Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation
Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesize...
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| Veröffentlicht in: | Amino acids 2018-08, Vol.50 (8), p.1131-1143 |
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| creator | Chayrov, Radoslav L. Stylos, Evgenios K. Chatziathanasiadou, Maria V. Chuchkov, Kiril N. Tencheva, Aleksandra I. Kostagianni, Androniki D. Milkova, Tsenka S. Angelova, Assia L. Galabov, Angel S. Shishkov, Stoyan A. Todorov, Daniel G. Tzakos, Andreas G. Stankova, Ivanka G. |
| description | Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity. |
| doi_str_mv | 10.1007/s00726-018-2590-y |
| format | Article |
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A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.</description><identifier>ISSN: 0939-4451</identifier><identifier>EISSN: 1438-2199</identifier><identifier>DOI: 10.1007/s00726-018-2590-y</identifier><identifier>PMID: 29779181</identifier><language>eng</language><publisher>Vienna: Springer Vienna</publisher><subject>Acids ; Acyclovir ; Acyclovir - chemistry ; Acyclovir - pharmacology ; Analytical Chemistry ; Animals ; Antiviral activity ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Antiviral drugs ; Assaying ; Bile ; Bile acids ; Bile Acids and Salts - chemistry ; Biochemical Engineering ; Biochemistry ; Biomedical and Life Sciences ; Blood plasma ; Cell Line ; Chemical compounds ; Chenodeoxycholate ; Cytotoxicity ; Drugs ; Epstein-Barr virus ; Herpes simplex ; Herpesvirus 1, Human - drug effects ; Herpesvirus 2, Human - drug effects ; Herpesvirus 4, Human - drug effects ; High performance liquid chromatography ; Humans ; Life Sciences ; Mass spectrometry ; Mass spectroscopy ; Neurobiology ; Original Article ; Prodrugs ; Prodrugs - chemical synthesis ; Prodrugs - pharmacology ; Proteomics ; Stability analysis ; Toxicity ; Valacyclovir ; Viruses</subject><ispartof>Amino acids, 2018-08, Vol.50 (8), p.1131-1143</ispartof><rights>Springer-Verlag GmbH Austria, part of Springer Nature 2018</rights><rights>Amino Acids is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-329e772ff694286060470ceb6becf0e9b59fce00a12a07b1a6899a363bc4bb013</citedby><cites>FETCH-LOGICAL-c415t-329e772ff694286060470ceb6becf0e9b59fce00a12a07b1a6899a363bc4bb013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00726-018-2590-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00726-018-2590-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29779181$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chayrov, Radoslav L.</creatorcontrib><creatorcontrib>Stylos, Evgenios K.</creatorcontrib><creatorcontrib>Chatziathanasiadou, Maria V.</creatorcontrib><creatorcontrib>Chuchkov, Kiril N.</creatorcontrib><creatorcontrib>Tencheva, Aleksandra I.</creatorcontrib><creatorcontrib>Kostagianni, Androniki D.</creatorcontrib><creatorcontrib>Milkova, Tsenka S.</creatorcontrib><creatorcontrib>Angelova, Assia L.</creatorcontrib><creatorcontrib>Galabov, Angel S.</creatorcontrib><creatorcontrib>Shishkov, Stoyan A.</creatorcontrib><creatorcontrib>Todorov, Daniel G.</creatorcontrib><creatorcontrib>Tzakos, Andreas G.</creatorcontrib><creatorcontrib>Stankova, Ivanka G.</creatorcontrib><title>Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation</title><title>Amino acids</title><addtitle>Amino Acids</addtitle><addtitle>Amino Acids</addtitle><description>Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.