Overview

The nascent field of chemical biology employs small molecules to study the biology of disease. Scientists are using the methods of chemical biology to understand the principles that underlie cell activity, and, ultimately, to develop new pharmaceuticals and therapies.

The breadth of topics presented by seven researchers during a symposium hosted by the Hunter College Center for Study of Gene Structure and Function reveals just how expansive the field of chemical biology has become. Topics ranged from how RNA interference could be used to prevent HIV infection, to how traditional healers in the Amazon concoct a termite-derived Viagra-like compound, to how a private company is using a new technology platform to redesign chemical entities to interact more flexibly with a diseased system.

Use the tabs above to find a meeting report and multimedia from this event.

 


Sponsorship

The Gene Center is supported by the Research Centers in Minority Institutions program of the National Center for Research Resources, at the National Institutes of Health on grant number G12 RR-03037.

Web Sites

Schreiber laboratory homepage
Includes links to recent articles describing his work in The Scientist, Drug Discovery Today, Molecular Cell, and Chemical & Engineering News as well as streaming video from several lectures.

ChemBank
A freely available collection of data about small molecules and resources for studying their properties, especially their effects on biology. It is being developed to assist biologists who wish to identify small molecules that can be used to perturb a particular biological system and chemists designing novel compounds or libraries, and to serve as a source of data for cheminformatic analyses.

What is Chemical Genetics?
As defined by the Howard Hughes Medical Institute's Biointeractive website.

ICCB-CGI
The homepage of the Initiative for Chemical Genetics at the Harvard Medical School Institute of Chemical and Cell Biology.

Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery
PDF of a review article by Stuart Schreiber that appeared in March 17, 2000 edition of Science describing diversity-oriented synthesis for drug discovery.

Cornell University Plant Biology Department homepage
Includes links to the L.H. Bailey Hortorium, which hosts an 845,000-specimen herbarium.

EsBaran Field Station
The home page of the Amazonian research station directed by Eloy Rodriguez dedicated to education, conservation, and the discovery of novel medicinal compounds from applied field chemoecology.

Biodiversity and Biological Collections Web Server
Devoted to information of interest to systematists and other biologists of the organismic kind. Hosted by Julian Humpheries at the University of New Orleans, it includes information about specimens in biological collections, taxonomic authority files, directories of biologists, reports by various standards bodies, an archive of the Taxacom, MUSE-L and CICHLID-L listservs, and access to online journals.

Medicinal Plants page of the Environmental and Natural Resource Management project
Hosted by the Canadian International Development and Research Center, which supports research projects, networks, and other activities on medicinal plants and natural products in Asia, Africa, and Latin America and the Caribbean. Program initiatives include one on the Sustainable Use of Biodiversity Ecosystem Approaches to Human Health Small, Medium, and Micro Enterprise Innovation and Technology.

American Botanical Council's Medicinal Plant Information page
Hosts links to numerous database and plant research information resources.

The World of Kampo
Information about traditional Japanese traditional herbal medicine and a link to Kampo Today, an English-language periodical devoted to Kampo and Kampo therapeutics.

Lieberman laboratory homepage

RNAi News
Weekly paid subscription newsletter of RNAi technology, research, and business.

RNAi Net
Free news and features about RNAi technologies and research.

siRNA Patents
Website hosted by patent holder the Massachusetts Institute of Technology, with contact information for licensing siRNA technology.

Silencing Genes in HIV
Article describing the work of Judy Lieberman and others in applying RNAi to the suppression of HIV.

Cravatt laboratory homepage

Surface Logix homepage

Whitesides Research Group
Homepage of the lab that developed the technology behind Surface Logix platform technology.


Books

F. Darvas, Guttman, A. & Dorman, G., Eds. 2004. Chemical Genomics. Marcel Dekker, New York, NY.

C. M. Dobson, Gerrard, J. A. & Pratt, A.J. 2002. Foundations of Chemical Biology. Oxford University Press, Oxford, UK.

D. Engelke. 2004. RNA Interference (RNAi): The Nuts & Bolts of siRNA Technology. DNA Press, Eagleville, PA.

G. Hannon. 2003. RNAi: A Guide to Gene Silencing. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

H. Waldmann, & Janning, P. 2004. Chemical Biology: A Practical Course. John Wiley & Sons, Hoboken, NJ.


Journal Articles

The Current State of Chemical Genetics

P. R. Andreana, Liu, C. L., & Schreiber, S. L. Stereochemical control of the Passerini reaction. Org. Lett. 6: 4231-4233. Full Text

S. Schreiber. 2004. Q & A: Stuart L. Schreiber. Curr. Biol. 14: R292-R293. Full Text

B. E. Bernstein, Humphrey, E. H., Liu, C. L. et al. 2004. The use of chromatin immunoprecipitation assays in genome-wide analyses of histone modifications. Methods Enzymol. 376: 350-361. Full Text

B. E. Bernstein, Kamal, M., Lindblad-Toh, K. et al. 2005. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120: 169-181.

