Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease
Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality a...
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| Veröffentlicht in: | PLoS neglected tropical diseases 2018-01, Vol.12 (1), p.e0006180-e0006180 |
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| creator | Gaspar, Luís Coron, Ross P KongThoo Lin, Paul Costa, David M Perez-Cabezas, Begoña Tavares, Joana Roura-Ferrer, Meritxell Ramos, Isbaal Ronin, Céline Major, Louise L Ciesielski, Fabrice Pemberton, Iain K MacDougall, Jane Ciapetti, Paola Smith, Terry K Cordeiro-da-Silva, Anabela |
| description | Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi. |
| doi_str_mv | 10.1371/journal.pntd.0006180 |
| format | Article |
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The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0006180</identifier><identifier>PMID: 29357372</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amastigotes ; Animals ; Antiprotozoal Agents - metabolism ; Benznidazole ; Biology and Life Sciences ; Cardiomyopathy ; Causes of ; Cell cycle ; Chagas disease ; Chagas Disease - drug therapy ; Chagas Disease - parasitology ; Chemical kinetics ; Disease control ; Disease Models, Animal ; Diseases ; Drug discovery ; Drug therapy ; Drugs ; Enzyme Inhibitors - metabolism ; Epimastigotes ; Formulations ; Funding ; Genetic aspects ; Health aspects ; Heart ; Inhibitors ; Medicine and Health Sciences ; Mice ; Morbidity ; NAD ; Niacinamide - metabolism ; Nicotinamide ; Parasites ; Parasitic diseases ; Pharmaceutical sciences ; Pharmacokinetics ; Pharmacology ; Physical Sciences ; Physiological aspects ; Proteins ; Protozoa ; Protozoan Proteins - antagonists & inhibitors ; Quinolones - metabolism ; R&D ; Research & development ; Sirtuins ; Specificity ; Spermidine ; Spermine - analogs & derivatives ; Spermine - metabolism ; Substrates ; Supervision ; Treatment Outcome ; Tropical diseases ; Trypanosoma cruzi ; Trypanosoma cruzi - drug effects ; Vector-borne diseases</subject><ispartof>PLoS neglected tropical diseases, 2018-01, Vol.12 (1), p.e0006180-e0006180</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Sir2 related protein 1 as potential drugs against Chagas disease. PLoS Negl Trop Dis 12(1): e0006180. https://doi.org/10.1371/journal.pntd.0006180</rights><rights>2018 Gaspar et al 2018 Gaspar et al</rights><rights>2018 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Sir2 related protein 1 as potential drugs against Chagas disease. PLoS Negl Trop Dis 12(1): e0006180. https://doi.org/10.1371/journal.pntd.0006180</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c651t-64bd4d6587762715ab071fc61a27a8f60a8f343a8bbc6bbddddd8417cabd62133</citedby><cites>FETCH-LOGICAL-c651t-64bd4d6587762715ab071fc61a27a8f60a8f343a8bbc6bbddddd8417cabd62133</cites><orcidid>0000-0003-1994-2009</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/PMC5794198/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794198/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29357372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gaspar, Luís</creatorcontrib><creatorcontrib>Coron, Ross P</creatorcontrib><creatorcontrib>KongThoo Lin, Paul</creatorcontrib><creatorcontrib>Costa, David M</creatorcontrib><creatorcontrib>Perez-Cabezas, Begoña</creatorcontrib><creatorcontrib>Tavares, Joana</creatorcontrib><creatorcontrib>Roura-Ferrer, Meritxell</creatorcontrib><creatorcontrib>Ramos, Isbaal</creatorcontrib><creatorcontrib>Ronin, Céline</creatorcontrib><creatorcontrib>Major, Louise L</creatorcontrib><creatorcontrib>Ciesielski, Fabrice</creatorcontrib><creatorcontrib>Pemberton, Iain K</creatorcontrib><creatorcontrib>MacDougall, Jane</creatorcontrib><creatorcontrib>Ciapetti, Paola</creatorcontrib><creatorcontrib>Smith, Terry K</creatorcontrib><creatorcontrib>Cordeiro-da-Silva, Anabela</creatorcontrib><title>Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.