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Antimicrobial Agents and Chemotherapy, September 1998, p. 2254-2258, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors

Andrey Semenov, Jed E. Olson, and Philip J. Rosenthal*

Department of Medicine, San Francisco General Hospital and University of California, San Francisco, California

Received 27 March 1998/Returned for modification 7 May 1998/Accepted 10 June 1998

It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.

* Corresponding author. Mailing address: Dept. of Medicine, Box 0811, University of California, San Francisco, CA 94143-0811. Phone: (415) 206-8845. Fax: (415) 206-6015. E-mail: rosnthl{at}itsa.ucsf.edu.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2254-2258, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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