Chalcones identify cTXNPx as a potential antileishmanial drug target
With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analo...
Gespeichert in:
| Veröffentlicht in: | PLoS neglected tropical diseases 2021-11, Vol.15 (11), p.e0009951-e0009951 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e0009951 |
|---|---|
| container_issue | 11 |
| container_start_page | e0009951 |
| container_title | PLoS neglected tropical diseases |
| container_volume | 15 |
| creator | Escrivani, Douglas O Charlton, Rebecca L Caruso, Marjolly B Burle-Caldas, Gabriela A Borsodi, Maria Paula G Zingali, Russolina B Arruda-Costa, Natalia Palmeira-Mello, Marcos V de Jesus, Jéssica B Souza, Alessandra M T Abrahim-Vieira, Bárbara Freitag-Pohl, Stefanie Pohl, Ehmke Denny, Paul W Rossi-Bergmann, Bartira Steel, Patrick G |
| description | With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones. |
| doi_str_mv | 10.1371/journal.pntd.0009951 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2610942571</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A685875873</galeid><doaj_id>oai_doaj_org_article_97dcebeea4914662b9ca60f477d72118</doaj_id><sourcerecordid>A685875873</sourcerecordid><originalsourceid>FETCH-LOGICAL-c624t-975bbf11dd6b46e22e05c79f9dbc492a8bcd1690c741426344bdea8cffcf3853</originalsourceid><addsrcrecordid>eNptkluLEzEUxwdR3LX6DUQHBPGlNcnkMnkRlnpbWNSHPvgWMrlMU9JJTTLifnszdnZpZUng5PI7_5yTc6rqJQQr2DD4fhfGOEi_OgxZrwAAnBP4qLqEvCFLxBry-GR9UT1LaQcA4aSFT6uLBrMWYAYuq4_rrfQqDCbVTpshO3tbq83Pbz_-1DLVsj6EPJ1KX8tivHFpu5fDtNdx7OssY2_y8-qJlT6ZF7NdVJvPnzbrr8ub71-u11c3S0URzkvOSNdZCLWmHaYGIQOIYtxy3SnMkWw7pSHlQDEMMaINxp02slXWKtu0pFlUr4-yBx-SmPNPAlEIOEaEwUJcHwkd5E4cotvLeCuCdOLfQYi9kDE75Y3gTCvTGSMxh5hS1HElKbCYMc0QhG3R-jC_NnZ7U-AhR-nPRM9vBrcVffgtWkoxKuEvqnezQAy_RpOy2LukjPdyMGEscRPeAkYYRQV98x_6cHYz1cuSgBtsKO-qSVRc0Za0rMymUKsHqDK02bup0raU8dzh7YnD1kiftyn4MbswpHMQH0EVQ0rR2PvPgEBMPXkXtZh6Usw9WdxenX7kvdNdEzZ_AcXp3a8</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2610942571</pqid></control><display><type>article</type><title>Chalcones identify cTXNPx as a potential antileishmanial drug target</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>Public Library of Science (PLoS)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Escrivani, Douglas O ; Charlton, Rebecca L ; Caruso, Marjolly B ; Burle-Caldas, Gabriela A ; Borsodi, Maria Paula G ; Zingali, Russolina B ; Arruda-Costa, Natalia ; Palmeira-Mello, Marcos V ; de Jesus, Jéssica B ; Souza, Alessandra M T ; Abrahim-Vieira, Bárbara ; Freitag-Pohl, Stefanie ; Pohl, Ehmke ; Denny, Paul W ; Rossi-Bergmann, Bartira ; Steel, Patrick G</creator><contributor>Donatelli Serafim, Tiago</contributor><creatorcontrib>Escrivani, Douglas O ; Charlton, Rebecca L ; Caruso, Marjolly B ; Burle-Caldas, Gabriela A ; Borsodi, Maria Paula G ; Zingali, Russolina B ; Arruda-Costa, Natalia ; Palmeira-Mello, Marcos V ; de Jesus, Jéssica B ; Souza, Alessandra M T ; Abrahim-Vieira, Bárbara ; Freitag-Pohl, Stefanie ; Pohl, Ehmke ; Denny, Paul W ; Rossi-Bergmann, Bartira ; Steel, Patrick G ; Donatelli Serafim, Tiago</creatorcontrib><description>With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0009951</identifier><identifier>PMID: 34780470</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alkynes ; Animals ; Antiprotozoal Agents - administration & dosage ; Antiprotozoal Agents - pharmacology ; Antiprotozoal Agents - therapeutic use ; Biology and Life Sciences ; Bone marrow ; Cells, Cultured ; Chalcone - administration & dosage ; Chalcone - analogs & derivatives ; Chalcone - metabolism ; Chalcone - pharmacology ; CRISPR ; Cytosol - drug effects ; Cytosol - enzymology ; Cytosol - parasitology ; Cytotoxicity ; Drug Discovery ; Drug therapy ; Drugs ; Enzymes ; Gene editing ; Global health ; Health aspects ; Homology ; Humans ; Incubation period ; Infections ; Labeling ; Labelling ; Laboratory animals ; Leishmania - classification ; Leishmania - drug effects ; Leishmaniasis ; Leishmaniasis - drug therapy ; Leishmaniasis - parasitology ; Macrophages ; Macrophages - drug effects ; Macrophages - parasitology ; Medicine and Health Sciences ; Mice ; Mice, Inbred BALB C ; Molecular docking ; Molecular Docking Simulation ; Parasites ; Parasitic diseases ; Peroxidase ; Peroxidases - antagonists & inhibitors ; Peroxidases - metabolism ; Phenotypes ; Polyphenols ; Proteins ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - metabolism ; Public health ; Research and Analysis Methods ; Testing ; Therapeutic targets ; Toxicity ; Tropical diseases ; Tryparedoxin peroxidase ; Vector-borne diseases</subject><ispartof>PLoS neglected tropical diseases, 2021-11, Vol.15 (11), p.e0009951-e0009951</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Escrivani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Escrivani et al 2021 Escrivani et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-975bbf11dd6b46e22e05c79f9dbc492a8bcd1690c741426344bdea8cffcf3853</citedby><cites>FETCH-LOGICAL-c624t-975bbf11dd6b46e22e05c79f9dbc492a8bcd1690c741426344bdea8cffcf3853</cites><orcidid>0000-0003-1244-3450 ; 0000-0003-0105-5815 ; 0000-0002-5051-1613 ; 0000-0002-3791-8996 ; 0000-0001-9986-405X ; 0000-0002-4872-8960 ; 0000-0001-9440-5292 ; 0000-0002-2493-5826 ; 0000-0003-2550-5315</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664226/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664226/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34780470$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Donatelli Serafim, Tiago</contributor><creatorcontrib>Escrivani, Douglas O</creatorcontrib><creatorcontrib>Charlton, Rebecca L</creatorcontrib><creatorcontrib>Caruso, Marjolly B</creatorcontrib><creatorcontrib>Burle-Caldas, Gabriela A</creatorcontrib><creatorcontrib>Borsodi, Maria Paula G</creatorcontrib><creatorcontrib>Zingali, Russolina B</creatorcontrib><creatorcontrib>Arruda-Costa, Natalia</creatorcontrib><creatorcontrib>Palmeira-Mello, Marcos V</creatorcontrib><creatorcontrib>de Jesus, Jéssica B</creatorcontrib><creatorcontrib>Souza, Alessandra M T</creatorcontrib><creatorcontrib>Abrahim-Vieira, Bárbara</creatorcontrib><creatorcontrib>Freitag-Pohl, Stefanie</creatorcontrib><creatorcontrib>Pohl, Ehmke</creatorcontrib><creatorcontrib>Denny, Paul W</creatorcontrib><creatorcontrib>Rossi-Bergmann, Bartira</creatorcontrib><creatorcontrib>Steel, Patrick G</creatorcontrib><title>Chalcones identify cTXNPx as a potential antileishmanial drug target</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.</description><subject>Alkynes</subject><subject>Animals</subject><subject>Antiprotozoal Agents - administration & dosage</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Antiprotozoal Agents - therapeutic use</subject><subject>Biology and Life Sciences</subject><subject>Bone marrow</subject><subject>Cells, Cultured</subject><subject>Chalcone - administration & dosage</subject><subject>Chalcone - analogs & derivatives</subject><subject>Chalcone - metabolism</subject><subject>Chalcone - pharmacology</subject><subject>CRISPR</subject><subject>Cytosol - drug effects</subject><subject>Cytosol - enzymology</subject><subject>Cytosol - parasitology</subject><subject>Cytotoxicity</subject><subject>Drug Discovery</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Gene editing</subject><subject>Global health</subject><subject>Health aspects</subject><subject>Homology</subject><subject>Humans</subject><subject>Incubation period</subject><subject>Infections</subject><subject>Labeling</subject><subject>Labelling</subject><subject>Laboratory animals</subject><subject>Leishmania - classification</subject><subject>Leishmania - drug effects</subject><subject>Leishmaniasis</subject><subject>Leishmaniasis - drug therapy</subject><subject>Leishmaniasis - parasitology</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - parasitology</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular docking</subject><subject>Molecular Docking Simulation</subject><subject>Parasites</subject><subject>Parasitic diseases</subject><subject>Peroxidase</subject><subject>Peroxidases - antagonists & inhibitors</subject><subject>Peroxidases - metabolism</subject><subject>Phenotypes</subject><subject>Polyphenols</subject><subject>Proteins</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Protozoan Proteins - metabolism</subject><subject>Public health</subject><subject>Research and Analysis Methods</subject><subject>Testing</subject><subject>Therapeutic targets</subject><subject>Toxicity</subject><subject>Tropical diseases</subject><subject>Tryparedoxin peroxidase</subject><subject>Vector-borne diseases</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNptkluLEzEUxwdR3LX6DUQHBPGlNcnkMnkRlnpbWNSHPvgWMrlMU9JJTTLifnszdnZpZUng5PI7_5yTc6rqJQQr2DD4fhfGOEi_OgxZrwAAnBP4qLqEvCFLxBry-GR9UT1LaQcA4aSFT6uLBrMWYAYuq4_rrfQqDCbVTpshO3tbq83Pbz_-1DLVsj6EPJ1KX8tivHFpu5fDtNdx7OssY2_y8-qJlT6ZF7NdVJvPnzbrr8ub71-u11c3S0URzkvOSNdZCLWmHaYGIQOIYtxy3SnMkWw7pSHlQDEMMaINxp02slXWKtu0pFlUr4-yBx-SmPNPAlEIOEaEwUJcHwkd5E4cotvLeCuCdOLfQYi9kDE75Y3gTCvTGSMxh5hS1HElKbCYMc0QhG3R-jC_NnZ7U-AhR-nPRM9vBrcVffgtWkoxKuEvqnezQAy_RpOy2LukjPdyMGEscRPeAkYYRQV98x_6cHYz1cuSgBtsKO-qSVRc0Za0rMymUKsHqDK02bup0raU8dzh7YnD1kiftyn4MbswpHMQH0EVQ0rR2PvPgEBMPXkXtZh6Usw9WdxenX7kvdNdEzZ_AcXp3a8</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Escrivani, Douglas O</creator><creator>Charlton, Rebecca L</creator><creator>Caruso, Marjolly B</creator><creator>Burle-Caldas, Gabriela A</creator><creator>Borsodi, Maria Paula G</creator><creator>Zingali, Russolina B</creator><creator>Arruda-Costa, Natalia</creator><creator>Palmeira-Mello, Marcos V</creator><creator>de Jesus, Jéssica B</creator><creator>Souza, Alessandra M T</creator><creator>Abrahim-Vieira, Bárbara</creator><creator>Freitag-Pohl, Stefanie</creator><creator>Pohl, Ehmke</creator><creator>Denny, Paul W</creator><creator>Rossi-Bergmann, Bartira</creator><creator>Steel, Patrick G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-1244-3450</orcidid><orcidid>https://orcid.org/0000-0003-0105-5815</orcidid><orcidid>https://orcid.org/0000-0002-5051-1613</orcidid><orcidid>https://orcid.org/0000-0002-3791-8996</orcidid><orcidid>https://orcid.org/0000-0001-9986-405X</orcidid><orcidid>https://orcid.org/0000-0002-4872-8960</orcidid><orcidid>https://orcid.org/0000-0001-9440-5292</orcidid><orcidid>https://orcid.org/0000-0002-2493-5826</orcidid><orcidid>https://orcid.org/0000-0003-2550-5315</orcidid></search><sort><creationdate>20211101</creationdate><title>Chalcones identify cTXNPx as a potential antileishmanial drug target</title><author>Escrivani, Douglas O ; Charlton, Rebecca L ; Caruso, Marjolly B ; Burle-Caldas, Gabriela A ; Borsodi, Maria Paula G ; Zingali, Russolina B ; Arruda-Costa, Natalia ; Palmeira-Mello, Marcos V ; de Jesus, Jéssica B ; Souza, Alessandra M T ; Abrahim-Vieira, Bárbara ; Freitag-Pohl, Stefanie ; Pohl, Ehmke ; Denny, Paul W ; Rossi-Bergmann, Bartira ; Steel, Patrick G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c624t-975bbf11dd6b46e22e05c79f9dbc492a8bcd1690c741426344bdea8cffcf3853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alkynes</topic><topic>Animals</topic><topic>Antiprotozoal Agents - administration & dosage</topic><topic>Antiprotozoal Agents - pharmacology</topic><topic>Antiprotozoal Agents - therapeutic use</topic><topic>Biology and Life Sciences</topic><topic>Bone marrow</topic><topic>Cells, Cultured</topic><topic>Chalcone - administration & dosage</topic><topic>Chalcone - analogs & derivatives</topic><topic>Chalcone - metabolism</topic><topic>Chalcone - pharmacology</topic><topic>CRISPR</topic><topic>Cytosol - drug effects</topic><topic>Cytosol - enzymology</topic><topic>Cytosol - parasitology</topic><topic>Cytotoxicity</topic><topic>Drug Discovery</topic><topic>Drug therapy</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Gene editing</topic><topic>Global health</topic><topic>Health aspects</topic><topic>Homology</topic><topic>Humans</topic><topic>Incubation period</topic><topic>Infections</topic><topic>Labeling</topic><topic>Labelling</topic><topic>Laboratory animals</topic><topic>Leishmania - classification</topic><topic>Leishmania - drug effects</topic><topic>Leishmaniasis</topic><topic>Leishmaniasis - drug therapy</topic><topic>Leishmaniasis - parasitology</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - parasitology</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular docking</topic><topic>Molecular Docking Simulation</topic><topic>Parasites</topic><topic>Parasitic diseases</topic><topic>Peroxidase</topic><topic>Peroxidases - antagonists & inhibitors</topic><topic>Peroxidases - metabolism</topic><topic>Phenotypes</topic><topic>Polyphenols</topic><topic>Proteins</topic><topic>Protozoan Proteins - antagonists & inhibitors</topic><topic>Protozoan Proteins - metabolism</topic><topic>Public health</topic><topic>Research and Analysis Methods</topic><topic>Testing</topic><topic>Therapeutic targets</topic><topic>Toxicity</topic><topic>Tropical diseases</topic><topic>Tryparedoxin peroxidase</topic><topic>Vector-borne diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Escrivani, Douglas O</creatorcontrib><creatorcontrib>Charlton, Rebecca L</creatorcontrib><creatorcontrib>Caruso, Marjolly B</creatorcontrib><creatorcontrib>Burle-Caldas, Gabriela A</creatorcontrib><creatorcontrib>Borsodi, Maria Paula G</creatorcontrib><creatorcontrib>Zingali, Russolina B</creatorcontrib><creatorcontrib>Arruda-Costa, Natalia</creatorcontrib><creatorcontrib>Palmeira-Mello, Marcos V</creatorcontrib><creatorcontrib>de Jesus, Jéssica B</creatorcontrib><creatorcontrib>Souza, Alessandra M T</creatorcontrib><creatorcontrib>Abrahim-Vieira, Bárbara</creatorcontrib><creatorcontrib>Freitag-Pohl, Stefanie</creatorcontrib><creatorcontrib>Pohl, Ehmke</creatorcontrib><creatorcontrib>Denny, Paul W</creatorcontrib><creatorcontrib>Rossi-Bergmann, Bartira</creatorcontrib><creatorcontrib>Steel, Patrick G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS neglected tropical diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Escrivani, Douglas O</au><au>Charlton, Rebecca L</au><au>Caruso, Marjolly B</au><au>Burle-Caldas, Gabriela A</au><au>Borsodi, Maria Paula G</au><au>Zingali, Russolina B</au><au>Arruda-Costa, Natalia</au><au>Palmeira-Mello, Marcos V</au><au>de