Development of protease inhibitors for protozoan infections.
OBJECTIVE
To highlight the promise of parasite proteases as targets for development of new antiparasitic chemotherapy. Proteolytic enzymes play key roles in the life cycle of protozoan parasites or the pathogenesis of diseases they produce. These roles include processing of host or parasite surface proteins for invasion of host cells, digestion of host proteins for nutrition, and inactivation of host immune defense mediators.


RESULTS
Drug development for other markets has shown that proteases are druggable targets, and protease inhibitors are now licensed or in clinical development to treat hypertension, diabetes, thrombosis, osteoporosis, infectious diseases, and cancer. Several protease targets have been validated by genetic or chemical knockout in protozoan parasites. Many other parasite proteases appear promising as targets, but require more work for validation, or to identify viable drug leads. Because homologous proteases function as key enzymes in several parasites, targeting these proteases may allow development of a single compound, or a set of similar compounds, that target multiple diseases including malaria, trypanosomiasis, leishmaniasis, toxoplasmosis, cryptosporidiosis, and amebiasis.


CONCLUSIONS
Proteases have been validated as targets in a number of parasitic infections. Proteases are druggable targets as evidenced by effective antiprotease drugs for the treatment of many human diseases including hypertension and AIDS. Future drug development targeting parasite proteases will be aided by the strong foundation of biochemical, structural, and computational databases already published or available online.
McKerrow
James H
JH
Department of Pathology, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158-2330, USA. jmck@cgl.ucsf.edu
Rosenthal
Philip J
PJ
Swenerton
Ryan
R
Doyle
Patricia
P
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D056890:Eukaryota / Q000187:drug effects*; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology*; D011528:Protozoan Infections / Q000188:drug therapy*
D000981:Antiprotozoal Agents; D011480:Protease Inhibitors