Benzophenone-Based Farnesyltransferase Inhibitors with High Activity against Trypanosoma cruzi

Esteva, M; Kettler, Katja; Maidana, Cristina Graciela; Fichera, Laura E.; Ruiz, Andrés M.; Bontempi, Esteban J.; Andersson, Björn; Dahse, Hans‐Martin; Haebel, Peter; Ortmann, Regina; Klebe, G.; Schlitzer, Martin

doi:10.1021/jm050456x

Cited by 36 publications

(30 citation statements)

References 22 publications

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“…The treatment of parasitic disease is another area under investigation (13). A number of FTIs have been developed that inhibit protozoan FTases, and in vivo testing is a continued effort (15,32). Although research is less advanced with respect to CaaX protease and ICMT inhibitors, RNA interference experiments on the bloodstream form of Trypanosoma brucei indicate that CaaX processing enzymes are required for viability and proliferation of the parasite (20).…”

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confidence: 99%

Heterologous Expression Studies of Saccharomyces cerevisiae Reveal Two Distinct Trypanosomatid CaaX Protease Activities and Identify Their Potential Targets

et al. 2009

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The CaaX tetrapeptide motif typically directs three sequential posttranslational modifications, namely, isoprenylation, proteolysis, and carboxyl methylation. In all eukaryotic systems evaluated to date, two CaaX proteases (Rce1 and Ste24/Afc1) have been identified. Although the Trypanosoma brucei genome also encodes two putative CaaX proteases, the lack of detectable T. brucei Ste24 activity in trypanosome cell extracts has suggested that CaaX proteolytic activity within this organism is solely attributed to T. brucei Rce1 (J. R. Gillespie et al., Mol. Biochem. Parasitol. 153:115-124. 2007). In this study, we demonstrate that both T. brucei Rce1 and T. brucei Ste24 are enzymatically active when heterologously expressed in yeast. Using a-factor and GTPase reporters, we demonstrate that T. brucei Rce1 and T. brucei Ste24 possess partially overlapping specificities much like, but not identical to, their fungal and human counterparts. Of interest, a CaaX motif found on a trypanosomal Hsp40 protein was not cleaved by either T. brucei CaaX protease when examined in the context of the yeast a-factor reporter but was cleaved by both in the context of the Hsp40 protein itself when evaluated using an in vitro radiolabeling assay. We further demonstrate that T. brucei Rce1 is sensitive to small molecules previously identified as inhibitors of the yeast and human CaaX proteases and that a subset of these compounds disrupt T. brucei Rce1-dependent localization of our GTPase reporter in yeast. Together, our results suggest the conserved presence of two CaaX proteases in trypanosomatids, identify an Hsp40 protein as a substrate of both T. brucei CaaX proteases, support the potential use of small molecule CaaX protease inhibitors as tools for cell biological studies on the trafficking of CaaX proteins, and provide evidence that protein context influences T. brucei CaaX protease specificity.Certain isoprenylated proteins are synthesized as precursors having a highly degenerate C-terminal tetrapeptide CaaX motif (C, cysteine; a, aliphatic amino acid; X, one of several amino acids). This motif typically directs three posttranslational modifications that include covalent attachment of an isoprenoid lipid to the cysteine residue, followed by endoproteolytic removal of the terminal three residues (i.e., aaX), and lastly, carboxyl methyl esterification of the farnesylated cysteine (49,50). Relevant examples of proteins subject to the above modifications, also referred to as CaaX proteins, include the Ras and Ras-related GTPases, G␥ subunits, prelamin A, members of the Hsp40 family of chaperones, and fungal mating pheromones.Isoprenylation of CaaX proteins is performed by either the farnesyltransferase (FTase) or the geranylgeranyl transferase I (GGTase I). The particular isoprenoid attached, C15 farnesyl or C20 geranylgeranyl, respectively, depends in part on the sequence of the CaaX motif (8,26,31). Proteolysis of isoprenylated intermediates is carried out by the otherwise unrelated Rce1p (Ras converting enzyme 1) and Ste24p (steril...

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confidence: 99%

Heterologous Expression Studies of Saccharomyces cerevisiae Reveal Two Distinct Trypanosomatid CaaX Protease Activities and Identify Their Potential Targets

et al. 2009

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“…There was a significant reduction in mortality, but irrelevant changes regarding myocardial disease when risedronate was administered subcutaneously thrice a week in mice infected with a Brazilian strain of Trypanosoma cruzi [68]. Some complexes including risedronate and metallic ions such as Cu, Co, Mn and Ni were synthesized and tested in vitro against epimastigotes and intracellular amastigotes of T. cruzi.…”

Section: Farnesyl Pyrophosphate Synthase (Fpps)mentioning

confidence: 99%

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

Oliveira¹,

Mendes²,

Almeida³

et al. 2014

CRJ

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Abstract:Chagas disease is an infectious illness with a broad distribution throughout the South American and African continents, importantly influencing human morbidity and mortality and a controversial relationship with the onset of cancers, especially of the gastrointestinal tract system. In addition, it is listed by the World Health Organization (WHO) as one ofthe most neglected tropical diseases. Although Chagas disease (CD) was discovered more than 100 years ago, the existing therapies show low efficacy and serious side effects and developing safer and more effective drugs remains a hard challenge. Thus, this review highlights the main, novel and promising treatments against Trypanosoma cruzi, including biomacromolecules, natural products, vaccines, and metabolic pathway targets and highlights a worsening of esophageal cancer prognosis in chagasic patients. Moreover, we also discuss the perspectives of obtaining original optimized drugs that take advantage of organic and inorganic medicinal chemistry advances, as well as molecular modeling and biotechnology.

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“…These inhibitors can be helpful in the treatment of Chaga's disease [53]. Researchers at the University of Washington also identified Tipifarnib as a potent inhibitor of Trypanosoma Cruzi with ED 50 of 4 nM.…”

Section: Development Of Farnesyltransferase Inhibitorsmentioning

confidence: 99%

Inhibition of farnesyltransferase: A rational approach to treat cancer?

Puntambekar

Giridhar

Yadav

2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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This article presents in brief the development of farnesyltransferase inhibitors (FTIs) and their preclinical and clinical status. In this review the mechanism of action of FTIs is discussed and their selectivity issue towards tumor cells is also addressed. The significant efficacy of FTIs as single or combined agents in preclinical studies stands in contrast with only moderate effects in Clinical Phase II-III studies. This suggests that there is a need to further explore and understand the complex mechanism of action of FTIs and their interaction with cytotoxic agents.

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Benzophenone-Based Farnesyltransferase Inhibitors with High Activity against Trypanosoma cruzi

Cited by 36 publications

References 22 publications

Heterologous Expression Studies of Saccharomyces cerevisiae Reveal Two Distinct Trypanosomatid CaaX Protease Activities and Identify Their Potential Targets

Heterologous Expression Studies of Saccharomyces cerevisiae Reveal Two Distinct Trypanosomatid CaaX Protease Activities and Identify Their Potential Targets

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

Inhibition of farnesyltransferase: A rational approach to treat cancer?

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