B. E. Bernstein, Liu, C. L., Humphrey, E. H. et al. 2004. Global determinants of nucleosome occupancy in yeast. Genome Biol. 5: R62. Full Text | Supplementary Data

M. D. Burke, Berger, E. M. & Schreiber, S. L. 2004. A synthesis strategy yielding skeletally diverse small molecules combinatorially. J. Am. Chem. Soc. 126: 14095-14104. Full Text

M. D. Burke, & Schreiber, S. L. 2004. A planning strategy for diversity-oriented synthesis. Angew. Chemie Int. Ed. Engl. 43: 46-58. Full Text

R. A. Butcher, & Schreiber, S. L. 2004. Identification of Ald6 as the target of a class of small molecule suppressors of FK506 and their use in network dissection. Proc. Natl. Acad. Sci. USA 101: 7868-7873. Full Text

S. J. Haggarty, Wong, J. C., Clemons, P. A. et al. 2004. Mapping chemical space using molecular descriptors and chemical genetics: deacetylase inhibitors. Comb. Chem. High Throughput Screen. 7: 669-676. Full Text

J. Huang, Zhu, H., Haggarty, S. J. et al. 2004. Finding new genetic modifiers of the target-of-rapamycin (TOR) signaling pathway through chemical genetics and proteome chips. Proc. Natl. Acad. Sci. USA 101: 16594-16599. Full Text

E. L. Humphrey, Shamji, A. F., Bernstein, B. E. et al. 2004. Rpd3p relocation mediates the transcriptional response to rapamycin in yeast. Chem. Biol. 11: 295-299. Full Text | Supplementary Data

Y.-K. Kim, Arai, M. A., Arai, T. et al. 2004. Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space. J. Am. Chem. Soc. 126: 14740-14745. Full Text

S. Krishnan, & Schreiber, S. L. 2004. Syntheses of stereochemicaly diverse nine-membered ring-containing biaryls. Org. Lett. 6: 4021-4024. Full Text

M.M.-C. Lo, Neumann, C. S., Nagayama, S. et al. 2004. A library of spirooxindoles based on a stereoselective three-component coupling reaction. J. Am. Chem. Soc. 126: 16077-16086. Full Text

P. Nghiem, Kim, Y.-S. & Schreiber, S. L. 2004. Protein kinases as targets in cancer therapy: validated and emerging approaches. In C. Brenner and Duggan, D., Eds.: 293-315. Oncogenomics: Molecular Approaches to Cancer. John Wiley & Sons, Hoboken, NJ.

H. Oguri, & Schreiber, S. L. 2005. Skeletal diversity via a folding pathway: synthesis of indole alkaloid-like skeletons. Org. Lett. 7: 47-50. Full Text

R. T. Peterson, Shaw, S. Y, Peterson, T. A. et al. 2004. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat. Biotechnol. 22:595-599. Full Text

D. R. Schmidt, Kwon, O. & Schreiber, S. L. 2004. Macrolactones in diversity-oriented synthesis: preparation of a pilot library and exploration of factors controlling macrocyclization. J. Comb. Chem. 6: 286-292. Full Text

S. Schreiber. 2001. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287: 1964-1969. Full Text

S. J. Taylor, Taylor, A. M. & Schreiber, S. L. 2004. Synthetic strategy toward skeletal diversity via solid-supported, otherwise unstable reactive intermediates. Angew. Chemie Int. Ed. Engl. 43: 1681-1685. Full Text

J. C. Wong, Sternson, S. M., Louca, J. B. et al. 2004. Modular synthesis and preliminary biological evaluation of stereochemically and skeletally diverse 1,3-dioxanes. Chem. Biol. 11: 1279-1291. Full Text

Engineering Biosynthetic Pathways for Natural Products to Generate Novel Antitumor Derivatives

C. Méndez & Salas, J. A. 2001. Altering the glycosylation pattern of bioactive compounds. Trends Biotechnol. 19: 449-456.