</description><subject>Acids</subject><subject>Acyclovir</subject><subject>Acyclovir - chemistry</subject><subject>Acyclovir - pharmacology</subject><subject>Analytical Chemistry</subject><subject>Animals</subject><subject>Antiviral activity</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral drugs</subject><subject>Assaying</subject><subject>Bile</subject><subject>Bile acids</subject><subject>Bile Acids and Salts - chemistry</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Blood plasma</subject><subject>Cell Line</subject><subject>Chemical compounds</subject><subject>Chenodeoxycholate</subject><subject>Cytotoxicity</subject><subject>Drugs</subject><subject>Epstein-Barr virus</subject><subject>Herpes simplex</subject><subject>Herpesvirus 1, Human - drug effects</subject><subject>Herpesvirus 2, Human - drug effects</subject><subject>Herpesvirus 4, Human - drug effects</subject><subject>High performance liquid chromatography</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Neurobiology</subject><subject>Original Article</subject><subject>Prodrugs</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - pharmacology</subject><subject>Proteomics</subject><subject>Stability analysis</subject><subject>Toxicity</subject><subject>Valacyclovir</subject><subject>Viruses</subject><issn>0939-4451</issn><issn>1438-2199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kctuFDEQRS1ERIbAB7BBltiwSIfyox9mhyIekSKxCWur7HbPOHK7B7s7UX8Cf40nE0BCysZVLp97rdIl5A2DCwbQfsjl4E0FrKt4raBan5ENk6LcmFLPyQaUUJWUNTslL3O-BWC8Y80LcspV2yrWsQ35dYM-TMnHLUW72jDd-UT3aerTss303s876uIOo3U9xTj78oyhoIduXj_ShLOfYhn1LvttPKd5jfOu9Pmc7pYRI90HzCPSPKPxoWiKTU99pEWfJuruMCwPHq_IyYAhu9eP9Yz8-PL55vJbdf3969Xlp-vKSlbPleDKtS0fhkZJ3jXQgGzBOtMYZwdwytRqsA4AGUdoDcOmUwpFI4yVxgATZ-T90bds-XNxedajz9aFgNFNS9YcJOdC8FYU9N1_6O20pLLtA8W44FDLQrEjZdOUc3KD3ic_Ylo1A33ISR9z0iUnfchJr0Xz9tF5MaPr_yr-BFMAfgTy_hCOS_--ftr1NzNDoNU</recordid><startdate>20180801</startdate><enddate>20180801</enddate><creator>Chayrov, Radoslav L.</creator><creator>Stylos, Evgenios K.</creator><creator>Chatziathanasiadou, Maria V.</creator><creator>Chuchkov, Kiril N.</creator><creator>Tencheva, Aleksandra I.</creator><creator>Kostagianni, Androniki D.</creator><creator>Milkova, Tsenka S.</creator><creator>Angelova, Assia L.</creator><creator>Galabov, Angel S.</creator><creator>Shishkov, Stoyan A.</creator><creator>Todorov, Daniel G.</creator><creator>Tzakos, Andreas G.</creator><creator>Stankova, Ivanka G.</creator><general>Springer Vienna</general><general>Springer Nature B.V</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>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20180801</creationdate><title>Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation</title><author>Chayrov, Radoslav L. ; Stylos, Evgenios K. ; Chatziathanasiadou, Maria V. ; Chuchkov, Kiril N. ; Tencheva, Aleksandra I. ; Kostagianni, Androniki D. ; Milkova, Tsenka S. ; Angelova, Assia L. ; Galabov, Angel S. ; Shishkov, Stoyan A. ; Todorov, Daniel G. ; Tzakos, Andreas G. ; Stankova, Ivanka G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-329e772ff694286060470ceb6becf0e9b59fce00a12a07b1a6899a363bc4bb013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acids</topic><topic>Acyclovir</topic><topic>Acyclovir - chemistry</topic><topic>Acyclovir - pharmacology</topic><topic>Analytical Chemistry</topic><topic>Animals</topic><topic>Antiviral activity</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral drugs</topic><topic>Assaying</topic><topic>Bile</topic><topic>Bile acids</topic><topic>Bile Acids and Salts - chemistry</topic><topic>Biochemical Engineering</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Blood plasma</topic><topic>Cell Line</topic><topic>Chemical compounds</topic><topic>Chenodeoxycholate</topic><topic>Cytotoxicity</topic><topic>Drugs</topic><topic>Epstein-Barr virus</topic><topic>Herpes simplex</topic><topic>Herpesvirus 1, Human - drug effects</topic><topic>Herpesvirus 2, Human - drug effects</topic><topic>Herpesvirus 4, Human - drug effects</topic><topic>High performance liquid chromatography</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Neurobiology</topic><topic>Original Article</topic><topic>Prodrugs</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - pharmacology</topic><topic>Proteomics</topic><topic>Stability analysis</topic><topic>Toxicity</topic><topic>Valacyclovir</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chayrov, Radoslav L.</creatorcontrib><creatorcontrib>Stylos, Evgenios K.</creatorcontrib><creatorcontrib>Chatziathanasiadou, Maria V.</creatorcontrib><creatorcontrib>Chuchkov, Kiril N.