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Development of protease inhibitors for protozoan infections

McKerrow, James Ha; Rosenthal, Philip Jb; Swenerton, Ryana; Doyle, Patriciaa

Current Opinion in Infectious Diseases: December 2008 - Volume 21 - Issue 6 - p 668–672
doi: 10.1097/QCO.0b013e328315cca9
Antimicrobials: Edited by Tania C. Sorrell and Deenan Pillay
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Purpose of review 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.

Recent findings 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.

Summary 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.

aSandler Center at Mission Bay, USA

bDepartment of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA

Correspondence to Dr James H. McKerrow, Department of Pathology, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158-2330, USA Tel: +1 415 476 2940; fax: +1 415 502 8193; e-mail: jmck@cgl.ucsf.edu

© 2008 Lippincott Williams & Wilkins, Inc.