C. Mendez & Salas, J. A. 2005. Engineering glycosylation in bioactive compounds by combinatorial biosynthesis. Ernst Schering Res. Found. Workshop 51: 127-46.

C. Méndez, Weitnauer, G., Bechthold, A. et al. 2000. Structure alteration of polyketides by recombinant DNA technology in producer organisms—prospects for the generation of novel pharmaceutical drugs. Curr. Pharmaceutical Biotechnol. 1: 355-395.

J. A. Salas & Méndez, C. 1998. Genetic manipulation of antitumor-agent biosynthesis to produce novel drugs. Trends Biotechnol. 16: 475-482.

Biomedicinal Chemistry of Tropical Small Molecules with Life-Altering Activities

Aregullin, M. & E. Rodriguez. 2000. Hydrophyllaceae. In J. Avalos, & Maibach, H., Eds.: 187-199. Dermatological Botany. CRC Press LLC, Boca Raton, FL.

Berry, J., McFerren, M. & Rodriguez, E. 1996. Zoopharmacognosy. A biorational approach to chemical prospecting. In D. Gustine, & Flores, H., Eds.: Phytochemicals in Health. Pennsylvania State University Press, University Park, PA.

Freeman, F., M. Aregulin & E. Rodriguez. 1993. Naturally occurring 1,2-dithiins. Rev. Heteroatom Chem. 9: 1-15.

Rodriguez, E. & J. West. 1994. The tropical rain forest: a rich source of natural medicines. Proceedings of the NIGMS-NIH Symposium, Atlanta, Georgia.

Rodriguez, E. & R. Wrangham. 1993. Zoopharmacognosy: the use of medicinal plants by animals. In H. Stafford, & Downum, K., Eds.: 89-105. Recent Advances in Phytochemistry. Plenum Press, New York, NY.

Activity Based Protein Profiling for Proteomics

G. C. Adam, Burbaum, J., Kozarich, J. W. et al. 2004. Mapping enzyme active sites in complex proteomes. J. Am. Chem. Soc. 126: 1363-1368. Full Text

K. T. Barglow, & Cravatt, B. F. 2004. Discovering disease-associated enzymes by proteome reactivity profiling. Chem. Biol. 11: 1523-1531. Full Text

N. Jessani, & Cravatt, B. F. 2004. The development and application of methods for activity-based protein profiling. Curr. Opin. Chem. Biol. 8: 54-59. Full Text

N. Jessani, Humphrey, M., McDonald, W. H. et al. 2004. Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo. Proc. Natl. Acad. Sci. USA 101: 13756-13761. Full Text

A. Saghatelian, Jessani, N., Joseph, A. et al. 2004. Activity-based probes for the proteomic profiling of metalloproteases. Proc. Natl. Acad. Sci. USA 101: 10000-10005. Full Text

S. A. Sieber, Mondala, T. S., Head, S. R. et al. 2004. Microarray platform for profiling enzyme activities in complex proteomes. J. Am. Chem. Soc. 126: 15640-15641. Full Text

A. E. Speers, & Cravatt, B. F. 2004. Profiling enzyme activities in vivo using click chemistry methods. Chem Biol. 11: 535-546. Full Text

A. E. Speers, & Cravatt, B. F. 2004. Chemical strategies for activity-based proteomics. Chembiochem 5: 41-47. Full Text

Harnessing RNA Interference for Therapy

J. Lieberman & Dykxhoorn, D. 2005. The Silent Revolution: RNA interference as a basic biology research tool and therapeutic. Ann Rev Med 401-423. [PDF]

C.D. Novina, Murray, M.F., Dykxhoorn, D.M., et al. 2002. siRNA-directed inhibition of HIV-1 infection. Nature Med 8:681-686.

E. Song, Lee S.-K., Wang J., et al. 2003. RNA interference targeting fax protects mice from fulminant hepatitis. Nature Med 9:347-351.

E. Song, Lee S.-K., Dykxhoorn D.M., et al. 2003. Sustained Small Interfering RNA-Mediated Human Immunodeficiency Virus Type 1 Inhibition in Primary Macrophages. J Virol 77:7174-7181. Full Text

P. Hamar, Song E., Kokeny G., et al. 2004. Short interfering RNA targeting Fas protects mice against renal ischernia-reperfusion injury. Proc Natl Acad USA 101:14883-14888.

