Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug
Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibito...
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creator | Pallavi, Rani Roy, Nainita Nageshan, Rishi Kumar Talukdar, Pinaki Pavithra, Soundara Raghavan Reddy, Raghunath Venketesh, S Kumar, Rajender Gupta, Ashok Kumar Singh, Raj Kumar Yadav, Suresh Chandra Tatu, Utpal |
description | Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases. |
doi_str_mv | 10.1074/jbc.M110.155317 |
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In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.155317</identifier><identifier>PMID: 20837488</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Acetylation - drug effects ; Adenosine Triphosphatases - antagonists & inhibitors ; Adenosine Triphosphatases - genetics ; Adenosine Triphosphatases - metabolism ; Animals ; Antiprotozoal Agents - pharmacology ; Benzoquinones - pharmacology ; Disease Models, Animal ; Enzyme Inhibitors - pharmacology ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - genetics ; HSP90 Heat-Shock Proteins - metabolism ; Humans ; Lactams, Macrocyclic - pharmacology ; Malaria, Falciparum - drug therapy ; Malaria, Falciparum - enzymology ; Malaria, Falciparum - genetics ; Mice ; Molecular Bases of Disease ; Plasmodium berghei - enzymology ; Plasmodium berghei - genetics ; Plasmodium falciparum - enzymology ; Plasmodium falciparum - genetics ; Protein Structure, Tertiary ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - genetics ; Protozoan Proteins - metabolism ; Trypanosoma - enzymology ; Trypanosoma - genetics ; Trypanosomiasis - drug therapy ; Trypanosomiasis - enzymology ; Trypanosomiasis - genetics</subject><ispartof>The Journal of biological chemistry, 2010-12, Vol.285 (49), p.37964-37975</ispartof><rights>2010 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992230/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992230/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20837488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pallavi, Rani</creatorcontrib><creatorcontrib>Roy, Nainita</creatorcontrib><creatorcontrib>Nageshan, Rishi Kumar</creatorcontrib><creatorcontrib>Talukdar, Pinaki</creatorcontrib><creatorcontrib>Pavithra, Soundara Raghavan</creatorcontrib><creatorcontrib>Reddy, Raghunath</creatorcontrib><creatorcontrib>Venketesh, S</creatorcontrib><creatorcontrib>Kumar, Rajender</creatorcontrib><creatorcontrib>Gupta, Ashok Kumar</creatorcontrib><creatorcontrib>Singh, Raj Kumar</creatorcontrib><creatorcontrib>Yadav, Suresh Chandra</creatorcontrib><creatorcontrib>Tatu, Utpal</creatorcontrib><title>Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.</description><subject>Acetylation - drug effects</subject><subject>Adenosine Triphosphatases - antagonists & inhibitors</subject><subject>Adenosine Triphosphatases - genetics</subject><subject>Adenosine Triphosphatases - metabolism</subject><subject>Animals</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Benzoquinones - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Lactams, Macrocyclic - pharmacology</subject><subject>Malaria, Falciparum - drug therapy</subject><subject>Malaria, Falciparum - enzymology</subject><subject>Malaria, Falciparum - genetics</subject><subject>Mice</subject><subject>Molecular Bases of Disease</subject><subject>Plasmodium berghei - enzymology</subject><subject>Plasmodium berghei - genetics</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Plasmodium falciparum - genetics</subject><subject>Protein Structure, Tertiary</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Protozoan Proteins - genetics</subject><subject>Protozoan Proteins - metabolism</subject><subject>Trypanosoma - enzymology</subject><subject>Trypanosoma - genetics</subject><subject>Trypanosomiasis - drug therapy</subject><subject>Trypanosomiasis - enzymology</subject><subject>Trypanosomiasis - genetics</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctu1TAQhi0EoofCmh3yjlWKL0nssEBCFfQgFbVSi8QumjiTE5fEDrZTqX3KPhLuaalgNnP79f0jDSFvOTviTJUfrjpz9J3fd1UluXpGNpxpWciK_3xONowJXjSi0gfkVYxXLEfZ8JfkQGSRKrXekLstQqJx9OYXXYJPaB1tGIVIgfZh3dEEYYeJwg6si2mv8bceHLVuQJOsd_Ej7aw3I87WwETNCAFMwmBv4X5N_UC3F-cZOgQ_0_MJ4ux7u850gMnYBUIuwfX0Mtws4Hz0M1C8BhftfpzLaX0i2RSz82g7m3x4ONNkle0h4f7g1-RF5kZ885gPyY-vXy6Pt8Xp2cm348-nxSLqKhVNiQjQi0YPdSdBqloZVXcNlJWquZFDB1gqrZVgEjVnoikNk0oaUaPRvZGH5NMDd1m7GXuDLgWY2iXYGcJN68G2_2-cHdudv25F0wghWQa8fwQE_3vFmNrZRoPTBA79GludX1rWquRZ-e5fqyePv1-UfwDfhaVl</recordid><startdate>20101203</startdate><enddate>20101203</enddate><creator>Pallavi, Rani</creator><creator>Roy, Nainita</creator><creator>Nageshan, Rishi