RESEARCH OVERVIEW

The Oberlies research group focuses on the isolation and structure elucidation of bioactive compounds from natural sources, including filamentous fungi, predator bacteria, and plants. Such studies have ramifications both in the realm of drug discovery (in search of new anticancer and/or antibiotic agents) and in the area of herbal drugs (developing reference standards and studying herb-drug interactions).

 Natural Products Drug Discovery

Nature has been a valuable source for new drugs, particularly in the anticancer and antibiotic arenas, where nearly 60% of all currently used pharmaceuticals are either derived directly or based upon a natural product. We have several projects that seek to identify new drug leads. For our largest project, we are exploring a library of filamentous fungi, which have the advantage that they can be grown in culture, for new anticancer leads. This research is part of a Program Project, supported by the National Cancer Institute, where other team members are searching for similar leads from both cyanobacteria and plants. We have identified several promising leads from filamentous fungi, and studies are ongoing to isolate and determine the structures of the anticancer constituents. Under a separate project, we are collaborating with colleagues at Virginia Tech and the Jordan University of Science and Technology to study a group of bacteria, termed ‘predator bacteria’. These organisms rise to the top of the bacterial food chain and kill other bacteria as a sole source of nutrients. We are using predator bacteria via a chemical ecology approach toward the identification of new antibiotic leads. Another project in the realm of drug discovery examines plants for new leads that are active in the central nervous system. The common theme for all of these projects is the use of natural substances to identify small molecules that affect biological systems.

 Herbal Drugs

The tools and the skill sets that my group develops in the realm of drug discovery are directly applicable to working with herbal drugs. The only difference is that the end goals between these projects are somewhat different. With herbal drugs, we are often developing reference standards, such that the herbal mixture can be characterized more fully. Also, in one of our newest projects, we are working with colleagues at the University of North Carolina at Chapel Hill to understand potential untoward interactions that may occur between a pharmaceutical and an herbal material taken concomitantly. For that project, we are using assays for metabolism (p450s) to direct the purification of compounds. The common theme for our herbal projects is using natural products chemistry to better understand how an herbal products works while making it safer and more consistent for consumers.

 Researchers working on projects in my group develop skills in analytical chemistry, spectroscopy/spectrometry, and organic chemistry. Chromatographic skills are honed to purify small molecules from crude extracts. Spectroscopy and spectrometry (particularly NMR and MS) are used to determine the structures of the isolated compounds de novo. The general principles of organic chemistry are used both to understand and predict chromatographic purifications and to assemble structures in a logical manner. Moreover, researchers in my group must develop an understanding and appreciation of biological assays and the biological effects of purified natural products.

RECENT PUBLICATIONS

Ayers, D., Graf, T.N., Adcock, A.F., Kroll, D.J., Matthew, S., Carache de Blanco, E.J., Shen, Q., Swanson, S.M., Wani, M.C., Pearce, C.J. and Oberlies, N.H. (2011) Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships. J. Nat. Prod. 74, 1126-1131. Junio, H.A., Sy-Cordero, A.A., Ettefagh, K.A., Burns, J.T., Micko, K.T., Graf, T.N., Richter, S.J., Cannon, R.E., Oberlies, N.H. and Cech, N.B. (2011) Synergy-directed fractionation of botanical medicines: a case study with goldenseal (Hydrastis canadensis). J. Nat. Prod. 74, 1621-1629.  Wagoner, J., Morishima, C., Graf, T.N., Oberlies, N.H., Teissier, E., Pecheur, E.I., Tavis, J.E. and Polyak, S.J. (2011) Differential in vitro effects of intravenous versus oral formulations of silibinin on the HCV life cycle and inflammation. PloS One 6, e16464. Strader, C.R., Pearce, C.J. and Oberlies, N.H. (2011) Fingolimod (FTY720): A recently approved multiple sclerosis drug based on a fungal secondary metabolite. J. Nat. Prod. 74, 900-907. Kim, E., Sy-Cordero, A., Graf, T.N., Brantley, S.J., Paine, M.F. and Oberlies, N.H. (2011) Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. Planta Med. 77, 265-270. Deep, G., Gangar, S.C., Oberlies, N.H., Kroll, D.J. and Agarwal, R. (2010) Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-kappaB, and androgen receptor signaling. Mol. Carcinog. 49, 902-912. Sy-Cordero, A.A., Graf, T.N., Wani, M.C., Kroll, D.J., Pearce, C.J. and Oberlies, N.H. (2010) Dereplication of macrocyclic trichothecenes from extracts of filamentous fungi through UV and NMR profiles. J. Antibiot. 63, 539-544. Ngo, N.; Brantley, S. J.; Carrizosa, D. R.; Kashuba, A. D. M.; Dees, E. C.; Kroll, D. J.; Oberlies, N. H. and Paine, M. F. (2010) The warfarin-cranberry juice interaction revisited: A systematic in vitro-in vivo evaluation. J. Exp. Pharmacol. 2, 83-91. Wagoner, J., Negash, A., Kane, O.J., Martinez, L.E., Nahmias, Y., Bourne, N., Owen, D.M., Grove, J., Brimacombe, C., McKeating, J.A., Pecheur, E.I., Graf, T.N., Oberlies, N.H., Lohmann, V., Cao, F., Tavis, J.E. and Polyak, S.J. (2010) Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51, 1912-1921. Sy-Cordero, A., Graf, T.N., Nakanishi, Y., Wani, M.C., Agarwal, R., Kroll, D.J. and Oberlies, N.H. (2010) Large-scale isolation of flavonolignans from Silybum marianum extract affords new minor constituents and preliminary structure-activity relationships. Planta Med. 76, 644-647. Polyak, S.J., Morishima, C., Lohmann, V., Pal, S., Lee, D.Y., Liu, Y., Graf, T.N. and Oberlies, N.H. (2010) Identification of hepatoprotective flavonolignans from silymarin. Proc. Natl. Acad. Sci. USA 107, 5995-5999. Brantley, S.J., Oberlies, N.H., Kroll, D.J. and Paine, M.F. (2010) Two flavonolignans from milk thistle (Silybum marianum) inhibit Cyp2c9-mediated warfarin metabolism at clinically achievable concentrations. J. Pharmacol. Exp. Ther. 332, 1081-1087. Morishima, C., Shuhart, M.C., Wang, C.C., Paschal, D.M., Apodaca, M.C., Liu, Y., Sloan, D.D., Graf, T.N., Oberlies, N.H., Lee, D.Y., Jerome, K.R. and Polyak, S.J. (2010) Silymarin inhibits in vitro T cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology 138, 671-681. Alali, F.Q., Gharaibeh, A.A., Ghawanmeh, A., Tawaha, K., Qandil, A., Burgess, J.P., Sy, A., Nakanishi, Y., Kroll, D.J. and Oberlies, N.H. (2010) Colchicinoids from Colchicum crocifolium Boiss. (Colchicaceae). Nat. Prod. Res. 24, 152-159.

 

NIH PubMed Publications for Nicholas Oberlies