Cysteine protease inhibitors as chemotherapy for parasitic infections

Analysis of the evolution, localization and biologic function of papain fam ily cysteine proteases in metazoan and protozoan parasites has provided imp ortant and often surprising insights into the biochemistry and cellular fun ction of this diverse enzyme family. Furthermore, the relative lack of redu ndancy of cysteine proteases in parasites compared to their mammalian hosts makes them attractive targets for the development of new antiparasitic che motherapy. The treatment of experimental models of parasitic diseases with cysteine protease inhibitors has provided an important 'proof of concept' f or the use of cysteine protease inhibitors in vivo. Evidence has now accumu lated that cysteine protease inhibitors can selectively arrest replication of a microbial pathogen without untoward toxicity to the host. Furthermore, this can be achieved with reasonable dosing schedules and oral administrat ion of the drug. Initial studies have confirmed the efficacy of cysteine pr otease inhibitors in treatment of Trypanosoma cruzi, Plasmodium falciparum and Leishmania major. Work on Trypanosoma brucei, the agent of African tryp anosomiasis, is preliminary but also promising. Target validation studies h ave shown that biotinylated or radiolabeled irreversible inhibitors specifi cally bind to the cysteine protease targets thought to represent the major activity within the parasite. Tn the case of T. cruzi, the effect of inhibi tors appears to be predominantly in blocking protease processing. Transfect ion studies using variant constructs have supported this model. Finally, th e generation of null mutants for the multiple protease genes in Leishmania mexicana has provided the first genetic support for the key role of this en zyme family in parasite virulence. Safety studies in rodents and analysis o f uptake of inhibitors by parasites and host cells suggest that the selecti vity of inhibitors for the parasite targets may reside in the lack of redun dancy of parasite proteases, the higher concentration of host proteases in intracellular compartments, and differential uptake of inhibitors by parasi tes. Attempts to elicit resistance to cysteine protease inhibitors in paras ite cultures suggest that mechanisms of induced resistance are independent of resistance to the traditional antiparasitic agents. This suggests that c ysteine protease inhibitors may provide an alternative to traditional thera py in drug-resistant organisms. (C) 1999 Elsevier Science Ltd. All rights r eserved.