Journal article

Structure- and function-based design of Plasmodium-selective proteasome inhibitors

Hao Li, Anthony J O'Donoghue, Wouter A van der Linden, Stanley C Xie, Euna Yoo, Ian T Foe, Leann Tilley, Charles S Craik, Paula CA da Fonseca, Matthew Bogyo

NATURE | NATURE PUBLISHING GROUP | Published : 2016

Abstract

The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properti..

View full abstract

Grants

Awarded by National Institutes of Health


Awarded by Medical Research Council


Awarded by American Heart Association


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

This work was support by National Institutes of Health grants R01AI078947, R01EB05011 to M.B., and by the Medical Research Council grant MC-UP-1201/5 to P.C.A.dF. H.L. was supported by an NSS-PhD scholarshpip from the Agency for Science, Technology and Research (A*STAR) Singapore. W.A.v.d.L. was supported by a Rubicon fellowship from the Netherlands Organization for Scientific Research (NWO). A.J.O. and C.S.C. were supported by the Program for Breakthrough Biomedical Research (PBBR) and the Sandler Foundation. I.T.F. was supported by American Heart Association grant 14POST20280004. We acknowledge support from the Australian Research Council and the Australian National Health and Medical Research Council. We thank K. Chotivanich for providing PL2 and PL7 parasites. We thank E. Yeh's group for help with P. falciparum D10 culture and for use of their equipment. We thank J. Boothroyd for providing the human fibroblast cells. We thank E. Morris and R. Henderson for discussions on image processing, FEI fellows and C. Savva for assisting in the use of the Titan Krios microscope, S. Chen for EM support, and J. Grimmet and T. Darling for computing support.