VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis
Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal...
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| Veröffentlicht in: | The Journal of infectious diseases 2015-11, Vol.212 (9), p.1439-1448 |
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| creator | Lepesheva, Galina I. Hargrove, Tatiana Y. Rachakonda, Girish Wawrzak, Zdzislaw Pomel, Sébastien Cojean, Sandrine Nde, Pius N. Nes, W. David Locuson, Charles W. Calcutt, M. Wade Waterman, Michael R. Daniels, J. Scott Loiseau, Philippe M. Villalta, Fernando |
| description | Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl) ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl) benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate. |
| doi_str_mv | 10.1093/infdis/jiv228 |
| format | Article |
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David ; Locuson, Charles W. ; Calcutt, M. Wade ; Waterman, Michael R. ; Daniels, J. Scott ; Loiseau, Philippe M. ; Villalta, Fernando</creator><creatorcontrib>Lepesheva, Galina I. ; Hargrove, Tatiana Y. ; Rachakonda, Girish ; Wawrzak, Zdzislaw ; Pomel, Sébastien ; Cojean, Sandrine ; Nde, Pius N. ; Nes, W. David ; Locuson, Charles W. ; Calcutt, M. Wade ; Waterman, Michael R. ; Daniels, J. Scott ; Loiseau, Philippe M. ; Villalta, Fernando ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl) ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl) benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate.</description><identifier>ISSN: 0022-1899</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/jiv228</identifier><identifier>PMID: 25883390</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Antiprotozoal Agents - pharmacokinetics ; Antiprotozoal Agents - pharmacology ; Benzamides - pharmacokinetics ; Benzamides - pharmacology ; Biotransformation ; Chagas Disease - drug therapy ; Cytochrome P-450 Enzyme Inhibitors - pharmacokinetics ; Cytochrome P-450 Enzyme Inhibitors - pharmacology ; Cytochrome P-450 Enzyme System - chemistry ; Disease Models, Animal ; Female ; Humans ; Imidazoles - pharmacology ; Inhibitory Concentration 50 ; Leishmaniasis, Visceral - drug therapy ; Major and Brief Reports ; Mice ; Mice, Inbred BALB C ; Microsomes, Liver - drug effects ; Molecular Structure ; Oxadiazoles - pharmacokinetics ; Oxadiazoles - pharmacology ; PARASITES ; Rats ; Structure-Activity Relationship ; Tissue Distribution ; Trypanosoma cruzi - drug effects</subject><ispartof>The Journal of infectious diseases, 2015-11, Vol.212 (9), p.1439-1448</ispartof><rights>Copyright © 2015 Oxford University Press on behalf of the Infectious Diseases Society of America</rights><rights>The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.</rights><rights>The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: . 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-c9434b3d1019d64c766f4a329b5df285951a398037b4402d9363622df4d4ff8f3</citedby><cites>FETCH-LOGICAL-c436t-c9434b3d1019d64c766f4a329b5df285951a398037b4402d9363622df4d4ff8f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/43709386$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/43709386$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,776,780,799,881,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25883390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1498351$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Lepesheva, Galina I.</creatorcontrib><creatorcontrib>Hargrove, Tatiana Y.</creatorcontrib><creatorcontrib>Rachakonda, Girish</creatorcontrib><creatorcontrib>Wawrzak, Zdzislaw</creatorcontrib><creatorcontrib>Pomel, Sébastien</creatorcontrib><creatorcontrib>Cojean, Sandrine</creatorcontrib><creatorcontrib>Nde, Pius N.</creatorcontrib><creatorcontrib>Nes, W. David</creatorcontrib><creatorcontrib>Locuson, Charles W.</creatorcontrib><creatorcontrib>Calcutt, M. Wade</creatorcontrib><creatorcontrib>Waterman, Michael R.</creatorcontrib><creatorcontrib>Daniels, J. Scott</creatorcontrib><creatorcontrib>Loiseau, Philippe M.</creatorcontrib><creatorcontrib>Villalta, Fernando</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis</title><title>The Journal of infectious diseases</title><addtitle>J Infect Dis</addtitle><description>Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl) ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl) benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate.