Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity
► Naphthoquinones derivatives decrease in vitro growth Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activi...
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| Veröffentlicht in: | Experimental parasitology 2011, Vol.127 (1), p.160-166 |
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| creator | Bourguignon, Saulo C. Cavalcanti, Danielle F.B. de Souza, Alessandra M.T. Castro, Helena C. Rodrigues, Carlos R. Albuquerque, Magaly G. Santos, Dilvani O. da Silva, Gabriel Gomes da Silva, Fernando C. Ferreira, Vitor F. de Pinho, Rosa T. Alves, Carlos R. |
| description | ► Naphthoquinones derivatives decrease
in vitro growth
Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activity of
T. cruzi. ► β-Lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting different proteinases.
In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of
Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against
T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major
T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against
T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the
T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting
T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds. |
| doi_str_mv | 10.1016/j.exppara.2010.07.007 |
| format | Article |
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in vitro growth
Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activity of
T. cruzi. ► β-Lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting different proteinases.
In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of
Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against
T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major
T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against
T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the
T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting
T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.</description><identifier>ISSN: 0014-4894</identifier><identifier>EISSN: 1090-2449</identifier><identifier>DOI: 10.1016/j.exppara.2010.07.007</identifier><identifier>PMID: 20647011</identifier><identifier>CODEN: EXPAAA</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>active sites ; Animals ; Anti-Infective Agents - pharmacology ; Biological and medical sciences ; Cercopithecus aethiops ; Chagas disease ; cruzipain ; Cysteine Endopeptidases ; Cysteine Proteinase Inhibitors - pharmacology ; drugs ; epimastigotes ; Epoxy-α-lap ; Fundamental and applied biological sciences. Psychology ; Human protozoal diseases ; Infectious diseases ; Leucine - analogs & derivatives ; Leucine - pharmacology ; Life cycle. Host-agent relationship. Pathogenesis ; Medical sciences ; molecular models ; Naphthoquinones ; Naphthoquinones - pharmacology ; Parasitic diseases ; parasitology ; Peptide Hydrolases - drug effects ; Peptide Hydrolases - metabolism ; Protease Inhibitors - pharmacology ; proteinase inhibitors ; Proteinases ; Protozoa ; Protozoal diseases ; Protozoan Proteins - antagonists & inhibitors ; serine proteinases ; toxicity ; Trypanosoma cruzi ; Trypanosoma cruzi - drug effects ; Trypanosoma cruzi - enzymology ; Trypanosoma cruzi - growth & development ; Trypanosomiasis ; Vero Cells ; viability ; β-Lapachone</subject><ispartof>Experimental parasitology, 2011, Vol.127 (1), p.160-166</ispartof><rights>2010 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-4a204b75e094853b65b74309ddeb6e8cc13a34c9f42f35f6a555b161808e225e3</citedby><cites>FETCH-LOGICAL-c497t-4a204b75e094853b65b74309ddeb6e8cc13a34c9f42f35f6a555b161808e225e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014489410002511$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23798084$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20647011$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bourguignon, Saulo C.</creatorcontrib><creatorcontrib>Cavalcanti, Danielle F.B.</creatorcontrib><creatorcontrib>de Souza, Alessandra M.T.</creatorcontrib><creatorcontrib>Castro, Helena C.</creatorcontrib><creatorcontrib>Rodrigues, Carlos R.</creatorcontrib><creatorcontrib>Albuquerque, Magaly G.</creatorcontrib><creatorcontrib>Santos, Dilvani O.</creatorcontrib><creatorcontrib>da Silva, Gabriel Gomes</creatorcontrib><creatorcontrib>da Silva, Fernando C.</creatorcontrib><creatorcontrib>Ferreira, Vitor F.</creatorcontrib><creatorcontrib>de Pinho, Rosa T.</creatorcontrib><creatorcontrib>Alves, Carlos R.</creatorcontrib><title>Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity</title><title>Experimental parasitology</title><addtitle>Exp Parasitol</addtitle><description>► Naphthoquinones derivatives decrease
