Venkata ; Yoo, Seung Wan ; Westwood, Nicholas J. ; Rogers, Graeme W. ; McArthur, Justin C. ; Haughey, Norman J. ; Slusher, Barbara S. ; Rojas, Camilo. / Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. In: PLoS One. 2015 ; Vol. 10, No. 5.
@article{71dd7bc2531c476c8760254cb8f84246,
title = "Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties",
abstract = "Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β- induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.",
author = "Mariana Figuera-Losada and Marigo Stathis and Dorskind, {Joelle M.} and Thomas, {Ajit G.} and {Ratnam Bandaru}, {Veera Venkata} and Yoo, {Seung Wan} and Westwood, {Nicholas J.} and Rogers, {Graeme W.} and McArthur, {Justin C.} and Haughey, {Norman J.} and Slusher, {Barbara S.} and Camilo Rojas",
year = "2015",
month = "5",
day = "1",
doi = "10.1371/journal.pone.0124481",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties

AU - Figuera-Losada, Mariana

AU - Stathis, Marigo

AU - Dorskind, Joelle M.

AU - Thomas, Ajit G.

AU - Ratnam Bandaru, Veera Venkata

AU - Yoo, Seung Wan

AU - Westwood, Nicholas J.

AU - Rogers, Graeme W.

AU - McArthur, Justin C.

AU - Haughey, Norman J.

AU - Slusher, Barbara S.

AU - Rojas, Camilo

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β- induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.

AB - Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β- induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.

UR - http://www.scopus.com/inward/record.url?scp=84952872952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952872952&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0124481

DO - 10.1371/journal.pone.0124481

M3 - Article

C2 - 26010541

AN - SCOPUS:84952872952

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - 0124481

ER -