Kumar</creator><creator>Talukdar, Pinaki</creator><creator>Pavithra, Soundara Raghavan</creator><creator>Reddy, Raghunath</creator><creator>Venketesh, S</creator><creator>Kumar, Rajender</creator><creator>Gupta, Ashok Kumar</creator><creator>Singh, Raj Kumar</creator><creator>Yadav, Suresh Chandra</creator><creator>Tatu, Utpal</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20101203</creationdate><title>Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug</title><author>Pallavi, Rani ; Roy, Nainita ; Nageshan, Rishi Kumar ; Talukdar, Pinaki ; Pavithra, Soundara Raghavan ; Reddy, Raghunath ; Venketesh, S ; Kumar, Rajender ; Gupta, Ashok Kumar ; Singh, Raj Kumar ; Yadav, Suresh Chandra ; Tatu, Utpal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p265t-94eeaad298f6b3a3767c76b9a45761c3fbae47887203e810294c0373c26ec8dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acetylation - drug effects</topic><topic>Adenosine Triphosphatases - antagonists & inhibitors</topic><topic>Adenosine Triphosphatases - genetics</topic><topic>Adenosine Triphosphatases - metabolism</topic><topic>Animals</topic><topic>Antiprotozoal Agents - pharmacology</topic><topic>Benzoquinones - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - genetics</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Lactams, Macrocyclic - pharmacology</topic><topic>Malaria, Falciparum - drug therapy</topic><topic>Malaria, Falciparum - enzymology</topic><topic>Malaria, Falciparum - genetics</topic><topic>Mice</topic><topic>Molecular Bases of Disease</topic><topic>Plasmodium berghei - enzymology</topic><topic>Plasmodium berghei - genetics</topic><topic>Plasmodium falciparum - enzymology</topic><topic>Plasmodium falciparum - genetics</topic><topic>Protein Structure, Tertiary</topic><topic>Protozoan Proteins - antagonists & inhibitors</topic><topic>Protozoan Proteins - genetics</topic><topic>Protozoan Proteins - metabolism</topic><topic>Trypanosoma - enzymology</topic><topic>Trypanosoma - genetics</topic><topic>Trypanosomiasis - drug therapy</topic><topic>Trypanosomiasis - enzymology</topic><topic>Trypanosomiasis - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pallavi, Rani</creatorcontrib><creatorcontrib>Roy, Nainita</creatorcontrib><creatorcontrib>Nageshan, Rishi Kumar</creatorcontrib><creatorcontrib>Talukdar, Pinaki</creatorcontrib><creatorcontrib>Pavithra, Soundara Raghavan</creatorcontrib><creatorcontrib>Reddy, Raghunath</creatorcontrib><creatorcontrib>Venketesh, S</creatorcontrib><creatorcontrib>Kumar, Rajender</creatorcontrib><creatorcontrib>Gupta, Ashok Kumar</creatorcontrib><creatorcontrib>Singh, Raj Kumar</creatorcontrib><creatorcontrib>Yadav, Suresh Chandra</creatorcontrib><creatorcontrib>Tatu, Utpal</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pallavi, Rani</au><au>Roy, Nainita</au><au>Nageshan, Rishi Kumar</au><au>Talukdar, Pinaki</au><au>Pavithra, Soundara Raghavan</au><au>Reddy, Raghunath</au><au>Venketesh, S</au><au>Kumar, Rajender</au><au>Gupta, Ashok Kumar</au><au>Singh, Raj Kumar</au><au>Yadav, Suresh Chandra</au><au>Tatu, Utpal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2010-12-03</date><risdate>2010</risdate><volume>285</volume><issue>49</issue><spage>37964</spage><epage>37975</epage><pages>37964-37975</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>20837488</pmid><doi>10.1074/jbc.M110.155317</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acetylation - drug effects Adenosine Triphosphatases - antagonists & inhibitors Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Animals Antiprotozoal Agents - pharmacology Benzoquinones - pharmacology Disease Models, Animal Enzyme Inhibitors - pharmacology HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Humans Lactams, Macrocyclic - pharmacology Malaria, Falciparum - drug therapy Malaria, Falciparum - enzymology Malaria, Falciparum - genetics Mice Molecular Bases of Disease Plasmodium berghei - enzymology Plasmodium berghei - genetics Plasmodium falciparum - enzymology Plasmodium falciparum - genetics Protein Structure, Tertiary Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - genetics Protozoan Proteins - metabolism Trypanosoma - enzymology Trypanosoma - genetics Trypanosomiasis - drug therapy Trypanosomiasis - enzymology Trypanosomiasis - genetics |
title | Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug |
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