Abstract
Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.
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Bacon C, Lakics V, Machesky L, Rumsby M (2007) N-WASP regulates extension of filopodia and processes by oligodendrocyte progenitors, oligodendrocytes, and Schwann cells-implications for axon ensheathment at myelination. Glia 55:844–858
Brotz-Oesterhelt H, Beyer D, Kroll HP, Endermann R, Ladel C, Schroeder W, Hinzen B, Raddatz S, Paulsen H, Henninger K, Bandow JE, Sahl HG, Labischinski H (2005) Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat Med 11:1082–1087
Butler MS (2004) The role of natural product chemistry in drug discovery. J Nat Prod 67:2141–2153
Carlson EE (2010) Natural products as chemical probes. ACS Chem Biol 5:639–653
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
Chaisson RE, Nuermberger EL (2012) Confronting multidrug-resistant tuberculosis. New Engl J Med 366:2223–2224
Chang J, Jung HJ, Jeong SH, Kim HK, Han J, Kwon HJ (2014) A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species. Biochem Biophys Res Commun 455:290–297
Chang J, Jung HJ, Park HJ, Cho SW, Lee SK, Kwon HJ (2015) Cell-permeable mitochondrial ubiquinol-cytochrome c reductase binding protein induces angiogenesis in vitro and in vivo. Cancer Lett 366:52–60
Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510:397–401
Cho YS, Jung HJ, Seok SH, Payumo AY, Chen JK, Kwon HJ (2013) Functional inhibition of UQCRB suppresses angiogenesis in zebrafish. Biochem Biophys Res Commun 433:396–400
Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42:355–357
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974
Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286
Gao W, Kim JY, Anderson JR, Akopian T, Hong S, Jin YY, Kandror O, Kim JW, Lee IA, Lee SY, McAlpine JB, Mulugeta S, Sunoqrot S, Wang Y, Yang SH, Yoon TM, Goldberg AL, Pauli GF, Suh JW, Franzblau SG, Cho S (2015) The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother 59:880–889
Gao W, Kim JY, Chen SN, Cho SH, Choi J, Jaki BU, Jin YY, Lankin DC, Lee JE, Lee SY, McAlpine JB, Napolitano JG, Franzblau SG, Suh JW, Pauli GF (2014) Discovery and characterization of the tuberculosis drug lead ecumicin. Org Lett 16:6044–6047
Gutman M, Singer TP, Beinert H, Casida JE (1970) Reaction sites of rotenone, piericidin A, and amytal in relation to the nonheme iron components of NADH dehydrogenase. Proc Natl Acad Sci USA 65:763–770
Hall C, Wu M, Crane FL, Takahashi H, Tamura S, Folkers K (1966) Piericidin A: a new inhibitor of mitochondrial electron transport. Biochem Biophys Res Commun 25:373–377
Harada T, Chelala C, Crnogorac-Jurcevic T, Lemoine NR (2009) Genome-wide analysis of pancreatic cancer using microarray-based techniques. Pancreatology 9:13–24
Harding MW, Galat A, Uehling DE, Schreiber SL (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341:758–760
Hart CP (2005) Finding the target after screening the phenotype. Drug Discov Today 10:513–519
Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov 14:111–129
Haut S, Brivet M, Touati G, Rustin P, Lebon S, Garcia-Cazorla A, Saudubray JM, Boutron A, Legrand A, Slama A (2003) A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis. Hum Genet 113:118–122
Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, Kinoshita T, Saito N, Ochiai A, Tomita M, Esumi H, Soga T (2009) Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res 69:4918–4925
Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348:555–557
Itazaki H, Nagashima K, Sugita K, Yoshida H, Kawamura Y, Yasuda Y, Matsumoto K, Ishii K, Uotani N, Nakai H et al (1990) Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J Antibiot (Tokyo) 43:1524–1532
Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, Shen F, Tang ZY, Wang XW (2007) Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res 13:1133–1139
Jin Y, Yu J, Yu YG (2002) Identification of hNopp140 as a binding partner for doxorubicin with a phage display cloning method. Chem Biol 9:157–162