J.Lieberman. 2003. Shooting the Messenger: Harnessing RNA Interference to Combat HIV Infection. Summary by Tim Horn; edited by Veronica Miller. The PRN Notebook 8:11-14.

J. Lieberman, Song E., Lee S.-K. & Shankar P. 2003. Interfering with disease: Opportunities and roadblocks to harnessing RNA interference. Trends Mol Med 9:397-403.

E. Song, Stern P., Palliser D., et al. 2004. RNA Interference in Animal Models. In M Sohail, editor. Gene Silencing by RNA Interference: Technology and Application, London: CRC Press.

P. Shankar & Lieberman J. 2005. RNAi and HIV: from here to therapy. In S. Butera, ed. HIV Chemotherapy: A Critical Review. Horizon Scientific Press. In press.

D. Dykxhoorn & Lieberman J. 2005. The Silent Revolution: RNA interference as basic biology, research tool and therapeutic. Ann Rev Med 56:401-423.

P. Shankar, Manjunath N. & Lieberman J. 2005. The Prospect of Silencing Disease Using RNA Interference. JAMA 293:1367-1373.

Keynote Speaker

Stuart L. Schreiber, PhD

Harvard University
email | web site | publications

Stuart L. Schreiber is an investigator at the Howard Hughes Medical Institute and is Morris Loeb Professor and chair of the department of chemistry and chemical biology at Harvard University. He is a founder and director of the Harvard Institute of Chemistry and Cell Biology (ICCB) and of its affiliated, National Cancer Institute-sponsored Initiative for Chemical Genetics, and a member of the faculty of the Broad Institute, a joint initiative of Harvard University and the Massachusetts Institute of Technology. He is also a member The Rockefeller University Board of Trustees.

Schreiber earned a PhD in organic chemistry at Harvard University before joining the faculty at Yale University in May of 1981. He returned to Harvard in 1988. He is known for having developed systematic ways to explore biology, especially disease biology, using small molecules (precursors to therapeutic drugs that are used as bioprobes) and for his role in the development of the field of chemical biology. Using his chemical approach, he has discovered principles that underlie information transfer and storage in cells.

He is a member of the National Academy of Sciences and the American Academy of Arts & Sciences and is a founder of several successful biotechnology firms, including Vertex Pharmaceuticals, ARIAD Pharmaceuticals, and Infinity Pharmaceuticals. To facilitate sharing of information derived from small molecules, Schreiber and the ICCB launched the online public database ChemBank in 2003.


Speakers

Benjamin F. Cravatt, PhD

The Scripps Research Institute
email | web site | publications

Benjamin F. Cravatt is a professor at the Skaggs Institute for Chemical Biology and the departments of cell biology and chemistry at The Scripps Research Institute, where he directs a research group that develops and applies an array of biochemical, chemical, and genetic technologies to elucidate the roles of enzymes in physiological and pathological processes, especially as pertains to the nervous system and cancer. Cravatt's research group has obtained fundamental insights into the chemical, biochemical, and physiological workings of several important mammalian serine hydrolases, including enzymes involved in the neurobiology of pain and in proteases associated with tumor progression.

Cravatt received a PhD in macromolecular and cellular structure and chemistry from The Scripps Research Institute in 1996. His honors include a graduate fellowship from the National Science Foundation (1992-1995), a Searle Scholar Award (1998-2001), a Technology Review's TR100 Top 100 Young Innovators Award (2002), the Promega Award for Early Career Life Scientists from the American Society for Cell Biology (2002), the Eli Lilly Award in Biological Chemistry (2004), and a Cope Scholar Award (2005).

Akira Kawamura, PhD

Hunter College, CUNY
email | web site | publications

Akira Kawamura received his BS and MS degrees in organic chemistry under the guidance of Kazuo Tachibana at the University of Tokyo, where he worked on the isolation and biochemical characterization of shark-repelling substances from the Moses sole flat fish. Kawamura received his PhD in chemistry from Columbia University under the direction of Koji Nakanishi and Nina Berova in 1999 for his microscale structural analyses on sphingolipids, brassinosteroids, and endogenous ouabain.

Before joining Hunter College as an assistant professor, Kawamura spent his postdoctoral stint in the group of Peter G. Schultz at the Scripps Research Institute, where he conducted genomic profiling of natural products and various biological systems, including angiogenesis, cellular density arrest, and hypertension from 1999 to 2002.

