SYNTHESIS, ENZYMOLOGY, AND DRUG DESIGN

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The synthesis, Enzymology, and Drug Design section is compromised of the research groups of Drs. Paul Ortiz de Montellano and George Kenyon. These two groups bring expertise in synthetic, mechanistic, enzymological, and medicinal chemistry to the collaborative effort and are responsible for the synthesis of all the compounds that are to be evaluated in this program project. The two groups have specific responsibilities and areas of interest within the program project: that of Dr. Ortiz de montellano is responsible for all chemical aspects of the work on HIV proteases, and that of Dr. Kenyon for studies of the HIV reverse transcriptase and ribonuclease H, and for the development of new technologies for the construction of antisense nucleic acid oligomers. It is likely, furthermore, that the responsibilities of the synthetic groups will expand as the crystal structures of other HIV proteins (e.g., integrase) become available, making them viable targets for the rational design of anti-HIV agents. The two synthetic groups will collaborate with the computation, modeling, and crystallography groups in the development of new approaches for the design and construction of enzyme inhibitors and DNA/RNA targeted agents. Once a candidate agent is defined by these methods, they will be responsible for its chemical synthesis. In addition, the Ortiz de Montellano group will provide chemical assistance to the bioassay group and will collaborate with it in elucidating the mechanisms of action of irreversible HIV protease inhibitors. The Kenyon group will be responsible for bioassays in the DNA/RNA area and will collaborate with several groups in evaluating the biological activities of nucleotide analogues. Although the two synthetic groups have distinct research plans and responsibilities, there is a strong interaction between the two groups. This interaction s promoted not only by their common interest in the development of anti-HIV agents, but also by the fact that their laboratories are adjacent to each other and include a shared laboratory space. This interaction increases the chemical expertise that can be brought to bear to resolve synthetic problems. The detailed research plans of the Ortiz de Montellano and Kenyon groups are presented in separate sections in the following pages.