Searching Adaptive Space

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Science  11 Jul 2003:
Vol. 301, Issue 5630, pp. 143
DOI: 10.1126/science.301.5630.143d

A common goal in drug design (whether by humans or microbes) is to target the foreign protein without interfering with any host proteins. One way of achieving the desired specificity is to design an inhibitor that is perfectly complementary to an enzyme active site. Unfortunately, such an inhibitor may be more vulnerable to a resistance-conferring mutation in the infectious agent or even in a population of transformed cells (compare Gleevec).

Nezami et al. have pursued the design of what they call adaptive inhibitors of the family of aspartyl proteases of Plasmodium falciparum. This parasite resides in blood cells and feeds on hemoglobin by digesting it with four structurally similar proteases, the plasmepsins, which display both conserved and distinctive amino acid residues in the substrate-binding site. An allophenylnorstatine-dimethylthioproline scaffold was derivatized at four positions with rotationally versatile groups in a search of an all-purpose anti-malarial, and this resulted in a single compound, KNI-10006, that inhibited all four proteases at submicromolar concentrations. This versatility did not extend to inhibition of the mammalian aspartyl protease pepsin, against which KNI-10006 was several orders of magnitude less active. — GJC

Biochemistry 10.1021/bi034131z (2003).

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