Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct

Sunnia Rajput; Kirsty J McLean; Harshwardhan Poddar; Irwin R Selvam; Gayathri Nagalingam; James A Triccas; Colin W Levy; Andrew W Munro; Craig A Hutton

doi:10.1021/acs.jmedchem.9b01199

Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct

Sunnia Rajput, Kirsty J McLean, Harshwardhan Poddar, Irwin R Selvam, Gayathri Nagalingam, James A Triccas, Colin W Levy, Andrew W Munro, Craig A Hutton

Research output: Contribution to journal › Article › peer-review

Abstract

A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.

Original language	English
Article number	doi: 10.1021/acs.jmedchem.9b01199
Pages (from-to)	9792-9805
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	21
Early online date	16 Oct 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01199
Publication status	Published - 2019

Keywords

Mycobacterium tuberculosis
cytochrome P450
CYP121
iodinated analogues
heme interactions
tight binding compounds
EPR spectroscopy
protein crystallography

Research Beacons, Institutes and Platforms

Biotechnology
Manchester Institute of Biotechnology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.9b01199

Manchester Synthetic Biology Research Centre for Fine and Speciality Chemicals
Scrutton, N., Azapagic, A., Balmer, A., Barran, P., Breitling, R., Delneri, D., Dixon, N., Faulon, J., Flitsch, S., Goble, C., Goodacre, R., Hay, S., Kell, D., Leys, D., Lloyd, J., Lockyer, N., Martin, P., Micklefield, J., Munro, A., Pedrosa Mendes, P., Randles, S., Salehi Yazdi, F., Shapira, P., Takano, E., Turner, N. & Winterburn, J.
14/11/14 → 13/05/20
Project: Research

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Rajput, S., McLean, K. J., Poddar, H., Selvam, I. R., Nagalingam, G., Triccas, J. A., Levy, C. W., Munro, A. W., & Hutton, C. A. (2019). Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct. Journal of Medicinal Chemistry, 62(21), 9792-9805. Article doi: 10.1021/acs.jmedchem.9b01199. Advance online publication. https://doi.org/10.1021/acs.jmedchem.9b01199

@article{a13cc89230894540935354121df6fc49,

title = "Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct",

abstract = "A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.",

keywords = "Mycobacterium tuberculosis, cytochrome P450, CYP121, iodinated analogues, heme interactions, tight binding compounds, EPR spectroscopy, protein crystallography",

author = "Sunnia Rajput and McLean, {Kirsty J} and Harshwardhan Poddar and Selvam, {Irwin R} and Gayathri Nagalingam and Triccas, {James A} and Levy, {Colin W} and Munro, {Andrew W} and Hutton, {Craig A}",

year = "2019",

doi = "10.1021/acs.jmedchem.9b01199",

language = "English",

volume = "62",

pages = "9792--9805",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "21",

}

Rajput, S, McLean, KJ, Poddar, H, Selvam, IR, Nagalingam, G, Triccas, JA, Levy, CW , Munro, AW & Hutton, CA 2019, 'Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct', Journal of Medicinal Chemistry, vol. 62, no. 21, doi: 10.1021/acs.jmedchem.9b01199, pp. 9792-9805. https://doi.org/10.1021/acs.jmedchem.9b01199

Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct. / Rajput, Sunnia; McLean, Kirsty J; Poddar, Harshwardhan et al.
In: Journal of Medicinal Chemistry, Vol. 62, No. 21, doi: 10.1021/acs.jmedchem.9b01199, 2019, p. 9792-9805.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121

T2 - Iodinated Analogues Promote Shift to High-Spin Adduct

AU - Rajput, Sunnia

AU - McLean, Kirsty J

AU - Poddar, Harshwardhan

AU - Selvam, Irwin R

AU - Nagalingam, Gayathri

AU - Triccas, James A

AU - Levy, Colin W

AU - Munro, Andrew W

AU - Hutton, Craig A

PY - 2019

Y1 - 2019

N2 - A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.

AB - A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.

KW - Mycobacterium tuberculosis

KW - cytochrome P450

KW - CYP121

KW - iodinated analogues

KW - heme interactions

KW - tight binding compounds

KW - EPR spectroscopy

KW - protein crystallography

U2 - 10.1021/acs.jmedchem.9b01199

DO - 10.1021/acs.jmedchem.9b01199

M3 - Article

C2 - 31618032

SN - 0022-2623

VL - 62

SP - 9792

EP - 9805

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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M1 - doi: 10.1021/acs.jmedchem.9b01199

ER -

Rajput S, McLean KJ, Poddar H, Selvam IR, Nagalingam G, Triccas JA et al. Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct. Journal of Medicinal Chemistry. 2019;62(21):9792-9805. doi: 10.1021/acs.jmedchem.9b01199. Epub 2019 Oct 16. doi: 10.1021/acs.jmedchem.9b01199

Structure-Activity Relationships of cyclo(l-Tyrosyl-l-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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