Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Renhe Liu; Xiaoxuan Lyu; Sarah Batt; Meihui Hsu; Michael B Harbut; Catherine Vilcheze; Bo Cheng; Kehinde Ajayi; Baiyuan Yang; Yun Yang; Hui Guo; Changyou Lin; Fei Gan; Chen Wang; Scott G Franzblau; William R Jacobs Jr.; Gurdyal Besra; Eric F Johnson; Mike Petrassi; Arnab K Chatterjee; Klaus Futterer; Feng Wang

doi:10.1002/anie.201707324

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Renhe Liu, Xiaoxuan Lyu, Sarah Batt, Meihui Hsu, Michael B Harbut, Catherine Vilcheze, Bo Cheng, Kehinde Ajayi, Baiyuan Yang, Yun Yang, Hui Guo, Changyou Lin, Fei Gan, Chen Wang, Scott G Franzblau, William R Jacobs Jr., Gurdyal Besra, Eric F Johnson, Mike Petrassi, Arnab K ChatterjeeKlaus Futterer, Feng Wang

Biosciences

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Abstract

Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Original language	English
Pages (from-to)	13011–13015
Journal	Angewandte Chemie (International Edition)
Volume	56
Issue number	42
Early online date	15 Aug 2017
DOIs	https://doi.org/10.1002/anie.201707324
Publication status	Published - 7 Sept 2017

Keywords

DprE1
CYP2C9
anti-tubercular drugs
drug-drug interactions
drug development

UN SDGs

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

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Liu_et_al-2017-Angewandte_Chemie_International_EditionFinal published version, 2.72 MBLicence: Creative Commons: Attribution (CC BY)

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Liu, R., Lyu, X., Batt, S., Hsu, M., Harbut, M. B., Vilcheze, C., Cheng, B., Ajayi, K., Yang, B., Yang, Y., Guo, H., Lin, C., Gan, F., Wang, C., Franzblau, S. G., Jacobs Jr., W. R., Besra, G., Johnson, E. F., Petrassi, M., ... Wang, F. (2017). Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angewandte Chemie (International Edition) , 56(42), 13011–13015. Advance online publication. https://doi.org/10.1002/anie.201707324

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abstract = "Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.",

keywords = "DprE1, CYP2C9, anti-tubercular drugs, drug-drug interactions, drug development",

author = "Renhe Liu and Xiaoxuan Lyu and Sarah Batt and Meihui Hsu and Harbut, {Michael B} and Catherine Vilcheze and Bo Cheng and Kehinde Ajayi and Baiyuan Yang and Yun Yang and Hui Guo and Changyou Lin and Fei Gan and Chen Wang and Franzblau, {Scott G} and {Jacobs Jr.}, {William R} and Gurdyal Besra and Johnson, {Eric F} and Mike Petrassi and Chatterjee, {Arnab K} and Klaus Futterer and Feng Wang",

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Liu, R, Lyu, X, Batt, S, Hsu, M, Harbut, MB, Vilcheze, C, Cheng, B, Ajayi, K, Yang, B, Yang, Y, Guo, H, Lin, C, Gan, F, Wang, C, Franzblau, SG, Jacobs Jr., WR, Besra, G, Johnson, EF, Petrassi, M, Chatterjee, AK, Futterer, K & Wang, F 2017, 'Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes', Angewandte Chemie (International Edition) , vol. 56, no. 42, pp. 13011–13015. https://doi.org/10.1002/anie.201707324

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AU - Liu, Renhe

AU - Lyu, Xiaoxuan

AU - Batt, Sarah

AU - Hsu, Meihui

AU - Harbut, Michael B

AU - Vilcheze, Catherine

AU - Cheng, Bo

AU - Ajayi, Kehinde

AU - Yang, Baiyuan

AU - Yang, Yun

AU - Guo, Hui

AU - Lin, Changyou

AU - Gan, Fei

AU - Wang, Chen

AU - Franzblau, Scott G

AU - Jacobs Jr., William R

AU - Besra, Gurdyal

AU - Johnson, Eric F

AU - Petrassi, Mike

AU - Chatterjee, Arnab K

AU - Futterer, Klaus

AU - Wang, Feng

PY - 2017/9/7

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N2 - Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

AB - Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

KW - DprE1

KW - CYP2C9

KW - anti-tubercular drugs

KW - drug-drug interactions

KW - drug development

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DO - 10.1002/anie.201707324

M3 - Article

SN - 1433-7851

VL - 56

SP - 13011

EP - 13015

JO - Angewandte Chemie (International Edition)

JF - Angewandte Chemie (International Edition)

IS - 42

ER -

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Abstract

Keywords

UN SDGs

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