Tel:	617-432- 2845
	Fax:	617-738- 3702
	E-Mail:	jon_clardy@hms.harvard.edu
	Location:	Room C-643 240 Longwood Avenue Boston MA 02115
	Homepage:	http://clardy.med.harvard.edu/

With an overall goal of understanding how small molecules control biological processes, the laboratory focuses on biologically active small molecules, especially those known as natural products, and their interactions with larger molecules. Projects can be divided into three groups: 1) discovery of biologically active small molecules using DNA-based approaches, 2) discovery of biologically active small molecules using high-throughput screening and chemical analysis, and 3) insight into how small molecules function as carriers of biological information.

1. A major focus of the laboratory is discovering new biologically active natural products using DNA-based approaches. Many of the most powerful drugs used today have come from microbes living in soil. Today studies on soil microbes increasingly lead to the rediscovery of known molecules. Several lines of evidence suggest that only a tiny fraction (certainly less than 1%) of the microbes that live in soil can be cultured by known techniques. Our laboratory has developed ways to capture the biologically active small molecules made by these uncultured microbes. We extract DNA directly from the environment (eDNA) and uses heterologous expression in readily cultured organisms to access small molecules. This process has yielded new molecules, new biosynthetic pathways, and new microbial biology that form the basis for individual projects.

2. We are also committed to the isolation and structure determination of biologically active small molecules discovered by high throughput screening at ICCB/ICG. One current project involves finding new agents to treat protozoal infections such as malaria and African sleeping sickness. The lab emphasizes phenotypic screens to find new targets, but there are also studies directed towards validated targets with no effective therapeutic agents.

3. The laboratory also studies biologically active small molecules in their natural, as opposed to therapeutic, context, and the small molecules that serve as biological information carriers are of special interest. One project asks how the sex pheromones of moths, apparently simple molecules, evoke biological responses with amazing potency and specificity. Other projects examine the perception of population density by fungi and C. elegans .

References:

Sinars, C.R., Cheung-Flynn, J., Rimerman, R.A., Scammell, J.G., Smith D.F., Clardy, J. 2003. Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes. Proc. Natl. Acad. Sci. USA 100:868-298.

Jin, M., Liu, L., Wright, S.A.I., Beer, S.V., Clardy, J. 2003. Structural and functional analysis of pantocin A, an antibiotic from Pantoea agglomerans discovered by heterologous expression of cloned genes. Angew. Chem. Int. Ed. 2003, 42:2898-2901.

Kau, T.R., Schroeder, F., Ramaswamy, S., Wojciechowski, C.L., Zhao, J.J., Roberts, T.M., Clardy, J., Sellers, W.R., Silver, P.A. A chemical genetic screen identified inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 2003 6:463-76 .

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