Introduction

Panic Away

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Discovering new drugs has never been a simple matter. From ancient times to the beginning of the last century, treatment for illness or disease was based mainly on folklore and traditional curative methods derived from plants and other natural sources. The isolation and chemical characterization of the principal components of some of these traditional medicines, mainly alkaloids and the like, spawned the development of the modern pharmaceutical industry and the production of drugs in mass quantities. Within the last century, however, the changes the industry has undergone have been profound. As the companion chapters of this volume describe, the emphasis has changed from isolation of active constituents to creation of new, potent chemical entities. This evolution from folklore to science is responsible for the thousands of pharmaceuticals available worldwide at present (1).

1.1 Chemistry-Driven Drug Discovery

The exacting process of discovering new chemical entities that are safe and effective drugs has itself undergone many changes, each of which was prompted by the introduction of some new technology (2, 3). In the 1920s, the first efforts at understanding why and how morphine works in terms of its chemical structure were initiated. During the 1940s, challenges for mass production of medicinally valuable natural products, such as the penicillins, were conquered. By the late 1950s, advances in synthetic organic chemistry enabled the generation of multitudes of novel structures for broad testing into the major focus of the modern pharmaceutical industry. Although serendipitous at best, this approach yielded many valuable compounds, most notably the benzodiazepine tranquilizers chlordi-azepoxide and diazepam (4). Even with these successful compounds, however, the process of drug discovery amounted to little more than evaluating available chemical entities in animal models suggestive of human disease.

By the mid-1960s, medicinal chemistry had clearly become the cornerstone technology of modern drug discovery. Systematic development of structure-activity relationships, even to the point at which predictions about activity might be made, became the hallmark of new drug discovery. Even then, however, an understanding of the actions of drugs at the molecular level was often lacking. Receptors and enzymes were still considered as functional "black boxes" whose structures and functions were poorly understood. The first successful attempts at actually designing a drug to work at a particular molecular target happened nearly simultaneously in the 1970s, with the discovery of cimetidine, a selective H2-antagonist for the treatment of ulcers (5), and captopril, an angiotensin-converting enzyme inhibitor for hypertension (6). The success of these two drugs sparked a realignment of chemistry-driven pharmaceutical research. Since then, the art of rational drug design has undergone an explosive evolution, making use of sophisticated computational and structural methodology to help in the effort (7). During the 1980s, mechanism-targeted design and screening combined to produce a number of novel chemical entities. These include the natural product HMG-CoA reductase inhibitor lo-vastatin for the treatment of hypercholesteremia (8)and the antihypertensive angiotensin II receptor antagonist losartan, synthetically optimized from a chemical library screening lead (9).

There is little doubt that the task of discovering new therapeutic agents that work potently, specifically, and without side effects has become increasingly important and coin-cidentally more difficult. Advances in medical research that have provided new clues to the previously obscured etiologies of diseases have revealed new opportunities for therapeutic intervention. This has forced the science of medicinal chemistry, once founded almost solely in near-blind synthesis and screening for in vivo effects, to become keenly aware of biochemical mechanisms as an intimate part cf the development process. Even with these major advances in the medicinal and pharmaceutical sciences, more fundamental questions remain. What determines a useful biological property? And how is it measured in the discovery process? The answers can determine the success or failure of any drug discovery program, because both the observation of a useful biological property in a novel molecule and the optimization of structure-activity relationships associated with ultimate clinical candidate selection have rightfully relied heavily on practices, and sometimes prejudices, founded in decades of empirical success (10). Although the task of drug development has now been refined into a process without major unidentified obstacles, the challenge to bring the discovery of novel compounds to a comparable state of maturity remains. As in the past, another research avenue synergistic with existing discovery technologies is necessary.

1.2 Advent of Recombinant DNA Technology

The evolution of recombinant DNA technology, from scientific innovation to pharmaceutical discovery process, has occurred in parallel with the development of contemporary medicinal chemistry (11-14). The traditional products of biotechnology research share few of the traits characteristic of traditional pharmaceuticals. These biotechnologically derived therapeutics are large extracellular proteins destined to be, with few exceptions, injectables for use in either chronic replacement therapies or in acute or near-term chronic situations for the treatment of life-threatening indications (15,16). Many of these products also satisfy urgent and previously unfulfilled therapeutic needs. However, their dissimilarity to traditional medicinal agents does not end there. Unlike most low molecular weight pharmaceuticals, these proteins were developed not because of the novelty of their structures, but because of the novelty of their actions. Their discovery hinged on recognition of a useful biological activity, its subsequent association with an effector protein, and the genetic identification, expression, and production of the effector by the application of recombinant DNA technology (17, 18).

If modulation of biochemical processes by a lew molecular weight compound has been the traditional goal of medicinal chemistry, then association of a biological effect with a distinct protein and its identification and production have been considered the domain of molecular genetics. The application of recombinant DNA technology to the identification of proteins and other macromolecules as drugs or drug targets and their production in meaningful quantity as products or discovery tools, respectively, provide an answer to at least one of the persistent problems of new lead discovery. Because a comprehensive review of the genetic engineering of important proteins is well beyond the scope of this volume, this chapter will instead highlight some novel examples of advances in recombinant DNA technology, with respect to both exciting new pharmaceuticals and potential applications of recombi-nantly produced proteins, be they enzymes, receptors, or hormones, to the more traditional processes of drug discovery.

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