Research
Research in our lab lies at the interface of chemistry and biology
and addresses multiple aspects of the drug discovery process ranging
from assay development, identification and structure determination of
bioactive small molecules, to studies toward the mechanism of action of
small-molecule drug candidates and the discovery of novel putative drug
targets.
Discovery of Bioactive Marine Natural Products
Most of the current drugs are natural products or derivatives thereof, demonstrating the potential of the natural resources for drug discovery. The structural diversity and biological activity displayed by natural products may be attributed to a long evolutionary selection process. In our quest for small molecules with biomedical utility for various disease indications we mainly scrutinize natural products. In particular, largely unexplored marine microorganisms such as marine cyanobacteria are evaluated as sources of bioactive secondary metabolites. A variety of assays is being implemented in an evolving screening program. Active compounds are isolated using bioassay-guided fractionation and their structures determined using a combination of spectroscopic techniques, predominantly NMR.
Sample Publications:
Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.; Corbett, T. H. “Total Structure Determination of Apratoxin A, a Potent Novel Cytotoxin from the Marine Cyanobacterium Lyngbya majuscula ” J. Am. Chem. Soc. 2001, 123, 5418–5423.
Matthew, S.; Ross, C.; Rocca, J. R.; Paul, V. J.; Luesch, H. “Lyngbyastatin 4, a Dolastatin 13 Analogue with Elastase and Chymotrypsin Inhibitory Activity from the Marine Cyanobacterium Lyngbya confervoides ” J. Nat. Prod. 2007, 70, 124–127.
Mode of Action Studies
Our subsequent endeavor is the characterization of the biological mechanism of action of these agents. Drug target identification and mode of action studies usually represent a bottleneck in drug discovery. The limited abundance of compound available for characterization studies is an additional and fundamental concern in natural products drug discovery. Various genomic, proteomic and metabolomic profiling techniques which require only minute quantities of the bioactive natural products are being evaluated in our lab to gain insight into how the compounds act globally on the molecular and cellular level. Some of the current approaches require synthetic modification and labeling of the parent structure. Genome-wide studies in yeast have proven useful to infer targets and target pathways of bioactive small molecules. These approaches are systematically transferred into more relevant mammalian systems in order to interrogate more complex pathways.
Luesch, H. Mol. BioSyst. 2006, 2, 609–620 (Reproduced by permission of The Royal Society of Chemistry).
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Sample Publications: Luesch, H.; Wu, T. Y. H.; Ren, P.; Gray, N. S.; Schultz, P. G.; Supek, F. “A Genome-Wide Overexpression Screen in Yeast for Small-Molecule Target Identification” Chem. Biol. 2005, 12, 55–63. Luesch, H.; Chanda, S. K.; Raya, R. M.; DeJesus, P. D.; Orth, A. P.; Walker, J. R.; Izpisúa Belmonte, J. C.; Schultz, P. G. “A Functional Genomics Approach to the Mode of Action of Apratoxin A” Nat. Chem. Biol. 2006, 2, 158–167. Luesch, H. “Towards High-Throughput Characterization of Small Molecule Mechanisms of Action” Mol. BioSyst. 2006, 2, 609–620. |
Functional Genomics
In parallel efforts, we are carrying out studies to disclose the function and action of genes/proteins that are putatively involved in cancer, aging and neurodegeneration. Candidate genes identified by high-throughput genome-wide screening are subjected to molecular and biological characterization including structure-function studies in cell- and animal-based models. The ultimate goal is to modulate gene or protein function with small molecules which then could become valuable chemical biology tools or even novel drugs. Our recent focus has been on gene products that modulate oxidative stress levels through activation of the antioxidant response element (ARE). In humans, the ARE regulates the expression of a number of cytoprotective antioxidant enzymes and scavengers which contribute to the endogenous defense against oxidative stress. The activation of the ARE in the absence of general oxidative stress could provide a novel therapeutic approach for the treatment of various neurodegenerative diseases, stroke and aging.
Sample Publication:
Liu, Y.; Kern, J. T.; Walker, J. R.; Johnson, J. A.; Schultz, P. G.; Luesch, H. “A Genomic Screen for Activators of the Antioxidant Response Element” Proc. Natl. Acad. Sci. USA 2007, 104, 5205–5210.
