James McKerrow
Principal Investigator

Research Interests:
The research interests of my group fall into three broad areas. The first is analysis of structure-function relationships in proteolytic enzymes, focusing principally on cysteine and serine proteases. We began with identification and cloning of a spectrum of related proteases from primitive eukaryotes (mostly parasites), and subsequent structural analysis of these proteases bound to small molecule inhibitors. Our second major interest is identification or design of small molecule inhibitors of cysteine proteases that are involved in the pathogenesis of infectious diseases (especially those caused by tropical parasites). In this latter project, we collaborate with a consortium of laboratories within and outside UCSF in a multidisciplinary approach that includes structural analysis of enzyme targets and synthesis of small molecule inhibitors utilizing a variety of synthetic approaches or computer-based drug design. These inhibitors can be used to study the biologic function of the target proteases by "chemical knockout" and several are leads for new chemotherapy. Lastly, we also have an interest in the host response to parasites focusing specifically on schistosomiasis.We are analyzing the cellular immunology of the granulomatous response to parasite eggs as well as the parasite's exploitation of that response for transmission to a new host.

Selected Publications:
Huete-Perez JA, Engel JC, Mottram JC and McKerrow JH. Intracellular protease trafficking in kinetoplastids is mediated by the prodomain. J Biol Chem. 274:16249-16256., 1999

Britton, C, McKerrow, JH, and Johnstone, IL. Regulation of the Caenorhabditis elegans gut cysteine protease gene cpr-1: Requirement for GATA motifs. J. Mol. Biol. 283:15-27, 1998

Engel JC, Doyle PS, Hsieh I and McKerrow JH. Cysteine protease inhibitors cure an experimental Trypanosoma cruzi infection. J. Exp. Med. (188)4:723-734, 1998.

Ward W, Alvarado L, Rawlings ND, Engel JC, Franklin C and McKerrow JH. A primitive enzyme for a primitive cell: the protease required for excystation of Giardia. Cell 89:437-444, 1997.

Amiri P, Locksley RM, Parslow TG, Sadick M, Rector E, Ritter D and McKerrow JH. Tumour necrosis factor restores granuloma formation and egg laying in schistosome infected SCID mice. Nature 356:604-607, 1992

Davies, S.J., Grogan, J.L., Blank, R.B., Lim, K.C., Locksley, R.M. & McKerrow, J.H. (2001) Modulation of blood fluke development in the liver by unconventional hepatic CD4+ lymphocytes. Science 294, 1358-1361