Malaria protease

Bjelic S, J Aqvist (2004) Computational prediction of structure, substrate binding mode, mechanism, and rate for a malaria protease with a novel type of active site. Biochemistry 43 (46) 14521-14528... 

Braun-Breton, C., and Pereira da Silva, L. H. (1993). Malaria proteases and red blood cell invasion. Parasitol. Today 9,92-96. 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

This pro-drug approach provides a paradigm for future antimalarial drug discovery efforts in the sense that this approach can be extended to any protease inhibitor that contains a carbonyl group as the reactive protease inhibitor warhead . Simply masking the carbonyl group within a trioxane or endoperoxide provides a unique and selective mechanism for targeting the malaria parasite by two different mechanisms . ... 

Greenbaum DC, Baruch A, Grainger M, Bozdech Z, Medzihradszky KF, Engel J, DeRisi J, Holder AA, Bogyo M (2002) A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298 2002... 

Baker RP, Wijetilaka R, Urban S. Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. PLoS Pathog. 2006 2 ell3. 

Croft A 2000 Malaria prevention in travellers. British Medical Journal 321 154-160 Flexner C 1998 HIV-protease inhibitors. New England Journal of Medicine 338 1281-1292 Gilden D H et al 2000 Neurological complications of the reactivation of varicella-zoster virus. New England Journal of Medicine 342 635-645 Gubareva L V, Kaiser L, Hayden F G 2000 Influenza virus neuraminidase inhibitors. Lancet 355 827-835... 

In 1990, Schrevel et al. were able to record the presence of a variety of acid aspartic and cysteine proteases and metalloproteases, as well as alkaline proteases and aminopeptidases in the erythrocytic stages of a variety of Plasmodium spp. Unfortunately, since many of the enzymes catalogued were only partially purified, and sometimes appeared aggregated, their biochemical characteristics remain ill defined at best. More recent findings for plasmodial enzymes—principally cysteine, aspartic and metalloproteases—can be found in Rosenthal (2005) and in the Plasmodium database PlasmoDB (http //plasmodb.org) as well as in the website developed and curated by Hagai Ginsburg (http //sites.huji.ac.il/malaria). 

Blackman, M. J. (2000). Proteases involved in erythrocyte invasion by the malaria parasite Function and potential as chemotherapeutic targets. Curr. Drug Targets 1,59-83. 

Blackman, M. J., Scott-Finnigan, T. J., Shai, S., and Holder, A. A. (1994). Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein. J. Exp. Med. 180, 389-393. 

Howell, S. A., Well, I., Fleck, S. L., Kettleborough, C., Collins, C. R., and Blackman, M. J. (2003). A single malaria merozoite serine protease mediates shedding of multiple surface proteins by juxtamembrane cleavage. ]. Biol. Chem. 278, 23890-23898. 

Schrevel, J., Deguercy, A., Mayer, R., and Monsigny, M. (1990). Proteases in malaria-infected red blood cells. Blood Cells 16,563-584. 

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