</description><subject>Amastigotes</subject><subject>Animals</subject><subject>Antiprotozoal Agents - metabolism</subject><subject>Benznidazole</subject><subject>Biology and Life Sciences</subject><subject>Cardiomyopathy</subject><subject>Causes of</subject><subject>Cell cycle</subject><subject>Chagas disease</subject><subject>Chagas Disease - drug therapy</subject><subject>Chagas Disease - parasitology</subject><subject>Chemical kinetics</subject><subject>Disease control</subject><subject>Disease Models, Animal</subject><subject>Diseases</subject><subject>Drug discovery</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Epimastigotes</subject><subject>Formulations</subject><subject>Funding</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Inhibitors</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Morbidity</subject><subject>NAD</subject><subject>Niacinamide - metabolism</subject><subject>Nicotinamide</subject><subject>Parasites</subject><subject>Parasitic diseases</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Protozoa</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Quinolones - metabolism</subject><subject>R&D</subject><subject>Research & development</subject><subject>Sirtuins</subject><subject>Specificity</subject><subject>Spermidine</subject><subject>Spermine - analogs & derivatives</subject><subject>Spermine - metabolism</subject><subject>Substrates</subject><subject>Supervision</subject><subject>Treatment Outcome</subject><subject>Tropical diseases</subject><subject>Trypanosoma cruzi</subject><subject>Trypanosoma cruzi - drug effects</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>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUlFrFDEQXkSxtfoPRANC8eXOJLubZF8K5ah6UPDB-hxnk-xdjr1kTbJC_fVmvW25kyaQDDPffDPzMUXxluAlKTn5tPNjcNAvB5f0EmPMiMDPinPSlPWC8rJ-fmSfFa9i3GFcN7UgL4szmgO85PS8-Ll2W9va5ENEvkN34X4A56PfA1Jh_GPRdxsoCqaHZDQagk_GOkQQRDRk2yULPdJh3EQEG7AuJrTaZisibaOBaF4XLzroo3kz_xfFj883d6uvi9tvX9ar69uFYjVJC1a1utKsFpwzykkNLeakU4wA5SA6hvNTViWItlWsbfV0REW4glYzSsryonh_4B16H-UsTpQUYzopw2lGrA8I7WEnh2D3EO6lByv_OXzYSAjJqt7IjpkKiNFd24hKYCpEbkfzymgCVYlx5rqaq43t3miVhQjQn5CeRpzdyo3_LWveVKQRmeDjTBD8r9HEJPc2KtP34IwfoyRNg6sGC8Yy9MN_0Kenm1EbyANY1_lcV02k8rqmdUM4xVPZ5ROofLXZW-Wd6Wz2nyRcHiVsDfRpG30_JutdPAVWB6AKPsZgukcxCJbTwj50LaeFlfPC5rR3x0I-Jj1saPkXK5Xntw</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Gaspar, Luís</creator><creator>Coron, Ross P</creator><creator>KongThoo Lin, Paul</creator><creator>Costa, David M</creator><creator>Perez-Cabezas, Begoña</creator><creator>Tavares, Joana</creator><creator>Roura-Ferrer, Meritxell</creator><creator>Ramos, Isbaal</creator><creator>Ronin, Céline</creator><creator>Major, Louise L</creator><creator>Ciesielski, Fabrice</creator><creator>Pemberton, Iain K</creator><creator>MacDougall, Jane</creator><creator>Ciapetti, Paola</creator><creator>Smith, Terry K</creator><creator>Cordeiro-da-Silva, Anabela</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/0000-0003-1994-2009</orcidid></search><sort><creationdate>20180101</creationdate><title>Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease</title><author>Gaspar, Luís ; Coron, Ross P ; KongThoo Lin, Paul ; Costa, David M ; Perez-Cabezas, Begoña ; Tavares, Joana ; Roura-Ferrer, Meritxell ; Ramos, Isbaal ; Ronin, Céline ; Major, Louise L ; Ciesielski, Fabrice ; Pemberton, Iain K ; MacDougall, Jane ; Ciapetti, Paola ; Smith, Terry K ; Cordeiro-da-Silva, Anabela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c651t-64bd4d6587762715ab071fc61a27a8f60a8f343a8bbc6bbddddd8417cabd62133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Amastigotes</topic><topic>Animals</topic><topic>Antiprotozoal