</description><subject>Animals</subject><subject>Antiprotozoal Agents - pharmacokinetics</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Benzamides - pharmacokinetics</subject><subject>Benzamides - pharmacology</subject><subject>Biotransformation</subject><subject>Chagas Disease - drug therapy</subject><subject>Cytochrome P-450 Enzyme Inhibitors - pharmacokinetics</subject><subject>Cytochrome P-450 Enzyme Inhibitors - pharmacology</subject><subject>Cytochrome P-450 Enzyme System - chemistry</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Leishmaniasis, Visceral - drug therapy</subject><subject>Major and Brief Reports</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microsomes, Liver - drug effects</subject><subject>Molecular Structure</subject><subject>Oxadiazoles - pharmacokinetics</subject><subject>Oxadiazoles - pharmacology</subject><subject>PARASITES</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Tissue Distribution</subject><subject>Trypanosoma cruzi - drug effects</subject><issn>0022-1899</issn><issn>1537-6613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1vEzEQxS0EoiFw5Aiyet_W9ni99gUJbVpaKWqRgEicLMcfiUOzW9lOEP89RksjOI0076c3T_MQekvJBSUKLuMQXMyXu3hkTD5DM9pC1whB4TmaEcJYQ6VSZ-hVzjtCCAfRvURnrJUSQJEZ-rG6XmGTscF3_ie-CsHbEo8e998_txR_KelgyyH5ZuFTXTu8SIcN7s3gojPF4zAm3G_NpjosYvYme1w1vIrZ-mQe8NLHvN2bIZoc82v0IpiH7N_8nXP07frqa3_TLO8_3fYfl42t8UpjFQe-BkcJVU5w2wkRuAGm1q0LTLaqpQaUJNCtOSfMKRAgGHOBOx6CDDBHHybfx8N67531Q6lZ9GOKe5N-6dFE_b8yxK3ejEfNRT1ZHzhH55PBmEvU2cbi7daOw1CfoylXElpaoWaCbBpzTj6cDlCi_1Sjp2r0VE3l3_-b6kQ_dVGBdxOwy2VMJ51DV82kgN9VnJWi</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Lepesheva, Galina I.</creator><creator>Hargrove, Tatiana Y.</creator><creator>Rachakonda, Girish</creator><creator>Wawrzak, Zdzislaw</creator><creator>Pomel, Sébastien</creator><creator>Cojean, Sandrine</creator><creator>Nde, Pius N.</creator><creator>Nes, W. 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Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lepesheva, Galina I.</au><au>Hargrove, Tatiana Y.</au><au>Rachakonda, Girish</au><au>Wawrzak, Zdzislaw</au><au>Pomel, Sébastien</au><au>Cojean, Sandrine</au><au>Nde, Pius N.</au><au>Nes, W. David</au><au>Locuson, Charles W.</au><au>Calcutt, M. Wade</au><au>Waterman, Michael R.</au><au>Daniels, J. Scott</au><au>Loiseau, Philippe M.</au><au>Villalta, Fernando</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis</atitle><jtitle>The Journal of infectious diseases</jtitle><addtitle>J Infect Dis</addtitle><date>2015-11-01</date><risdate>2015</risdate><volume>212</volume><issue>9</issue><spage>1439</spage><epage>1448</epage><pages>1439-1448</pages><issn>0022-1899</issn><eissn>1537-6613</eissn><abstract>Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl) ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl) benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>25883390</pmid><doi>10.1093/infdis/jiv228</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of infectious diseases, 2015-11, Vol.212 (9), p.1439-1448 |
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| source | Jstor Complete Legacy; Oxford University Press Journals All Titles (1996-Current); MEDLINE; Alma/SFX Local Collection |
| subjects | Animals Antiprotozoal Agents - pharmacokinetics Antiprotozoal Agents - pharmacology Benzamides - pharmacokinetics Benzamides - pharmacology Biotransformation Chagas Disease - drug therapy Cytochrome P-450 Enzyme Inhibitors - pharmacokinetics Cytochrome P-450 Enzyme Inhibitors - pharmacology Cytochrome P-450 Enzyme System - chemistry Disease Models, Animal Female Humans Imidazoles - pharmacology Inhibitory Concentration 50 Leishmaniasis, Visceral - drug therapy Major and Brief Reports Mice Mice, Inbred BALB C Microsomes, Liver - drug effects Molecular Structure Oxadiazoles - pharmacokinetics Oxadiazoles - pharmacology PARASITES Rats Structure-Activity Relationship Tissue Distribution Trypanosoma cruzi - drug effects |
| title | VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis |
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