Judy Lieberman, MD, PhD

CBR Institute for Biomedical Research, Harvard Medical School
email | web site | publications

Judy Lieberman, senior investigator at the Harvard Medical School Center for Blood Research and professor in pediatrics, received her PhD in theoretical physics at Rockefeller University and an MD in the joint Harvard-Massachusetts Institute of Technology Program in Health, Science and Technology. She trained in internal medicine and hematology/oncology at New England Medical Center, and learned about T cell immunology in the laboratory of Herman Eisen in the Center for Cancer Research at MIT.

Lieberman's laboratory studies cytotoxic T lymphocytes (CTLs), key cells in the immune defense against viral infection and cancer, and their role in antiviral immunity. A major focus is studying the molecular pathways used by CTLs to induce cell death. Lieberman and her coworkers have identified a novel caspase-independent apoptotic pathway induced by the CTL protease granzyme A. Other work centers on understanding how CTL function is regulated.

Her laboratory has been characterizing the CTL response to HIV-1, the virus that causes AIDS, and trying to understand why it does not ultimately control the virus. She is also working to develop an oral HIV vaccine using Listeria monocytogenes as a vector. Her interest in HIV led to recent work on harnessing RNA interference (RNAi) to suppress HIV infection. Her laboratory is working on translating RNAi for therapeutic use against HIV and other indications. She was the first to demonstrate in an animal model that RNAi could protect animals from disease.

Carmichael S. Roberts, PhD

Surface Logix, Inc.
email | web site

Carmichael C. Roberts is cofounder and president of Surface Logix, Inc., a drug optimization company focused on combining proprietary small-molecule chemistries with known biologically relevant pharmacophores to create new chemical entities with improved pharmacodynamic and pharmacokinetic properties. Previously, Roberts worked in business development at GelTex Pharmaceuticals, which was acquired by Genzyme, where he designed business development strategies for a preclinical product line for infectious disease and obesity.

Roberts received a PhD in organic chemistry from Duke University and was a National Science Foundation Fellow at Harvard University's department of chemistry and chemical biology under Professor George Whitesides. He holds an MBA from the Massachusetts Institute of Technology Sloan School of Management.

Eloy Rodriguez, PhD

Cornell University
email | web site | publications

Eloy Rodriguez describes himself as "a biological chemist interested in the organic chemistry of natural drugs from plants, insects, and fungi." He is the James A. Perkins Professor of Environmental Studies at Cornell University where he specializes in the chemical properties of tropical and desert plants. He developed and directs both the Punta Cana Cornell Biodiversity Center in the Dominican Republic and the university's EsBaran Amazon Field Station and Laboratory in Peru. Since 2000 he has also been associate director of the Cornell's Weill Medical College Center for Complementary and Integrative medicine, located in New York City.

Rodriguez, with Richard Wrangham of Harvard, is known for establishing the field of and coining the term zoopharmacognosy, the study of animals' observed ability to self-medicate and to protect themselves from disease. He earned a doctorate in phytochemistry and plant biology from the University of Texas at Austin in 1975. His past positions include professor in the School of Medicine and departments of developmental cell biology and ecology and evolutionary biology at the University of California at Irvine. He has published more than 155 articles and two books on a wide variety of topics in plant chemistry.

Jose A. Salas, PhD

University of Oviedo
email | web site | publications

Jose A. Salas is a professor of microbiology at the University of Oviedo in Spain, where he obtained his PhD in 1980 by conducting studies of cell differentiation in Streptomyces. His postdoctoral work in the UK at the University of Cambridge and the University of Leicester looked at molecular resistance mechanisms in antibiotic-producing actinomycetes.

Salas heads a group of 20 scientists focused on the isolation and characterization of antibiotic and antitumor biosynthesis gene clusters. The group, which aims to engineer these biosynthetic pathways to generate novel derivatives with potential clinical application, has published more than 120 papers and filed 10 patents based on scientific discoveries.


Adrienne Burke

Adrienne Burke is founder of Genomic Society Consulting, which provides market research and communications services to the life sciences industry. She has been a science and health journalist since 1993. She was the founding editor-in-chief of Genome Technology magazine and editorial director of GenomeWeb.com. She also served as editor-in-chief of BioInform, a weekly newsletter for the bioinformatics industry, and oversaw launches of the newsletters ProteoMonitor and Agricultural Genomics. Earlier, she was a managing editor of a magazine for occupational health professionals.