Johnson R, Streicher EM, Louw GE, Warren RM, van Helden PD, Victor TC (2006) Drug resistance in Mycobacterium tuberculosis. Curr Issues Mol Biol 8:97–111
Jung HJ, Cho M, Kim Y, Han G, Kwon HJ (2014) Development of a novel class of mitochondrial ubiquinol-cytochrome c reductase binding protein (UQCRB) modulators as promising antiangiogenic leads. J Med Chem 57:7990–7998
Jung HJ, Kim KH, Kim ND, Han G, Kwon HJ (2011) Identification of a novel small molecule targeting UQCRB of mitochondrial complex III and its anti-angiogenic activity. Bioorganic Med Chem Lett 21:1052–1056
Jung HJ, Kim Y, Chang J, Kang SW, Kim JH, Kwon HJ (2013) Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells. J Mol Med 91:1117–1128
Jung HJ, Kwon HJ (2013) Exploring the role of mitochondrial UQCRB in angiogenesis using small molecules. Mol BioSyst 9:930–939
Jung HJ, Lee HB, Kim CJ, Rho JR, Shin J, Kwon HJ (2003) Anti-angiogenic activity of terpestacin, a bicyclo sesterterpene from Embellisia chlamydospora. J Antibiot (Tokyo) 56:492–496
Jung HJ, Shim JS, Lee J, Song YM, Park KC, Choi SH, Kim ND, Yoon JH, Mungai PT, Schumacker PT, Kwon HJ (2010) Terpestacin inhibits tumor angiogenesis by targeting UQCRB of mitochondrial complex III and suppressing hypoxia-induced reactive oxygen species production and cellular oxygen sensing. J Biol Chem 285:11584–11595
Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 268:22429–22435
Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 40:1249–1255
Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T, Goto T, Okuhara M, Kohsaka M, Aoki H et al (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40:1256–1265
Kitagawa M, Ikeda S, Tashiro E, Soga T, Imoto M (2010) Metabolomic identification of the target of the filopodia protrusion inhibitor glucopiericidin A. Chem Biol 17:989–998
Kume S, Yamato M, Tamura Y, Jin G, Nakano M, Miyashige Y, Eguchi A, Ogata Y, Goda N, Iwai K, Yamano E, Watanabe Y, Soga T, Kataoka Y (2015) Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. PLoS One 10:e0120106
Kwon HJ, Owa T, Hassig CA, Shimada J, Schreiber SL (1998) Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc Natl Acad Sci USA 95:3356–3361
Lai K, Selinger DW, Solomon JM, Wu H, Schmitt E, Serluca FC, Curtis D, Benson JD (2013) Integrated compound profiling screens identify the mitochondrial electron transport chain as the molecular target of the natural products manassantin, sesquicillin, and arctigenin. ACS Chem Biol 8:257–267
Lascorz J, Bevier M, Schonfels WV, Kalthoff H, Aselmann H, Beckmann J, Egberts J, Buch S, Becker T, Schreiber S, Hampe J, Hemminki K, Forsti A, Schafmayer C (2012) Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer. BMC Med Genet 13:31
Lomenick B, Hao R, Jonai N, Chin RM, Aghajan M, Warburton S, Wang J, Wu RP, Gomez F, Loo JA, Wohlschlegel JA, Vondriska TM, Pelletier J, Herschman HR, Clardy J, Clarke CF, Huang J (2009) Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci USA 106:21984–21989
Lomenick B, Jung G, Wohlschlegel JA, Huang J (2011) Target identification using drug affinity responsive target stability (DARTS). Curr Protoc Chem Biol 3:163–180
Low WK, Dang Y, Schneider-Poetsch T, Shi Z, Choi NS, Merrick WC, Romo D, Liu JO (2005) Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol Cell 20:709–722
Matsumoto M, Mogi K, Nagaoka K, Ishizeki S, Kawahara R, Nakashima T (1987) New piericidin glucosides, glucopiericidins A and B. J Antibiot (Tokyo) 40:149–156
Mattila PK, Lappalainen P (2008) Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9:446–454
Moffat JG, Rudolph J, Bailey D (2014) Phenotypic screening in cancer drug discovery—past, present and future. Nat Rev Drug Discov 13:588–602
Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (1998) FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241:126–133
Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477
Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, Saito K, Kato K, Kato Y, Wakabayashi T, Soga T, Natsume A (2014) Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biol 35:5911–5920