</creatorcontrib><creatorcontrib>Tencheva, Aleksandra I.</creatorcontrib><creatorcontrib>Kostagianni, Androniki D.</creatorcontrib><creatorcontrib>Milkova, Tsenka S.</creatorcontrib><creatorcontrib>Angelova, Assia L.</creatorcontrib><creatorcontrib>Galabov, Angel S.</creatorcontrib><creatorcontrib>Shishkov, Stoyan A.</creatorcontrib><creatorcontrib>Todorov, Daniel G.</creatorcontrib><creatorcontrib>Tzakos, Andreas G.</creatorcontrib><creatorcontrib>Stankova, Ivanka 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>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Materials Science Collection</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><jtitle>Amino acids</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chayrov, Radoslav L.</au><au>Stylos, Evgenios K.</au><au>Chatziathanasiadou, Maria V.</au><au>Chuchkov, Kiril N.</au><au>Tencheva, Aleksandra I.</au><au>Kostagianni, Androniki D.</au><au>Milkova, Tsenka S.</au><au>Angelova, Assia L.</au><au>Galabov, Angel S.</au><au>Shishkov, Stoyan A.</au><au>Todorov, Daniel G.</au><au>Tzakos, Andreas G.</au><au>Stankova, Ivanka G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation</atitle><jtitle>Amino acids</jtitle><stitle>Amino Acids</stitle><addtitle>Amino Acids</addtitle><date>2018-08-01</date><risdate>2018</risdate><volume>50</volume><issue>8</issue><spage>1131</spage><epage>1143</epage><pages>1131-1143</pages><issn>0939-4451</issn><eissn>1438-2199</eissn><abstract>Bile acid prodrugs have served as a viable strategy for refining the pharmaceutical profile of parent drugs through utilizing bile acid transporters. A series of three ester prodrugs of the antiherpetic drug acyclovir (ACV) with the bile acids cholic, chenodeoxycholic and deoxycholic were synthesized and evaluated along with valacyclovir for their in vitro antiviral activity against herpes simplex viruses type 1 and type 2 (HSV-1, HSV-2). The in vitro antiviral activity of the three bile acid prodrugs was also evaluated against Epstein–Barr virus (EBV). Plasma stability assays, utilizing ultra-high performance liquid chromatography coupled with tandem mass spectrometry, in vitro cytotoxicity and inhibitory experiments were conducted in order to establish the biological profile of ACV prodrugs. The antiviral assays demonstrated that ACV-cholate had slightly better antiviral activity than ACV against HSV-1, while it presented an eight-fold higher activity with respect to ACV against HSV-2. ACV-chenodeoxycholate presented a six-fold higher antiviral activity against HSV-2 with respect to ACV. Concerning EBV, the highest antiviral effect was demonstrated by ACV-chenodeoxycholate. Human plasma stability assays revealed that ACV-deoxycholate was more stable than the other two prodrugs. These results suggest that decorating the core structure of ACV with bile acids could deliver prodrugs with amplified antiviral activity.</abstract><cop>Vienna</cop><pub>Springer Vienna</pub><pmid>29779181</pmid><doi>10.1007/s00726-018-2590-y</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Amino acids, 2018-08, Vol.50 (8), p.1131-1143 |
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| subjects | Acids Acyclovir Acyclovir - chemistry Acyclovir - pharmacology Analytical Chemistry Animals Antiviral activity Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Antiviral drugs Assaying Bile Bile acids Bile Acids and Salts - chemistry Biochemical Engineering Biochemistry Biomedical and Life Sciences Blood plasma Cell Line Chemical compounds Chenodeoxycholate Cytotoxicity Drugs Epstein-Barr virus Herpes simplex Herpesvirus 1, Human - drug effects Herpesvirus 2, Human - drug effects Herpesvirus 4, Human - drug effects High performance liquid chromatography Humans Life Sciences Mass spectrometry Mass spectroscopy Neurobiology Original Article Prodrugs Prodrugs - chemical synthesis Prodrugs - pharmacology Proteomics Stability analysis Toxicity Valacyclovir Viruses |
| title | Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation |
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