compounds synthesized previously in the course of other research programs. Discovery is optimized by scanning as wide a range of structural types as possible (within resource constraints), including compounds found in nature.

Drug discovery has benefited significantly from the study of compounds that organisms have evolved for their own purposes. All of the drugs discovered at the Merck Research Laboratories that became available to patients in the last decade emerged from programs that benefited from knowledge of biological diversity. Some drugs were discovered via natural product screens (2, 3). Others emerged from medicinal chemistry efforts that drew on knowledge such as how the venom of a Brazilian viper lowers blood pressure (4-6). Another program was inspired by a human genetic variation that indicated that a particular enzyme would be a good drug target (7).

SELECTION OF DRUG DISCOVERY TARGETS

A key step in the process of selecting a molecular target for a drug discovery program involves a demonstration that altering the activity of the proposed target should affect the disease. This is illustrated by the choice of the HIV protease as a target. When the HIV genome was sequenced, Asp-Thr-Gly was recognized, based on previous work with other organisms, as a sequence found in aspartyl proteases. Viral-encoded proteases were known to free active proteins from a viral polyprotein precursor. Therefore, it was considered possible that inactivating the proposed HIV aspartyl protease might prevent the formation of viable virus and, thus, that the HIV protease would be an important target for a drug discovery effort (8). To test this hypothesis, a genetic approach was taken to inactivate the aspartyl protease, changing the proposed active site Asp to Asn. This mutation did indeed inactivate the HIV protease; further, mutant HIV, lacking an active protease, was not viable (Figure 1). With this proof of concept in hand, an intensive effort was mounted to find an HIV protease inhibitor. This proof of concept has been reinforced as small molecule inhibitors of the HIV protease have subsequently been found to block the spread of the virus in tissue culture (9).

The search for inhibitors of the HIV protease began with compounds that had been prepared during prior work to inhibit related proteases, notably renin, an aspartyl protease involved in blood pressure regulation (9, 10). While new structures that inhibit the HIV protease have emerged from natural product screens (11, 12) [one structure that inhibits aspartyl proteases, the statine moiety, had been discovered through screening bacterial natural products before the emergence of HIV (10)], the most significant advances in this program have come through an extensive



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