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Fragment-based approaches to TB drugs

Published online by Cambridge University Press:  02 November 2016

CHIARA MARCHETTI ,
DANIEL S. H. CHAN ,
ANTHONY G. COYNE  and
CHRIS ABELL
CHIARA MARCHETTI
Affiliation:
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
DANIEL S. H. CHAN
Affiliation:
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
ANTHONY G. COYNE*
Affiliation:
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
CHRIS ABELL*
Affiliation:
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
*
*Corresponding author: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. E-mail: ca26@cam.ac.uk; agc40@cam.ac.uk
*Corresponding author: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. E-mail: ca26@cam.ac.uk; agc40@cam.ac.uk
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Summary

Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.

Keywords

tuberculosisfragment-based approachesmedicinal chemistrycytochrome P450pantothenate synthetaseEthRBioA
Type
Special Issue Review
Information
Parasitology , Volume 145 , Special Issue 2: Microbial protein targets: towards understanding and intervention , February 2018 , pp. 184 - 195
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Copyright
Copyright © Cambridge University Press 2016 

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References

Barr, A. J., Ugochukwu, E., Lee, W. H., King, O. N., Filippakopoulos, P., Alfano, I., Savitsky, P., Burgess-Brown, N. A., Müller, S. and Knapp, S. (2009). Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 136, 352–363.CrossRefGoogle ScholarPubMed
Belin, P., Le Du, M. H., Fielding, A., Lequin, O., Jacquet, M., Charbonnier, J. B. Lecoq, A., Thai, R., Courçon, M., Masson, C., Dugave, C., Genet, R., Pernodet, J. L. and Gondry, M. (2009). Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis . Proceedings of the National Academy of Sciences of the United States of America 106(18), 7426–7431.CrossRefGoogle ScholarPubMed
Belisle, J. T., Vissa, V. D., Sievert, T., Takayama, K., Brennan, P. J. and Besra, G. S. (1997). Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276, 1420–1422.CrossRefGoogle ScholarPubMed
Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S. V., Eiglmeier, K., Gas, S., Barry, C. E., Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Krogh, A., McLean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J. et al. (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544.Google Scholar
Congreve, M., Chessari, G., Tisi, D. and Woodhead, A. J. (2008). Recent developments in fragment based drug discovery. Journal of Medicinal Chemistry 51, 3661–3680.Google Scholar
Dai, R., Wilson, D. J., Geders, T. W., Aldrich, C. C. and Finzel, B. C. (2014). Inhibition of Mycobacterium tuberculosis transaminase BioA by Aryl Hydrazines and Hydrazides. ChemBioChem 15, 575–586.Google Scholar
Dover, L. G., Corsino, P. E., Daniels, I. R., Cocklin, I. R., Tatituri, V., Besra, G. S. and Fütterer, K. (2004). Crystal Structure of the TetR/CamR Family Repressor Mycobacterium tuberculosis EthR Implicated in Ethionamide Resistance. Journal of Molecular Biology 340, 1095–1105.CrossRefGoogle ScholarPubMed
Engohang-Ndong, J., Baillat, D., Aumercier, M., Bellefontaine, F., Besra, G. S., Locht, C. and Baulard, A. R. (2004). EthR, a repressor of the TetR/CamR family implicated in ethionamide resistance in mycobacteria, octamerizes cooperatively on its operator. Molecular Microbiology 51, 175–188.Google Scholar
Flipo, M., Desroses, M., Lecat-Guillet, N., Dirié, B., Carette, X., Leroux, F., Piveteau, C., Demirkaya, F., Lens, Z., Rucktooa, P., Villeret, V., Christophe, T., Jeon, H. K., Locht, C., Brodin, P., Déprez, B., Baulard, A. R. and Willand, N. (2011). Ethionamide boosters: synthesis, biological activity, and structure–activity relationships of a series of 1,2,4-Oxadiazole EthR inhibitors. Journal of Medicinal Chemistry 54, 2994–3010.CrossRefGoogle Scholar
Flipo, M., Desroses, M., Lecat-Guillet, N., Villemagne, B., Blondiaux, N., Leroux, F., Piveteau, C., Mathys, V., Flament, M. P., Siepmann, J., Villeret, V., Wohlkönig, A., Wintjens, R., Soror, S. H., Christophe, T., Jeon, H. K., Locht, C., Brodin, P., Déprez, B., Baulard, A. R. and Willand, N. (2012 a). Ethionamide boosters. 2. combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1,2,4-Oxadiazole EthR inhibitors. Journal of Medicinal Chemistry 55, 68–83.CrossRefGoogle Scholar
