Chemistry Reference
In-Depth Information
4
Mimicking Enzymes with Antibodies
Donald Hilvert
4.1
Introduction
Enzymes have fascinated chemists and biologists for over a century, as few man-made
agents match the speed or selectivity of these natural catalysts. Although chemical
synthesis and recombinant technologies have made many enzymes available for med-
ical and biotechnological applications, the design of artificial protein catalysts for tasks
unimagined in biology remains a challenging undertaking.
Diverse strategies for creating new enzymes have been explored. One of the most
versatile exploits the mammalian immune system's ability to produce high-affinity
receptor molecules, called antibodies, for a nearly limitless range of ligands. Immune
recognition is based on shape and chemical complementarity between antibodies and
their antigens [1]. As a consequence, immunization with appropriately designed tem-
plate molecules can afford tailored antibody binding sites that exhibit many of the
properties of authentic enzymes, including rate accelerations, substrate specificity,
and regio- and stereoselectivity.
Antibody catalysts have been created for many classes of reaction [2, 3]. In addition to
simple model reactions, transformations for which natural enzymes are unavailable
have been successfully promoted. From a practical standpoint, the exacting control of
reaction pathway and absolute stereochemistry that can be achieved with these agents
is particularly notable. Because genetic and structural information is generally readily
available, these catalysts are also valuable tools for studying how natural enzymes work
and evolve.
This chapter surveys the significant progress made in engineering catalytic antibo-
dies over the last two decades, using a few representative examples to illustrate key
lessons and to highlight some of the challenges still facing this technology. Where
possible, evolutionary and structural aspects are emphasized.
