Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung, Régis; Zhao, Yanqing; Li, Wanren; Tam, Tim F.; Karimian, Khashayar; Spino, Michael

doi:10.2174/092986706776055733

Cited by 60 publications

(60 citation statements)

References 206 publications

(338 reference statements)

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“…A now widespread strategy for developing cysteine peptidase inhibitors is to add ketones, aldehydes, or other "warheads" to short peptide sequences derived from their native substrate. 37 As the function of TgATG4 appears to be crucial for the development of the parasites, such a strategy could be at the basis of a future drug design approach to fight these pathogens.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

et al. 2013

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in the process of autophagy, the Atg8 protein is conjugated, through a ubiquitin-like system, to the lipid phosphatidylethanolamine (Pe) to associate with the membrane of forming autophagosomes. There, it plays a crucial role in the genesis of these organelles and in autophagy in general. in most eukaryotes, the cysteine peptidase Atg4 processes the c terminus of cytosolic Atg8 to regulate its association with autophagosomal membranes and also delipidates Atg8 to release this protein from membranes. The parasitic protist Toxoplasma gondii contains a functional, yet apparently reduced, autophagic machinery. T. gondii Atg8 homolog, in addition to a cytosolic and occasionally autophagosomal localization, also localizes to the apicoplast, a nonphotosynthetic plastid bounded by four membranes. Our attempts to interfere with TgATG8 function showed that it appears to be essential for parasite multiplication inside its host cell. This protein also displays a peculiar c terminus that does not seem to necessitate processing prior to membrane association and yet an unusually large Toxoplasma homolog of ATG4 is predicted in the parasite genome. A TgATG4 conditional expression mutant that we have generated is severely affected in growth, and displays significant alterations at the organellar level, noticeably with a fragmentation of the mitochondrial network and a loss of the apicoplast. TgATG4-depleted parasites appear to be defective in the recycling of membrane-bound TgATG8. Overall, our data highlight a role for the TgATG8 conjugation pathway in maintaining the homeostasis of the parasite's organelles and suggest that Toxoplasma has evolved a specialized autophagic machinery with original regulation.

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Section: Discussionmentioning

confidence: 99%

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

et al. 2013

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“…Based on this relationship, AC has been recently found to be inhibited by the cysteine protease inhibitors, cystatins ( 50 ). During the course of this study, we identifi ed novel potent and specifi c inhibitors of AC within a series of small molecules inspired in reported irreversible cyteine protease inhibitors (51)(52)(53). These compounds feature either an ␣ -halocarbonyl unit or an ␣ , ␤ -double-bond Michael acceptor moiety.…”

Section: Discussionmentioning

confidence: 99%

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Camacho

Meca-Cortés

Abad

et al. 2013

Journal of Lipid Research

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Supplementary key words ceramide • metastasis • inhibitorsCancer cells develop a lipogenic phenotype that supports the energy and membrane synthesis requirements associated with the enhanced proliferation and survival under stress inherent to malignant progression ( 1, 2 ). The recognition of the importance of this phenotype in cancer has led to the use of enzymes of lipid metabolism as markers to monitor neoplastic progression and response to therapy, as well as to the development of drugs targeted at key lipogenic enzymes, such as fatty acid synthase (FASN) ( 2, 3 ). The excess fatty acid synthesis that results from the coordinated activation of lipogenic enzymes in many types of cancer leads to the accumulation of palmitate, which needs to be further processed by the cells due to the toxic effects of its accumulation. One pathway that Abstract Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confi rm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specifi c AC inhibitors could act by counteracting critical growth properties of SAF2008-00706 and SAF2011-22444 (to G.F.) Press, February 18, 2013 DOI 10.1194 Acid ceramidase as a therapeutic target in metastatic prostate cancer Abbreviations: AC, acid ceramidase; CMH, ceramide monohexoside; MDR1, multidrug resistant protein 1; NC, neutral ceramidase; PC, prostate cancer; PIN, prostate intraepithelial neoplasia; S1P, sphingosine-1-phosphate. This work was supported by Ministry of Science and Innovation Grants ; Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1072 (to G.F.); Ministry of Science and Innovation Grants SAF2008-04136-C02-01 and SAF2011-24686 (to T.M.T.); Ministry of Economy and Competitivity Grant SAF2012-40017-C02-01 (to T.M.T.); Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1482 (to T.M.T.); Xarxa de Bancs de Tumours de Catalunya-Pla Director d'Oncologia and Fondo Europeo de Desarrollo...

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“…The active-site cleft of falcipain-2 subfamily proteases, as for other C1A proteases and cysteine proteases in general, represents a prime target for therapeutic intervention (59,60). Peptides and irreversible peptidic inhibitors have traditionally been used to probe the substrate specificity of cysteine proteases and to generate information that can be translated into the design of non-peptidic inhibitors with drug-like properties.…”

Section: Structural Determinants Of Protein Folding and Hemoglobinmentioning

confidence: 99%

Structural and Functional Characterization of Falcipain-2, a Hemoglobinase from the Malarial Parasite Plasmodium falciparum

Hogg

Nagarajan

Herzberg

et al. 2006

Journal of Biological Chemistry

111

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Malaria is caused by protozoan erythrocytic parasites of the Plasmodium genus, with Plasmodium falciparum being the most dangerous and widespread disease-causing species. Falcipain-2 (FP-2) of P. falciparum is a papain-family (C1A) cysteine protease that plays an important role in the parasite life cycle by degrading erythrocyte proteins, most notably hemoglobin. Inhibition of FP-2 and its paralogues prevents parasite maturation, suggesting these proteins may be valuable targets for the design of novel antimalarial drugs, but lack of structural knowledge has impeded progress toward the rational discovery of potent, selective, and efficacious inhibitors. As a first step toward this goal, we present here the crystal structure of mature FP-2 at 3.1 Å resolution, revealing novel structural features of the FP-2 subfamily proteases including a dynamic ␤-hairpin hemoglobin binding motif, a flexible N-terminal ␣-helical extension, and a unique active-site cleft. We also demonstrate by biochemical methods that mature FP-2 can proteolytically process its own precursor in trans at neutral to weakly alkaline pH, that the binding of hemoglobin to FP-2 is strictly pH-dependent, and that FP-2 preferentially binds methemoglobin over hemoglobin. Because the specificity and proteolytic activity of FP-2 toward its multiple targets appears to be pH-dependent, we suggest that environmental pH may play an important role in orchestrating FP-2 function over the different life stages of the parasite. Moreover, it appears that selectivity of FP-2 for methemoglobin may represent an evolutionary adaptation to oxidative stress conditions within the host cell.

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Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Cited by 60 publications

References 206 publications

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

Regulation of ATG8 membrane association by ATG4 in the parasitic protistToxoplasma gondii

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Structural and Functional Characterization of Falcipain-2, a Hemoglobinase from the Malarial Parasite Plasmodium falciparum

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