Flipo, M., Willand, N., Lecat-Guillet, N., Hounsou, C., Desroses, M., Leroux, F., Lens, Z., Villeret, V., Wohlkönig, A., Wintjens, R., Christophe, T., Kyoung Jeon, H., Locht, C., Brodin, P., Baulard, A. R. and Déprez, B. (2012 b). Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis. Journal of Medicinal Chemistry 55, 6391–6402.Google Scholar
Frénois, F., Engohang-Ndong, J., Locht, C., Baulard, A. R. and Villeret, V. (2004). Structure of EthR in a ligand bound conformation reveals therapeutic perspectives against tuberculosis. Molecular Cell 16, 301–307.Google Scholar
Hotta, K., Kitahara, T. and Okami, Y. (1975). Studies on the mode of action of amiclenomycin. Journal of Antibiotics 28, 222–228.Google Scholar
Hudson, S. A., McLean, K. J., Munro, A. W. and Abell, C. (2012 a). Mycobacterium tuberculosis cytochrome P450 enzymes: a cohort of novel TB drug targets. Biochemical Society Transactions 40(3), 573–579.CrossRefGoogle ScholarPubMed
Hudson, S. A., McLean, K. J., Surade, S., Yang, Y. Q., Leys, D., Ciulli, A., Munro, A. W. and Abell, A. (2012 b). Application of fragment screening and merging to the discovery of inhibitors of the Mycobacterium tuberculosis cytochrome P450 CYP121. Angewandte Chemie International Edition 51, 9311–9316.CrossRefGoogle Scholar
Hudson, S. A., Surade, S., Coyne, A. G., McLean, K. J., Leys, D., Munro, A. W. and Abell, C. (2013). Overcoming the limitations of fragment merging: rescuing a strained merged fragment series targeting Mycobacterium tuberculosis CYP121. ChemMedChem 8, 1451–1456.Google Scholar
Hung, A. W., Silvestre, H. L., Wen, S., Ciulli, A., Blundell, T. L. and Abell, C. (2009). Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angewandte Chemie International Edition 48, 8452–8456.Google Scholar
Hung, A. W., Silvestre, H. L., Wen, S., George, G. P., Boland, J., Blundell, T. L., Ciulli, A. and Abell, C. (2016). Optimization of inhibitors of Mycobacterium tuberculosis pantothenate synthetase based on group efficiency analysis. ChemMedChem 11, 38–42.Google Scholar
Jackson, M., Raynaud, C., Lanéelle, M. A., Guilhot, C., Laurent-Winter, C., Ensergueix, D., Gicquel, B. and Daffé, M. (1999). Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Molecular Microbiology 31, 1573–1587.CrossRefGoogle ScholarPubMed
Kavanagh, M. E., Coyne, A. G., McLean, K. J., James, G. G., Levy, C. W., Marino, L. B., de Carvalho, L. P. S., Chan, D. S. H., Hudson, S. A., Surade, S., Leys, D., Munro, A. W. and Abell, C. (2016). Fragment-based approaches to the development of Mycobacterium tuberculosis CYP121 inhibitors. Journal of Medicinal Chemistry 59, 3272–3302.Google Scholar
Koul, A., Arnoult, E., Lounis, N., Guillemont, J. and Andries, K. (2011). The challenge for new drug discovery for tuberculosis. Nature 469, 483–490.Google Scholar
Leys, D., Mowat, C. G., McLean, K. J., Richmond, A., Chapman, S. K., Walkinshaw, M. D. and Munro, A. W. (2003). Atomic structure of Mycobacterium tuberculosis CYP121 to 1·06 A reveals novel features of cytochrome P450. Journal of Biological Chemistry 278, 5141–5147.Google Scholar
Mascarello, A., Mori, M., Chiaradia-Delatorre, L. D., Menegatti, A. C., Delle Monache, F., Ferrari, F., Yunes, R. A., Nunes, R. J., Terenzi, H., Botta, B. and Botta, M. (2013). Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) inhibitors from natural products. PLoS ONE 8, e77081.Google Scholar
Mashalidis, E., Śledź, P., Lang, S. and Abell, C. (2013). A three-stage biophysical screening cascade for fragment-based drug discovery. Nature Protocols 8, 2309–2324.Google Scholar
McLean, K. J., Carroll, P., Lewis, D. G., Dunford, A. J., Seward, H. E., Neeli, R., Cheesman, M. R., Marsollier, L., Douglas, P., Smith, W. E., Rosenkrands, I., Cole, S. T., Leys, D., Parish, T. and Munro, A. W. (2008). Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv. Journal of Biological Chemistry 283, 33406–33416.CrossRefGoogle ScholarPubMed
Murray, C. W. and Blundell, T. L. (2010). Structural biology in fragment-based drug design. Current Opinion in Structural Biology 20, 497–507.Google Scholar
Nikiforov, P. O., Surade, S., Blaszczyk, M., Delorme, V., Brodin, P., Baulard, A. R., Blundell, T. L. and Abell, C. (2016). A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters. Organic and Biomolecular Chemistry 14, 2318–2326.Google Scholar
Park, S. W., Klotzsche, M., Wilson, D. J., Boshoff, H. I., Eoh, H., Manjunatha, U., Blumenthal, A., Rhee, K., Barry, C. E. III, Aldrich, C. C., Ehrt, S. and Schnappinger, D. (2011). Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprtication using regulated gene expression. PLoS Pathogens 7, e1002264, 1–0.Google Scholar
