Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase

Suresh K Tipparaju, Stephen P Muench, Ernest J Mui, Sergey N Ruzheinikov, Jeffrey Z. Lu, Samuel L Hutson, Michael J. Kirisits, Sean T. Prigge, Craig Roberts, Fiona L Henriquez, Alan P Kozikowski, David W Rice, Rima L McLeod

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
LanguageEnglish
Pages6287-6300
Number of pages14
JournalJournal of Medicinal Chemistry
Volume53
Issue number17
Early online date10 Aug 2010
DOIs
Publication statusPublished - 2010

Fingerprint

Toxoplasma
Oxidoreductases
Type II Fatty Acid Synthase
Toxoplasmosis
Hypersensitivity
Parasites
Morbidity
Mortality
Enzymes

Keywords

  • animals
  • cultured cells
  • coccidiostats
  • crystallography X-Ray
  • cytochrome P-450 enzyme system
  • enoyl-(acyl-carrier-protein) reductase (NADH)
  • fibroblasts
  • humans
  • mice
  • microbial sensitivity tests
  • liver microsomes
  • molecular models
  • molecular structure
  • nitriles
  • nitrobenzenes
  • phenyl ethers
  • pyridines
  • structure-activity relationship
  • toxoplasma
  • toxoplasmosis

Cite this

Tipparaju, S. K., Muench, S. P., Mui, E. J., Ruzheinikov, S. N., Lu, J. Z., Hutson, S. L., ... McLeod, R. L. (2010). Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. Journal of Medicinal Chemistry, 53(17), 6287-6300. https://doi.org/10.1021/jm9017724
Tipparaju, Suresh K ; Muench, Stephen P ; Mui, Ernest J ; Ruzheinikov, Sergey N ; Lu, Jeffrey Z. ; Hutson, Samuel L ; Kirisits, Michael J. ; Prigge, Sean T. ; Roberts, Craig ; Henriquez, Fiona L ; Kozikowski, Alan P ; Rice, David W ; McLeod, Rima L. / Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 17. pp. 6287-6300.
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Tipparaju, SK, Muench, SP, Mui, EJ, Ruzheinikov, SN, Lu, JZ, Hutson, SL, Kirisits, MJ, Prigge, ST, Roberts, C, Henriquez, FL, Kozikowski, AP, Rice, DW & McLeod, RL 2010, 'Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase' Journal of Medicinal Chemistry, vol. 53, no. 17, pp. 6287-6300. https://doi.org/10.1021/jm9017724

Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. / Tipparaju, Suresh K; Muench, Stephen P; Mui, Ernest J; Ruzheinikov, Sergey N; Lu, Jeffrey Z.; Hutson, Samuel L; Kirisits, Michael J.; Prigge, Sean T.; Roberts, Craig; Henriquez, Fiona L; Kozikowski, Alan P; Rice, David W; McLeod, Rima L.

In: Journal of Medicinal Chemistry, Vol. 53, No. 17, 2010, p. 6287-6300.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase

AU - Tipparaju, Suresh K

AU - Muench, Stephen P

AU - Mui, Ernest J

AU - Ruzheinikov, Sergey N

AU - Lu, Jeffrey Z.

AU - Hutson, Samuel L

AU - Kirisits, Michael J.

AU - Prigge, Sean T.

AU - Roberts, Craig

AU - Henriquez, Fiona L

AU - Kozikowski, Alan P

AU - Rice, David W

AU - McLeod, Rima L

PY - 2010

Y1 - 2010

N2 - Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.

AB - Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.

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KW - cultured cells

KW - coccidiostats

KW - crystallography X-Ray

KW - cytochrome P-450 enzyme system

KW - enoyl-(acyl-carrier-protein) reductase (NADH)

KW - fibroblasts

KW - humans

KW - mice

KW - microbial sensitivity tests

KW - liver microsomes

KW - molecular models

KW - molecular structure

KW - nitriles

KW - nitrobenzenes

KW - phenyl ethers

KW - pyridines

KW - structure-activity relationship

KW - toxoplasma

KW - toxoplasmosis

U2 - 10.1021/jm9017724

DO - 10.1021/jm9017724

M3 - Article

VL - 53

SP - 6287

EP - 6300

JO - Journal of Medicinal Chemistry

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JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

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Tipparaju SK, Muench SP, Mui EJ, Ruzheinikov SN, Lu JZ, Hutson SL et al. Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. Journal of Medicinal Chemistry. 2010;53(17):6287-6300. https://doi.org/10.1021/jm9017724