Progress in Designing Small Inhibitors which Discriminate among Trypsin-Like Enzymes

Abstract

Affinity labelling has provided an approach to the labelling of the active centers of enzymes which has been of value in protein chemistry [1]. At the same time, it has been appreciated that this approach is also of promise as a means of devising new chemotherapeutic agents [1, 2]. The useful application of affinity labelling in drug design depends, of course, on the recognition of suitable target enzymes. The increasing number of trypsin-like enzymes of physiological importance (Table 1) provides some opportunities for chemotherapy that have already been recognized for some time. The group includes, in addition, other members whose suitability as target enzymes for therapeutic inactivation remains to be demonstrated. Not only are these enzymes similar to trypsin in specificity but several have now been shown to be homologous in sequence (Table 1) and we can conclude that these have a common three-dimensional structure in the active center region. Ultimately this may prove to be true of the whole group. If the active center regions are identical, it would appear very difficult to achieve selective inactivation of one of these enzymes by a small molecule affinity label. However, I shall show several examples of selective action which indicate that the pessimism expressed, for example, by Baker [3] is not justified.

Research carried out at Brookhaven National Laboratory under the auspices of the U.S. Atomic Energy Commission.