Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin

Sanjeewani Sooriyaarachchi, René Chofor, Martijn D P Risseeuw, Terese Bergfors, Jenny Pouyez, Cynthia S. Dowd, Louis Maes, Johan Wouters, T. Alwyn Jones, Serge Van Calenbergh, Sherry L. Mowbray

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

langue originaleAnglais
Pages (de - à)2024-2036
Nombre de pages13
journalChemMedChem
Les DOIs
étatPublié - 20 sept. 2016

Empreinte digitale

Plasmodium falciparum
Polyisoprenyl Phosphates
Enzymes
Plasmodium
Biosynthesis
Biosynthetic Pathways
Terpenes
Tryptophan
Plasticity
Catalytic Domain
Parasites
Phosphates
X-Rays
X rays
Growth
fosmidomycin
xylulose-5-phosphate
phosphonic acid

Citer ceci

Sooriyaarachchi, Sanjeewani ; Chofor, René ; Risseeuw, Martijn D P ; Bergfors, Terese ; Pouyez, Jenny ; Dowd, Cynthia S. ; Maes, Louis ; Wouters, Johan ; Jones, T. Alwyn ; Van Calenbergh, Serge ; Mowbray, Sherry L. / Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin. Dans: ChemMedChem. 2016 ; p. 2024-2036.
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abstract = "Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.",
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author = "Sanjeewani Sooriyaarachchi and Ren{\'e} Chofor and Risseeuw, {Martijn D P} and Terese Bergfors and Jenny Pouyez and Dowd, {Cynthia S.} and Louis Maes and Johan Wouters and Jones, {T. Alwyn} and {Van Calenbergh}, Serge and Mowbray, {Sherry L.}",
year = "2016",
month = "9",
day = "20",
doi = "10.1002/cmdc.201600249",
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Sooriyaarachchi, S, Chofor, R, Risseeuw, MDP, Bergfors, T, Pouyez, J, Dowd, CS, Maes, L, Wouters, J, Jones, TA, Van Calenbergh, S & Mowbray, SL 2016, 'Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin', ChemMedChem, p. 2024-2036. https://doi.org/10.1002/cmdc.201600249

Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin. / Sooriyaarachchi, Sanjeewani; Chofor, René; Risseeuw, Martijn D P; Bergfors, Terese; Pouyez, Jenny; Dowd, Cynthia S.; Maes, Louis; Wouters, Johan; Jones, T. Alwyn; Van Calenbergh, Serge; Mowbray, Sherry L.

Dans: ChemMedChem, 20.09.2016, p. 2024-2036.

Résultats de recherche: Contribution à un journal/une revueArticle

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T1 - Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin

AU - Sooriyaarachchi, Sanjeewani

AU - Chofor, René

AU - Risseeuw, Martijn D P

AU - Bergfors, Terese

AU - Pouyez, Jenny

AU - Dowd, Cynthia S.

AU - Maes, Louis

AU - Wouters, Johan

AU - Jones, T. Alwyn

AU - Van Calenbergh, Serge

AU - Mowbray, Sherry L.

PY - 2016/9/20

Y1 - 2016/9/20

N2 - Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

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KW - antibiotics

KW - antiprotozoal agents

KW - oxidoreductases

KW - structural biology

KW - structure–activity relationships

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