Solid Phase Interative Biocatalysis for Drug Discovery

Clark, Douglas

Abstract

application): The identification of new drug candidates and subsequent synthesis of large numbers of new derivatives are crucial, yet time-consuming and expensive, steps in the development of drugs with optimal biological activity. The objective of this two-phase program is the development of solid-phase combinatorial biocatalysis as a new and versatile method for rapidly generating libraries of molecules from which biologically active compounds, such as anticancer agents and other types of drugs, can be obtained.
The specific aims of Phase I are: 1. Attach the anticancer compound doxorubicin to a solid support and implement strategies for enzymatic release of doxorubicin derivatives from the support; 2. Identify enzymes with reactivity against doxorubicin in solution through application of high-throughput screens; 3. Apply existing methods of protease solubilization in organic solvents to different enzyme classes for modification of substrates attached to solid supports; 4. Modify solid-supported doxorubicin using enzymes dissolved in both aqueous and organic media. This research represents a collaboration between EnzyMed, a division of Albany Molecular Research, Inc., in Iowa City, Iowa, and researchers at the University of California Berkeley, and Rensselaer Polytechnic Institute. The focus of Phase I is to develop the basic tools of solid-phase biocatalytic combinatorial chemistry. In Phase II the applicant will expand upon these tools to generate and screen libraries of natural product derivatives for anticancer activity.

Proposed Commercial Applications

The

Proposed Commercial Applications

of solid-phase combinatorial biocatalysis is as a new method for generating pharmaceuticals and other high-value compounds. New doxorubicin derivatives may also have commercial applications as anticancer drugs and as therapeutics against other diseases.