It's Not Just Biochemistry

The field of chemical biology embraces the use of new chemical techniques and approaches to solve biologic problems. An ever-increasing exchange of ideas between chemists and biologists is improving drug discovery. Other fields are likely to benefit, too.

Facing Challenges

The focus of the laboratory of Paramjit Arora, Assistant Professor of Chemistry, New York University, New York, NY, is to design and synthesize structured mimetics of biomolecules, including peptides, nucleic acids, and carbohydrates. Peptidomimetics may be used to regulate protein-protein interactions. “One big challenge in chemical biology is to control these interactions with high specificity,” Arora says. Part of the problem resides in the large surface area that must be targeted, in contrast with the small target size required to interrupt a nucleic acid-protein interaction. “Chemists like to make small molecules,” Arora observes. “They are easy to make and, as drugs, they may have lower side effects [than larger molecules], but they can't disrupt huge surfaces.” Another challenge is to make effective mimetics with well-defined conformations. These molecules will be larger than typical drug molecules, but must be small enough to get into the appropriate cell if they are designed to regulate intracellular processes. The key, says Arora, is to identify the part of the molecule that binds and exerts the desired effect and narrow down the size of the active molecule to be synthesized. Arora's laboratory works on α-helix mimetics, locking peptide chains into helical shapes. Other groups are approaching the problem using nonprotein scaffold molecules to which they add various side chains.

“We have three projects we are pretty excited about,” says Arora. One is blocking the entry of human immunodeficiency virus (HIV) into cells by blocking the envelope glycoprotein gp41. Another project involves synthesizing compounds that will initiate apoptosis, or programmed cell death, by binding to one or more proteins involved in the apoptotic pathway, including p53, mdm2, and bcl-xL. The third project is aimed at controlling the transcription of the gene encoding vascular endothelial growth factor (VEGF), which is implicated in angio-genesis and underlies several disease processes, including tumor survival and age-related macular degeneration, a significant cause of blindness. These projects must overcome additional challenges. Once inside the cell, the molecule has to go to the correct compartment before it can find its target, to mitochondria in the case of apoptotic molecules and to the nucleus in the case of VEGF transcription antagonists. Finally, peptidomimetics must keep their conformation and avoid degradation. Chemical biologists, Arora explains, must try to do as much as possible in one lab, including chemical design and synthesis and preliminary cell culture work. “For us, the bottleneck is going from in vitro data to great in vivo results. Chemists can design great molecules, but nature has made it difficult for these molecules to get into cells.”

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Out of the Depths

William Fenical, Distinguished Professor of Oceanography and Pharmaceutical Sciences, Scripps Institution of Oceanography, University of California, San Diego, CA, is interested in biomedical applications of organic molecules produced by marine organisms. His group has been isolating and defining these molecules and examining their potential to treat disease. “Most people would agree that the discovery of penicillin is one of the most important medical discoveries in the last 100 years,” Fenical observes. “Soil organisms have been recognized as a horn of plenty of new drugs, including antibiotics and immunosuppressants used in organ transplantation.” He points out that although 70% of the earth is covered by oceans, the potential of marine organisms has not been adequately explored. “Our biggest discovery is identifying new genera of bacteria adapted to sea life in both the shallow and deep ocean that are related to but not the same as land organisms. At least 125 drugs used today and thousands of biologically active substances have been isolated from land organisms.” Fenical believes that marine organisms will be a source of new anticancer drugs, new antibiotics, and perhaps new therapeutics for Alzheimer disease, obesity, and other health problems. “The chemical diversity in the ocean is great, so new classes of drugs are possible.” One drug that is in clinical trials in patients with cancer is salinosporamide A, a proteasome inhibitor isolated from the marine bacterium Salinispora tropica, a new marine actinomycete. It appears to have a different mechanism of action from that of the already approved first in class proteasome inhibitor, bortezomib.