Active drug targeting

Proguanil appears to have a dual activity. Part of it is metabolized to cycloguanil, which subsequently inhibits the protozaon dihydrofolate reduc-tase/thymidylate synthase (DHFR/TS) (Fig. 4). In addition, the native form, proguanil itself, exerts a potent antimalarial activity, especially in combination with other antimalarial drugs. The target of proguanil is unknown. 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

L. Ilium and S. S. Davis, Passive and active targeting using colloidal carrier systems, in Drug Targeting (P. Buri and A. Gumma, eds.), Elsevier Science Publishers, Amsterdam, 1985, p. 65. 

FIGURE 1 Selection of the HIV protease as a drug discovery target. Demonstration that inactivation of the HIV protease interferes with HIV infectiv-ity. Immunoblot of HIV proteins in mock-transfected cells (lane 1), cells transfected with HIV containing active protease (lanes 2 and 4), and cells transfected with HIV in which the protease was inactivated. Reprinted with permission from ref. 8 (copyright Kohl et al). 

The impact of the in vitro screens applied to each stage in the drug discovery process will be different. The optimal set of assays at the early stages should assess drug activity against a small number of targets that play a key role in the function of core physiological systems. 

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