Oka M, Iimura S, Tenmyo O, Sawada Y, Sugawara M, Ohkusa N, Yamamoto H, Kawano K, Hu SL, Fukagawa Y et al (1993) Terpestacin, a new syncytium formation inhibitor from Arthrinium sp. J Antibiot (Tokyo) 46:367–373
Papetti M, Herman IM (2002) Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 282:C947–C970
Piggott AM, Karuso P (2008) Rapid identification of a protein binding partner for the marine natural product kahalalide F by using reverse chemical proteomics. Chem Bio Chem 9:524–530
Ralser M, Wamelink MM, Struys EA, Joppich C, Krobitsch S, Jakobs C, Lehrach H (2008) A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth. Proc Natl Acad Sci USA 105:17807–17811
Sche PP, McKenzie KM, White JD, Austin DJ (1999) Display cloning: functional identification of natural product receptors using cDNA-phage display. Chem Biol 6:707–716
Shim JS, Lee J, Park HJ, Park SJ, Kwon HJ (2004) A new curcumin derivative, HBC, interferes with the cell cycle progression of colon cancer cells via antagonization of the Ca2+/calmodulin function. Chem Biol 11:1455–1463
Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM (1997) The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci USA 94:6099–6103
Sugita K, Yoshida H, Matsumoto M, Matsutani S (1992) A novel compound, depudecin, induces production of transformation to the flat phenotype of NIH3T3 cells transformed by ras-oncogene. Biochem Biophys Res Commun 182:379–387
Suzuki H, Hosokawa Y, Toda H, Nishikimi M, Ozawa T (1988) Cloning and sequencing of a cDNA for human mitochondrial ubiquinone-binding protein of complex III. Biochem Biophys Res Commun 156:987–994
Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10:507–519
Tomioka H, Namba K (2006) Development of antituberculous drugs: current status and future prospects. Kekkaku 81:753–774
Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M (1994) FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. J Antibiot (Tokyo) 47:301–310
van Hattum H, Waldmann H (2014) Biology-oriented synthesis: harnessing the power of evolution. J Am Chem Soc 136:11853–11859
Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370. doi:10.1038/nm.2537
Wrzeszczynski KO, Varadan V, Byrnes J, Lum E, Kamalakaran S, Levine DA, Dimitrova N, Zhang MQ, Lucito R (2011) Identification of tumor suppressors and oncogenes from genomic and epigenetic features in ovarian cancer. PLoS One 6:e28503
Xu M, Liu K, Swaroop M, Porter FD, Sidhu R, Firnkes S, Ory DS, Marugan JJ, Xiao J, Southall N, Pavan WJ, Davidson C, Walkley SU, Remaley AT, Baxa U, Sun W, McKew JC, Austin CP, Zheng W (2012) Delta-Tocopherol reduces lipid accumulation in Niemann–Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem 287:39349–39360
Yoshida M, Beppu T (1988) Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A. Exp Cell Res 177:122–131
Zheng W, Thorne N, McKew JC (2013) Phenotypic screens as a renewed approach for drug discovery. Drug Discov Today 18:1067–1073
Acknowledgments
This work was partly supported by grants from the National Research Foundation of Korea funded by the Korean Government (MSIP, 2010-0017984 and 2012M3A9D1054520), the Translational Research Center for Protein Function Control, NRF (2009-0083522), the Ministry of Health and Welfare (0620360-1), and the Brain Korea 21 Plus Project, Republic of Korea.
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Special Issue: Natural Product Discovery and Development in the Genomic Era. Dedicated to Professor Satoshi Ōmura for his numerous contributions to the field of natural products.
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Chang, J., Kwon, H.J. Discovery of novel drug targets and their functions using phenotypic screening of natural products. J Ind Microbiol Biotechnol 43, 221–231 (2016). https://doi.org/10.1007/s10295-015-1681-y
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DOI: https://doi.org/10.1007/s10295-015-1681-y