in vitro growth
Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activity of
T. cruzi. ► β-Lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting different proteinases.
In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of
Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against
T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major
T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against
T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the
T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting
T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.</description><subject>active sites</subject><subject>Animals</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cercopithecus aethiops</subject><subject>Chagas disease</subject><subject>cruzipain</subject><subject>Cysteine Endopeptidases</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>drugs</subject><subject>epimastigotes</subject><subject>Epoxy-α-lap</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Human protozoal diseases</subject><subject>Infectious diseases</subject><subject>Leucine - analogs & derivatives</subject><subject>Leucine - pharmacology</subject><subject>Life cycle. Host-agent relationship. Pathogenesis</subject><subject>Medical sciences</subject><subject>molecular models</subject><subject>Naphthoquinones</subject><subject>Naphthoquinones - pharmacology</subject><subject>Parasitic diseases</subject><subject>parasitology</subject><subject>Peptide Hydrolases - drug effects</subject><subject>Peptide Hydrolases - metabolism</subject><subject>Protease Inhibitors - pharmacology</subject><subject>proteinase inhibitors</subject><subject>Proteinases</subject><subject>Protozoa</subject><subject>Protozoal diseases</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>serine proteinases</subject><subject>toxicity</subject><subject>Trypanosoma cruzi</subject><subject>Trypanosoma cruzi - drug effects</subject><subject>Trypanosoma cruzi - enzymology</subject><subject>Trypanosoma cruzi - growth & development</subject><subject>Trypanosomiasis</subject><subject>Vero Cells</subject><subject>viability</subject><subject>β-Lapachone</subject><issn>0014-4894</issn><issn>1090-2449</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhi0EokvhEYBcUE9Zxokdx1wqVBWoVIkD7YGTNXEmu17t2qmdFJanx6td4MhpJM83M78-M_aaw5IDb95vlvRzHDHisoL8BmoJoJ6wBQcNZSWEfsoWAFyUotXijL1IaQMALa_Ec3ZWQSMUcL5g3-_ifkQfUthhYeP8y30obnxyq_WUCuenUHgc19M6PMzOB08FDQPZ3Au-WMXwY1oX6PtijGEi5zFRgXZyj27av2TPBtwmenWq5-z-0_Xd1Zfy9uvnm6uPt6UVWk2lwApEpySBFq2su0Z2StSg-566hlpreY21sHoQ1VDLoUEpZccb3kJLVSWpPmcXx705w8NMaTI7lyxtt-gpzMm0qsmcFjyT8kjaGFKKNJgxuh3GveFgDlLNxpykmoNUA8pkqXnuzenC3O2o_zv1x2IG3p0ATBa3Q0RvXfrH1UrnuCJzb4_cgMHgKmbm_lu-JPNHKdnKw6bLI0HZ2KOjaJJ15C31Lmbtpg_uP2F_A2omoes</recordid><startdate>2011</startdate><enddate>2011</enddate><creator>Bourguignon, Saulo C.</creator><creator>Cavalcanti, Danielle F.B.</creator><creator>de Souza, Alessandra M.T.</creator><creator>Castro, Helena C.</creator><creator>Rodrigues, Carlos R.</creator><creator>Albuquerque, Magaly G.</creator><creator>Santos, Dilvani O.</creator><creator>da Silva, Gabriel Gomes</creator><creator>da Silva, Fernando C.</creator><creator>Ferreira, Vitor F.</creator><creator>de Pinho, Rosa T.</creator><creator>Alves, Carlos R.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>M7N</scope></search><sort><creationdate>2011</creationdate><title>Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity</title><author>Bourguignon, Saulo C. ; Cavalcanti, Danielle F.B. ; de Souza, Alessandra M.T. ; Castro, Helena C. ; Rodrigues, Carlos R. ; Albuquerque, Magaly G. ; Santos, Dilvani O. ; da Silva, Gabriel Gomes ; da Silva, Fernando C. ; Ferreira, Vitor F. ; de Pinho, Rosa T. ; Alves, Carlos R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-4a204b75e094853b65b74309ddeb6e8cc13a34c9f42f35f6a555b161808e225e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>active sites</topic><topic>Animals</topic><topic>Anti-Infective Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cercopithecus aethiops</topic><topic>Chagas disease</topic><topic>cruzipain</topic><topic>Cysteine Endopeptidases</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>drugs</topic><topic>epimastigotes</topic><topic>Epoxy-α-lap</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Human protozoal diseases</topic><topic>Infectious diseases</topic><topic>Leucine - analogs & derivatives</topic><topic>Leucine - pharmacology</topic><topic>Life cycle. Host-agent relationship. Pathogenesis</topic><topic>Medical sciences</topic><topic>molecular models</topic><topic>Naphthoquinones</topic><topic>Naphthoquinones - pharmacology</topic><topic>Parasitic diseases</topic><topic>parasitology</topic><topic>Peptide Hydrolases - drug effects</topic><topic>Peptide Hydrolases - metabolism</topic><topic>Protease Inhibitors - pharmacology</topic><topic>proteinase inhibitors</topic><topic>Proteinases</topic><topic>Protozoa</topic><topic>Protozoal diseases</topic><topic>Protozoan Proteins - antagonists & inhibitors</topic><topic>serine proteinases</topic><topic>toxicity</topic><topic>Trypanosoma cruzi</topic><topic>Trypanosoma cruzi - drug effects</topic><topic>Trypanosoma cruzi - enzymology</topic><topic>Trypanosoma cruzi - growth & development</topic><topic>Trypanosomiasis</topic><topic>Vero Cells</topic><topic>viability</topic><topic>β-Lapachone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bourguignon, Saulo C.</creatorcontrib><creatorcontrib>Cavalcanti, Danielle F.B.</creatorcontrib><creatorcontrib>de Souza, Alessandra M.T.</creatorcontrib><creatorcontrib>Castro, Helena C.</creatorcontrib><creatorcontrib>Rodrigues, Carlos R.</creatorcontrib><creatorcontrib>Albuquerque, Magaly G.</creatorcontrib><creatorcontrib>Santos, Dilvani O.</creatorcontrib><creatorcontrib>da Silva, Gabriel Gomes</creatorcontrib><creatorcontrib>da Silva, Fernando C.</creatorcontrib><creatorcontrib>Ferreira, Vitor F.</creatorcontrib><creatorcontrib>de Pinho, Rosa T.</creatorcontrib><creatorcontrib>Alves, Carlos R.</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>Experimental parasitology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bourguignon, Saulo C.</au><au>Cavalcanti, Danielle F.B.</au><au>de Souza, Alessandra M.T.</au><au>Castro, Helena C.</au><au>Rodrigues, Carlos R.</au><au>Albuquerque, Magaly G.</au><au>Santos, Dilvani O.</au><au>da Silva, Gabriel Gomes</au><au>da Silva, Fernando C.</au><au>Ferreira, Vitor F.</au><au>de Pinho, Rosa T.</au><au>Alves, Carlos R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity</atitle><jtitle>Experimental parasitology</jtitle><addtitle>Exp Parasitol</addtitle><date>2011</date><risdate>2011</risdate><volume>127</volume><issue>1</issue><spage>160</spage><epage>166</epage><pages>160-166</pages><issn>0014-4894</issn><eissn>1090-2449</eissn><coden>EXPAAA</coden><abstract>► Naphthoquinones derivatives decrease
in vitro growth
Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activity of
T. cruzi. ► β-Lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting different proteinases.
In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of
Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against
T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major
T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against
T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of
T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the
T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit
T. cruzi epimastigotes growth by affecting
T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>20647011</pmid><doi>10.1016/j.exppara.2010.07.007</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Experimental parasitology, 2011, Vol.127 (1), p.160-166 |
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| subjects | active sites Animals Anti-Infective Agents - pharmacology Biological and medical sciences Cercopithecus aethiops Chagas disease cruzipain Cysteine Endopeptidases Cysteine Proteinase Inhibitors - pharmacology drugs epimastigotes Epoxy-α-lap Fundamental and applied biological sciences. Psychology Human protozoal diseases Infectious diseases Leucine - analogs & derivatives Leucine - pharmacology Life cycle. Host-agent relationship. Pathogenesis Medical sciences molecular models Naphthoquinones Naphthoquinones - pharmacology Parasitic diseases parasitology Peptide Hydrolases - drug effects Peptide Hydrolases - metabolism Protease Inhibitors - pharmacology proteinase inhibitors Proteinases Protozoa Protozoal diseases Protozoan Proteins - antagonists & inhibitors serine proteinases toxicity Trypanosoma cruzi Trypanosoma cruzi - drug effects Trypanosoma cruzi - enzymology Trypanosoma cruzi - growth & development Trypanosomiasis Vero Cells viability β-Lapachone |
| title | Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity |
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