Cysteine Proteinases of Trypanosome Parasites Novel Targets for Chemotherapy

Caffrey, Conor R.; Scory, Stefan; Steverding, Dietmar

doi:10.2174/1389450003349290

Cited by 92 publications

(75 citation statements)

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“…Both in vitro and in vivo studies have shown that cysteine protease activity is required for T. brucei survival (5,6,29,30). RNAi studies implicated tbcatB as an essential protease (4).…”

Section: Discussionmentioning

confidence: 99%

A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition

O'Brien

Mackey

Fetter

et al. 2008

Journal of Biological Chemistry

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Cysteine proteases of the Clan CA (papain) family are the predominant protease group in primitive invertebrates. Cysteine protease inhibitors arrest infection by the protozoan parasite, Trypanosoma brucei. RNA interference studies implicated a cathepsin B-like protease, tbcatB, as a key inhibitor target. Utilizing parasites in which one of the two alleles of tbcatb has been deleted, the key role of this protease in degradation of endocytosed host proteins is delineated. TbcatB deficiency results in a decreased growth rate and dysmorphism of the flagellar pocket and the subjacent endocytic compartment. Western blot and microscopic analysis indicate that deficiency in tbcatB results in accumulation of both host and parasite proteins, including the lysosomal marker p67. A critical function for parasitism is the degradation of host transferrin, which is necessary for iron acquisition. Substrate specificity analysis of recombinant tbcatB revealed the optimal peptide cleavage sequences for the enzyme and these were confirmed experimentally using FRET-based substrates. Degradation of transferrin was validated by SDS-PAGE and the specific cleavage sites identified by N-terminal sequencing. Because even a modest deficiency in tbcatB is lethal for the parasite, tbcatB is a logical target for the development of new anti-trypanosomal chemotherapy.Proteases are ubiquitous enzymes that function in virtually all biological phenomena. Two of the major groups of proteases, Clan CA (papain-like) cysteine proteases and Clan SA (trypsin-like) serine proteases, underwent an evolutionary inversion whereby the more abundant cysteine proteases of primitive eukaryotes gave way to serine proteases with the evolution of arthropods (1) (merops.sanger.ac.uk/). Therefore, an analysis of the role of cysteine proteases in protozoa can provide insights into differential use and molecular evolution of this protease class.Trypanosoma brucei is a protozoan parasite and the causative agent of human African trypanosomiasis, a fatal disease that is transmitted by the bite of the tsetse fly. Only four drugs are available to treat human African trypanosomiasis: two for the first stage of the disease when parasites proliferate in the blood (pentamidine and suramin) and two for the second stage when parasites have established infection in the cerebrospinal fluid (melarsoprol and eflornithine). These drugs cause serious side effects and are expensive to manufacture and administer (2). There is an obvious and urgent need to develop new chemotherapies to treat human African trypanosomiasis.Two Clan CA cysteine proteases have been identified in T. brucei: rhodesain, which is cathepsin L-like and most abundant (3), and tbcatB, a cathepsin B-like enzyme (4). Treatment of parasites in culture with the nonspecific cysteine protease inhibitor, benzyloxycarbonyl-phenylalanyl-alanyl diazomethane (Z-Phe-Ala-CHN 2 ) 2 is lethal to cultured parasites at 10 M (5). Parasites treated with this inhibitor exhibit altered cell morphology, are unable to undergo cytokinesis, ...

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“…Both in vitro and in vivo studies have shown that cysteine protease activity is required for T. brucei survival (5,6,29,30). RNAi studies implicated tbcatB as an essential protease (4).…”

Section: Discussionmentioning

confidence: 99%

A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition

O'Brien

Mackey

Fetter

et al. 2008

Journal of Biological Chemistry

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“…infections (91), could also be involved in AT-induced immune depression, anemia, thrombocytopenia, or central nervous system (CNS) invasion (7,8,42,63,111,152). In addition, CPs are considered potential targets for future drug design (trypanocide and antidisease) as well as antidisease vaccine candidates (29,64,92). Although most of the literature has dealt with T. cruzi CP (cruzain or cruzipain), CPs from T. brucei brucei, T. congolense, and T. brucei rhodesiense have also been extensively studied (8,28,42,56,67,90,119,134,152).…”

Section: The Major Candidatesmentioning

confidence: 99%

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

2009

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“…In this regard, biochemical pathways general to parasites but absent from mammalian hosts have long been an attractive source of molecular targets for anti-infective drug development [23,27]. Additionally, biochemical peculiarities of the parasites such as (i) turnover rates [42,43]; (ii) structure of biological membranes [44][45][46][47]; (iii) cell signaling [48] and (iv) protein expression and regulation [49] have also been investigated as potential targets for drug intervention [50].…”

Section: Molecular Targets For Drug Designmentioning

confidence: 99%

Structure-Based Drug Discovery for Tropical Diseases

Güido

Oliva

2009

CTMC

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Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.

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Cysteine Proteinases of Trypanosome Parasites Novel Targets for Chemotherapy

Cited by 92 publications

References 0 publications

A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition

A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

Structure-Based Drug Discovery for Tropical Diseases

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