Jesus, Jéssica B</au><au>Souza, Alessandra M T</au><au>Abrahim-Vieira, Bárbara</au><au>Freitag-Pohl, Stefanie</au><au>Pohl, Ehmke</au><au>Denny, Paul W</au><au>Rossi-Bergmann, Bartira</au><au>Steel, Patrick G</au><au>Donatelli Serafim, Tiago</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chalcones identify cTXNPx as a potential antileishmanial drug target</atitle><jtitle>PLoS neglected tropical diseases</jtitle><addtitle>PLoS Negl Trop Dis</addtitle><date>2021-11-01</date><risdate>2021</risdate><volume>15</volume><issue>11</issue><spage>e0009951</spage><epage>e0009951</epage><pages>e0009951-e0009951</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><abstract>With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34780470</pmid><doi>10.1371/journal.pntd.0009951</doi><orcidid>https://orcid.org/0000-0003-1244-3450</orcidid><orcidid>https://orcid.org/0000-0003-0105-5815</orcidid><orcidid>https://orcid.org/0000-0002-5051-1613</orcidid><orcidid>https://orcid.org/0000-0002-3791-8996</orcidid><orcidid>https://orcid.org/0000-0001-9986-405X</orcidid><orcidid>https://orcid.org/0000-0002-4872-8960</orcidid><orcidid>https://orcid.org/0000-0001-9440-5292</orcidid><orcidid>https://orcid.org/0000-0002-2493-5826</orcidid><orcidid>https://orcid.org/0000-0003-2550-5315</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1935-2735 |
| ispartof | PLoS neglected tropical diseases, 2021-11, Vol.15 (11), p.e0009951-e0009951 |
| issn | 1935-2735 1935-2727 1935-2735 |
| language | eng |
| recordid | cdi_plos_journals_2610942571 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Alkynes Animals Antiprotozoal Agents - administration & dosage Antiprotozoal Agents - pharmacology Antiprotozoal Agents - therapeutic use Biology and Life Sciences Bone marrow Cells, Cultured Chalcone - administration & dosage Chalcone - analogs & derivatives Chalcone - metabolism Chalcone - pharmacology CRISPR Cytosol - drug effects Cytosol - enzymology Cytosol - parasitology Cytotoxicity Drug Discovery Drug therapy Drugs Enzymes Gene editing Global health Health aspects Homology Humans Incubation period Infections Labeling Labelling Laboratory animals Leishmania - classification Leishmania - drug effects Leishmaniasis Leishmaniasis - drug therapy Leishmaniasis - parasitology Macrophages Macrophages - drug effects Macrophages - parasitology Medicine and Health Sciences Mice Mice, Inbred BALB C Molecular docking Molecular Docking Simulation Parasites Parasitic diseases Peroxidase Peroxidases - antagonists & inhibitors Peroxidases - metabolism Phenotypes Polyphenols Proteins Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - metabolism Public health Research and Analysis Methods Testing Therapeutic targets Toxicity Tropical diseases Tryparedoxin peroxidase Vector-borne diseases |
| title | Chalcones identify cTXNPx as a potential antileishmanial drug target |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T20%3A00%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Chalcones%20identify%20cTXNPx%20as%20a%20potential%20antileishmanial%20drug%20target&rft.jtitle=PLoS%20neglected%20tropical%20diseases&rft.au=Escrivani,%20Douglas%20O&rft.date=2021-11-01&rft.volume=15&rft.issue=11&rft.spage=e0009951&rft.epage=e0009951&rft.pages=e0009951-e0009951&rft.issn=1935-2735&rft.eissn=1935-2735&rft_id=info:doi/10.1371/journal.pntd.0009951&rft_dat=%3Cgale_plos_%3EA685875873%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2610942571&rft_id=info:pmid/34780470&rft_galeid=A685875873&rft_doaj_id=oai_doaj_org_article_97dcebeea4914662b9ca60f477d72118&rfr_iscdi=true |