Agents - 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antagonists & inhibitors</topic><topic>Quinolones - metabolism</topic><topic>R&D</topic><topic>Research & development</topic><topic>Sirtuins</topic><topic>Specificity</topic><topic>Spermidine</topic><topic>Spermine - analogs & derivatives</topic><topic>Spermine - metabolism</topic><topic>Substrates</topic><topic>Supervision</topic><topic>Treatment Outcome</topic><topic>Tropical diseases</topic><topic>Trypanosoma cruzi</topic><topic>Trypanosoma cruzi - drug effects</topic><topic>Vector-borne diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gaspar, Luís</creatorcontrib><creatorcontrib>Coron, Ross P</creatorcontrib><creatorcontrib>KongThoo Lin, Paul</creatorcontrib><creatorcontrib>Costa, David M</creatorcontrib><creatorcontrib>Perez-Cabezas, Begoña</creatorcontrib><creatorcontrib>Tavares, Joana</creatorcontrib><creatorcontrib>Roura-Ferrer, Meritxell</creatorcontrib><creatorcontrib>Ramos, Isbaal</creatorcontrib><creatorcontrib>Ronin, Céline</creatorcontrib><creatorcontrib>Major, Louise L</creatorcontrib><creatorcontrib>Ciesielski, Fabrice</creatorcontrib><creatorcontrib>Pemberton, Iain K</creatorcontrib><creatorcontrib>MacDougall, Jane</creatorcontrib><creatorcontrib>Ciapetti, Paola</creatorcontrib><creatorcontrib>Smith, Terry K</creatorcontrib><creatorcontrib>Cordeiro-da-Silva, Anabela</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>Gaspar, Luís</au><au>Coron, Ross P</au><au>KongThoo Lin, Paul</au><au>Costa, David M</au><au>Perez-Cabezas, Begoña</au><au>Tavares, Joana</au><au>Roura-Ferrer, Meritxell</au><au>Ramos, Isbaal</au><au>Ronin, Céline</au><au>Major, Louise L</au><au>Ciesielski, Fabrice</au><au>Pemberton, Iain K</au><au>MacDougall, Jane</au><au>Ciapetti, Paola</au><au>Smith, Terry K</au><au>Cordeiro-da-Silva, Anabela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease</atitle><jtitle>PLoS neglected tropical diseases</jtitle><addtitle>PLoS Negl Trop Dis</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>12</volume><issue>1</issue><spage>e0006180</spage><epage>e0006180</epage><pages>e0006180-e0006180</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><abstract>Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29357372</pmid><doi>10.1371/journal.pntd.0006180</doi><orcidid>https://orcid.org/0000-0003-1994-2009</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1935-2735 |
| ispartof | PLoS neglected tropical diseases, 2018-01, Vol.12 (1), p.e0006180-e0006180 |
| issn | 1935-2735 1935-2727 1935-2735 |
| language | eng |
| recordid | cdi_plos_journals_2002618072 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access |
| subjects | Amastigotes Animals Antiprotozoal Agents - metabolism Benznidazole Biology and Life Sciences Cardiomyopathy Causes of Cell cycle Chagas disease Chagas Disease - drug therapy Chagas Disease - parasitology Chemical kinetics Disease control Disease Models, Animal Diseases Drug discovery Drug therapy Drugs Enzyme Inhibitors - metabolism Epimastigotes Formulations Funding Genetic aspects Health aspects Heart Inhibitors Medicine and Health Sciences Mice Morbidity NAD Niacinamide - metabolism Nicotinamide Parasites Parasitic diseases Pharmaceutical sciences Pharmacokinetics Pharmacology Physical Sciences Physiological aspects Proteins Protozoa Protozoan Proteins - antagonists & inhibitors Quinolones - metabolism R&D Research & development Sirtuins Specificity Spermidine Spermine - analogs & derivatives Spermine - metabolism Substrates Supervision Treatment Outcome Tropical diseases Trypanosoma cruzi Trypanosoma cruzi - drug effects Vector-borne diseases |
| title | Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease |
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