An amino acid created in the laboratory of a UC Irvine chemist holds the potential of aiding research for new drugs that can regulate the activity of molecules involved with cancer, HIV and neurodegenerative diseases such as Alzheimer's.

James Nowick, UCI professor of chemistry, working with UC Davis cancer researcher Kit S. Lam, has created an amino acid building block that can be attached to small protein strands called peptides to make them fold into beta-sheet structures. Beta-sheets are ribbon-like elements in proteins that initiate many key molecular interactions identified with disease, as well as with normal protein function. The findings appeared in the May 8 issue of the Journal of the American Chemical Society.

"When our amino acid is incorporated into peptides, the peptides participate in the same types of beta-sheet interactions that the proteins involved in these diseases participate in," Nowick said. "By studying the interactions of peptides containing our amino acid, we hope to learn more about the protein interactions and to ultimately learn how to develop compounds that control these interactions. Thus, our amino acid may eventually serve as the basis for developing new drugs to control these diseases."

This new amino acid, Orn(i-PrCO-Hao), attaches to a peptide like a splint, hydrogen bonding to the amino acids to form a beta-sheet. A vital component of this new amino acid is the synthetic molecule Hao, which the Nowick lab created in order to introduce the hydrogen-bonding capabilities of a beta-sheet in peptides. Nowick published his Hao findings in the Aug. 15, 2000, issue of the Journal of the American Chemical Society.

In this earlier work, the Nowick laboratory established that Hao acted like a prosthetic when placed into peptides, replacing three amino acids and inducing beta-sheet interactions. In the new amino acid, the Nowick team discovered that they could make the Hao amino acid act like a splint, rather than a prosthetic, by combining it with the amino acid ornithine. This combination of the two amino acids serves to rigidify a peptide without replacing a big segment of it, thus allowing the peptide to better resemble a natural protein. A particularly attractive feature of the Orn(i-PrCO-Hao) amino acid is that it is capable of attaching onto any peptide, making it particularly versatile.

Beta-sheets are integral parts of complex protein structures and are involved with many key protein interactions. However, when the protein is either mutated or part of a viral or bacterial agent, these same beta-sheet interactions can be involved in disease.

In HIV, for example, beta-sheet interactions are integral in the assembly of key enzymes essential for the life cycle of the virus. Blocking these beta-sheet interactions can stop the assembly of the enzyme and renders it inactive. "One possible approach of anti-HIV drugs is to block this enzyme assembly," Nowick added. "It's not the only approach one can take, but it's an alternative approach to existing HIV drugs."

In cancer, Nowick points to beta-sheet interactions of oncoproteins. Beta-sheet interactions between oncoproteins and an enzyme are involved in normal cell growth and proliferation. But when a mutation in the oncoprotein occurs, this interaction ceases to work properly, inducing a proliferation of molecules that triggers cancerous growth. So the development of a beta-sheet modulating drug specifically for the mutant oncoprotein could block this proliferation.

"The work is of unusual urgency, significance and interest, because beta-sheet folding and interactions are fundamentally important, as well as a vital research topic, yet there are essentially no amino acids that induce beta-sheet folding and interactions in peptides," Nowick said. "Our interest is developing molecules involved with well-defined beta sheet interactions. By understanding these interactions and learning how to control them, then ultimately the tools for creating new drugs can be developed."

Tatyana V. Khasanova, William E. Kemnitzer, Santanu Maitra and Hao T. Mee of UCI and Ruiwu Liu of UC Davis assisted Nowick and Lam in the study. The National Institutes of Health and the National Science Foundation supported the research.