Rawls, K. A., Lang, T. P., Takeuchi, J., Imamura, S., Baguley, T. D., Grundner, C., Alber, T. and Ellman, J. A. (2009). Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorganic and Medicinal Chemistry Letters 19, 6851–6854.CrossRefGoogle ScholarPubMed
Sambandamurthy, V. K., Wang, X., Chen, B., Russell, R. G., Derrick, S., Collins, F. M., Morris, S. L. and Jacobs, W. R. (2002). A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nature Medicine 8, 1171–1174.Google Scholar
Scheich, C., Puetter, V. and Schade, M. (2010). Novel small molecule inhibitors of MDR Mycobacterium tuberculosis by NMR fragment screening of antigen 85 °C. Journal of Medicinal Chemistry 53, 8362–8367.Google Scholar
Schmidt, M. F., Groves, M. R. and Rademann, J. (2011). Dynamic substrate enhancement for the identification of specific, second-site-binding fragments targeting a set of protein tyrosine phosphatases. ChemBioChem 12, 2640–2646.Google Scholar
Scott, D. E., Coyne, A. G., Hudson, S. A. and Abell, C. (2012). Fragment based approaches in drug discovery and chemical biology. Biochemistry 51, 4990–5003.Google Scholar
Shi, C. and Aldrich, C. C. (2012). Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis. Journal of Organic Chemistry 77, 6051–6058.Google Scholar
Silvestre, H. L., Blundell, T. L., Abell, C. and Ciulli, A. (2013). Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery. Proceedings of the National Academy of Sciences of the United States of America 110, 12984–12989.Google Scholar
Singh, R., Rao, V., Shakila, H., Gupta, R., Khera, A., Dhar, N., Singh, A., Koul, A., Singh, Y., Naseema, M., Narayanan, P. R., Paramasivan, C. N., Ramanathan, V. D. and Tyagi, A. K. (2003). Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Molecular Microbiology 50, 751–762.Google Scholar
Soellner, M. B., Rawls, K. A., Grundner, C., Alber, T. and Ellman, J. A. (2007). Fragment-based substrate activity screening method for the identification of potent inhibitors of the Mycobacterium tuberculosis phosphatase PtpB. Journal of the American Chemical Society 129, 9613–9615.Google Scholar
Spry, C., Kirk, K. and Saliba, K. J. (2008). Coenzyme A biosynthesis: an antimicrobial drug target. FEMS Microbiology Reviews 32, 56–106.CrossRefGoogle ScholarPubMed
Surade, S., Ty, N., Hengrung, N., Lechartier, B., Cole, S. T., Abell, C. and Blundell, T. L. (2014). A structure-guided fragment-based approach for the discovery of allosteric inhibitors targeting the lipophilic binding site of transcription factor EthR. Biochemical Journal 458, 387–394.Google Scholar
Tan, L. P., Wu, H., Yang, P. Y., Kalesh, K. A., Zhang, X., Hu, M., Srinivasan, R. and Yao, S. Q. (2009). High-throughput discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitors using click chemistry. Organic Letters 11, 5102–5105.CrossRefGoogle ScholarPubMed
Tonks, N. K. (2006). Protein tyrosine phosphatases: from genes, to function, to disease. Nature Reviews Molecular Cell Biology 7, 833–846.Google Scholar
Vannelli, T. A., Dykman, A. and Ortiz de Montellano, P. R. (2002). The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. Journal of Biological Chemistry 77, 12824–12829.Google Scholar
Villemagne, B., Flipo, M., Blondiaux, N., Crauste, C., Malaquin, S., Leroux, F., Piveteau, C., Villeret, V., Brodin, P., Villoutreix, B. O., Sperandio, O., Soror, S. H., Wohlkönig, A., Wintjens, R., Deprez, B., Baulard, A. R. and Willand, N. (2014). Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches. Journal of Medicinal Chemistry 57, 4876–4888.Google Scholar
Wang, S. and Eisenberg, D. (2003). Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Science 12, 1097–1108.CrossRefGoogle Scholar
Webb, M. E., Smith, A. G. and Abell, C. (2002). Biosynthesis of pantothenate. Natural Product Reports 21, 695–721.Google Scholar
Willand, N., Dirié, B., Carette, X., Bifani, P., Singhal, A., Desroses, M., Leroux, F., Willery, E., Mathys, V., Déprez-Poulain, R., Delcroix, G., Frénois, F., Aumercier, M., Locht, C., Villeret, V., Déprez, B. and Baulard, A. R. (2009). Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nature Medicine 15, 537–544.CrossRefGoogle ScholarPubMed
Woong Park, S., Klotzsche, M., Wilson, D. J., Boshoff, H. I., Eoh, H., Manjunatha, U., Blumenthal, A., Rhee, K., Barry, C. E. III, Aldrich, C. C., Ehrt, S. and Schnappinger, D. (2011). Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. PLoS Pathogens 7, e1002264.Google Scholar
World Health Organisation (2015). Global tuberculosis report, Geneva; (http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1 (accessed October 2016).Google Scholar