Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

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

doi:10.1002/anie.201707324

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

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

Microbiology & Immunology

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

32 Scopus citations

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 (US)
Pages (from-to)	13011-13015
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	42
DOIs	https://doi.org/10.1002/anie.201707324
State	Published - Oct 9 2017

Keywords

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

ASJC Scopus subject areas

Catalysis
Chemistry(all)

UN SDGs

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

Access to Document

10.1002/anie.201707324

Cite this

Liu, R., Lyu, X., Batt, S. M., Hsu, M. H., Harbut, M. B., Vilchèze, C., Cheng, B., Ajayi, K., Yang, B., Yang, Y., Guo, H., Lin, C., Gan, F., Wang, C., Franzblau, S. G., Jacobs, W. R., Besra, G. S., 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. https://doi.org/10.1002/anie.201707324

Liu, R, Lyu, X, Batt, SM, Hsu, MH, Harbut, MB, Vilchèze, C, Cheng, B, Ajayi, K, Yang, B, Yang, Y, Guo, H, Lin, C, Gan, F, Wang, C, Franzblau, SG, Jacobs, WR, Besra, GS, Johnson, EF, Petrassi, M, Chatterjee, AK, Fütterer, 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

@article{c0c9cb5105464de98833eb9d39eb188b,

title = "Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes",

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

author = "Renhe Liu and Xiaoxuan Lyu and Batt, {Sarah M.} and Hsu, {Mei Hui} and Harbut, {Michael B.} and Catherine Vilch{\`e}ze 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, {William R.} and Besra, {Gurdyal S.} and Johnson, {Eric F.} and Mike Petrassi and Chatterjee, {Arnab K.} and Klaus F{\"u}tterer and Feng Wang",

note = "Funding Information: We thank Dr. Stewart Cole and GSK for providing DprE1 substrate FPR and Drs. Cliff Barry and Tanya Parish, Katarina Mikusova, and Danling Wang for technical support or helpful discussion. This work was supported, in part, by the Bill and Melinda Gates Foundation, the Global Alliance for TB Drug Development, and NIH Grants AI0-51519 (W.R.J.), GM031001 (E.F.J.), a Personal Research Chair from Mr James Bardrick and a Royal Society Wolfson Research Merit Award (G.S.B.), MRC (MR/K012118/1) (G.S.B. and K.F.), the Diamond Light Source (proposal number MX8359), and the Stanford Synchrotron Radiation Lightsource (DE-AC02-76SF00515 and NIH P41GM103393). Publisher Copyright: {\textcopyright} 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.",

year = "2017",

month = oct,

day = "9",

doi = "10.1002/anie.201707324",

language = "English (US)",

volume = "56",

pages = "13011--13015",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "John Wiley and Sons Ltd",

number = "42",

}

TY - JOUR

T1 - Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

AU - Liu, Renhe

AU - Lyu, Xiaoxuan

AU - Batt, Sarah M.

AU - Hsu, Mei Hui

AU - Harbut, Michael B.

AU - Vilchèze, 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, William R.

AU - Besra, Gurdyal S.

AU - Johnson, Eric F.

AU - Petrassi, Mike

AU - Chatterjee, Arnab K.

AU - Fütterer, Klaus

AU - Wang, Feng

N1 - Funding Information: We thank Dr. Stewart Cole and GSK for providing DprE1 substrate FPR and Drs. Cliff Barry and Tanya Parish, Katarina Mikusova, and Danling Wang for technical support or helpful discussion. This work was supported, in part, by the Bill and Melinda Gates Foundation, the Global Alliance for TB Drug Development, and NIH Grants AI0-51519 (W.R.J.), GM031001 (E.F.J.), a Personal Research Chair from Mr James Bardrick and a Royal Society Wolfson Research Merit Award (G.S.B.), MRC (MR/K012118/1) (G.S.B. and K.F.), the Diamond Light Source (proposal number MX8359), and the Stanford Synchrotron Radiation Lightsource (DE-AC02-76SF00515 and NIH P41GM103393). Publisher Copyright: © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

PY - 2017/10/9

Y1 - 2017/10/9

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 - CYP2C9

KW - DprE1

KW - anti-tubercular drugs

KW - drug development

KW - drug–drug interactions

UR - http://www.scopus.com/inward/record.url?scp=85028927430&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028927430&partnerID=8YFLogxK

U2 - 10.1002/anie.201707324

DO - 10.1002/anie.201707324

M3 - Article

C2 - 28815830

AN - SCOPUS:85028927430

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

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this