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The Skaggs Institute for Chemical Biology

Julius Rebek, Jr., Ph.D., Chairman

uring the last two decades, scientists have begun to understand the molecular basis of disease in terms of malfunctioning protein and nucleic acid molecules. This has resulted in new therapies, small molecule drugs that are specifically directed to correcting the malfunctioning molecules. However, long before such drugs can be designed, specific questions need to be answered for each disease: Where are the malfunctioning molecules? What are their structures? How do they operate? Can we make drugs to influence them? If so, how do the drugs and the targets interact? These questions bring together the disciplines of structural biology, cellular biology, catalysis, organic synthesis, and molecular recognition -- the range of disciplines investigated by researchers at The Skaggs Institute for Chemical Biology.

The institute was established in 1996, made possible by a commitment of $100 million from Aline and L.S. Skaggs through the Skaggs Institute for Research and their family foundation, the ALSAM foundation. In the last five years, Skaggs investigators have determined the structures and functions of many proteins and nucleic acids, particularly those involved in cancer and diseases of the immune system; they have invented new methods for the synthesis of small and large molecules; and they have discovered new catalysts for chemical reactions of interest to medicinal chemistry.

WINNER OF THE NOBEL PRIZE

This year, those at the institute celebrated the award of the 2001 Nobel Prize in Chemistry to one of its members, K. Barry Sharpless, Ph.D. Sharpless was given the prize for his development of methods for the selective synthesis of chiral molecules. Chirality is the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image -- its right- or left-"handedness." Proteins, DNA, and carbohydrates are all chiral molecules: without the correct handedness, they will not function as the basic molecules of life. Many drugs must also be of correct chirality; indeed, in some cases, the molecules with the wrong chirality can be toxic.

In 1980, Sharpless reported a breakthrough in synthesizing chiral molecules with a method that is now used routinely, and he has since developed other methods that have revolutionized organic chemistry by transforming asymmetric synthesis from nearly impossible to routine. Sharpless's methods allow for the manufacture of safer and more effective antibiotics, anti-inflammatory drugs, heart medicines, and agricultural chemicals because they allow chiral forms to be synthesized selectively, rather than separated later.

Several Skaggs investigators synthesize molecules that may have the potential to be used in the clinic. Two members of The Skaggs Institute, K.C. Nicolaou, Ph.D., and Dale Boger, Ph.D., have, together with their research teams, successfully completed the total synthesis of vancomycin, which acts as the last line of defense against life-threatening antibiotic-resistant infections.

The last decade has seen the emergence of a strain of Staphylococcus aureus that is resistant to vancomycin's mode of action, in which the molecule binds to the cell wall of a bacteria and arrests its growth. Staphylococcus aureus's resistance involves a subtle, single-atom change in the components of the growing cell wall. The resistance is encoded in the DNA of the organism and this DNA is mobile -- it can be passed from one bacterial cell to another, similar to the way in which penicillin resistance spreads. Researchers at The Skaggs Institute are positioned to overcome this resistance. Boger's group is making the complementary changes on the synthetic vancomycin, hoping to restore the binding to the bacterial cell wall and overcome the resistant bacteria's defense.

Nicolaou's lab is taking a different approach to overcoming antibiotic resistance. Using the methods known as combinatorial chemistry, a large number of vancomycin-like molecules are being prepared and screened for antibiotic activity in a short time.

Another member of The Skaggs Institute, Chi-Huey Wong, Ph.D., has also used the combinatorial technique to overcome bacterial resistance. By binding two molecules of the aminoglycoside antibiotic family to each other at different distances, he has made molecules that show potent activity against infectious organisms.

New treatments for pain, especially chronic pain syndromes, are desperately needed. The research group of Benjamin Cravatt, Ph.D., is dedicated to identifying, characterizing, and validating new targets for the treatment of chronic pain. Opioid-based molecules like morphine are effective for treating acute pain following injury, but this approach has failed to provide relief from persistent pain that results from neural damage and/or chronic inflammation. These clinical shortcomings arise because the human receptors -- the targets of opioid drugs -- become unresponsive or desensitized in situations of persistent pain, and morphine and related opioid-based therapeutics are addictive. The Cravatt group has recently determined that the brain enzyme fatty acid amide hydrolase (FAAH) is a novel target for the treatment of pain.

Members of the Cravatt lab isolated and genetically manipulated the key proteins involved in neural pain pathways and showed that FAAH is responsible for regulating the levels and activities of a family of neural signaling molecules called fatty acid amides. When these fatty acid amides are present, pain sensations are reduced. Cravatt's group found that if one eliminates FAAH, fatty acid amides accumulate naturally and signal to reduce pain without affecting motility or cognition systems. These exciting results argue that chemical inhibitors of FAAH may provide the much sought-after relief of chronic pain without inducing addiction (as seen with opioids) or motility/cognitive defects (as seen with marijuana).

BLOCKING COCAINE TO FIGHT ADDICTION

The Skaggs Institute currently has one potential therapy scheduled to go into human clinical trials. Licensed by Drug Abuse Sciences of Mountain View, CA, the antibody was developed by the laboratory of Kim Janda, Ph.D., as a vaccine to prevent cocaine from reaching the brain.

Normally, brain levels of cocaine rise rapidly once it is taken into the system. The drug accumulates in the ventral tegmental area of the brain, which is connected by nerve cells to the nucleus accumbens, the brain's so-called pleasure center. There, the cocaine molecules interfere with the normal regulation of dopamine by binding to dopamine transporters and blocking them from recycling the neurotransmitter. This produces a euphoric feeling in the user -- a quick rush that hits seconds after taking the drug and lasts several minutes. These vaccines suppress this euphoria and, therefore, the reinforcing aspects of the drug.

Interestingly, unlike other types of treatment, the vaccines developed by the Janda lab do not interfere with the neurological targets of the drug, but instead help the body keep cocaine from ever reaching the brain. The vaccines do this by inducing an active immune response that creates antibodies against cocaine in the bloodstream. If an addict later takes a hit, the antibodies will clear the cocaine from the system.

These examples show how understanding the scientific underpinnings of a medical problem can lead to therapies. Many of these scientists' projects represent radically new ways of thinking and could not have drawn support from traditional funding sources.

The Skaggs Institute also seeks to provide a nurturing environment for the next generation of research scientists. To further this goal, the institute has established the Skaggs Predoctoral Fellows Program and the Skaggs Postdoctoral Fellows Program. The Skaggs Fellowships were created to grant financial support, further the careers of young men and women at TSRI, and provide tomorrow's leaders in drug development. Awards will be given to the best and brightest students who show outstanding promise in chemical biology research as it relates to human health.