Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy
Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-05, Vol.56 (10), p.3959-3968 |
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| container_end_page | 3968 |
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| container_issue | 10 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 56 |
| creator | Bailey, Christopher M Sullivan, Todd J Iyidogan, Pinar Tirado-Rives, Julian Chung, Raymond Ruiz-Caro, Juliana Mohamed, Ebrahim Jorgensen, William Hunter, Roger Anderson, Karen S |
| description | Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication. |
| doi_str_mv | 10.1021/jm400160s |
| format | Article |
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These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm400160s</identifier><identifier>PMID: 23659183</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Anti-HIV Agents - chemical synthesis ; Anti-HIV Agents - pharmacology ; Dinucleoside Phosphates - chemistry ; Dinucleoside Phosphates - isolation & purification ; DNA Primers ; Drug Design ; HIV Reverse Transcriptase - chemistry ; HIV Reverse Transcriptase - isolation & purification ; HIV Reverse Transcriptase - metabolism ; HIV-1 - drug effects ; Humans ; Indicators and Reagents ; Mass Spectrometry ; Models, Molecular ; Oligonucleotides - chemistry ; Oligonucleotides - isolation & purification ; Polyethylene Glycols - pharmacology ; Reverse Transcriptase Inhibitors - chemical synthesis ; Reverse Transcriptase Inhibitors - pharmacology ; Structure-Activity Relationship ; Virus Replication - drug effects ; X-Ray Diffraction</subject><ispartof>Journal of medicinal chemistry, 2013-05, Vol.56 (10), p.3959-3968</ispartof><rights>Copyright © 2013 American Chemical Society</rights><rights>XXXX American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a471t-179dfbe82cfa9f1df5541bbe92ea99ede0eed089cdbb17f0fdd531269f7ad5873</citedby><cites>FETCH-LOGICAL-a471t-179dfbe82cfa9f1df5541bbe92ea99ede0eed089cdbb17f0fdd531269f7ad5873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm400160s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm400160s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23659183$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bailey, Christopher M</creatorcontrib><creatorcontrib>Sullivan, Todd J</creatorcontrib><creatorcontrib>Iyidogan, Pinar</creatorcontrib><creatorcontrib>Tirado-Rives, Julian</creatorcontrib><creatorcontrib>Chung, Raymond</creatorcontrib><creatorcontrib>Ruiz-Caro, Juliana</creatorcontrib><creatorcontrib>Mohamed, Ebrahim</creatorcontrib><creatorcontrib>Jorgensen, William</creatorcontrib><creatorcontrib>Hunter, Roger</creatorcontrib><creatorcontrib>Anderson, Karen S</creatorcontrib><title>Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.</description><subject>Anti-HIV Agents - chemical synthesis</subject><subject>Anti-HIV Agents - pharmacology</subject><subject>Dinucleoside Phosphates - chemistry</subject><subject>Dinucleoside Phosphates - isolation & purification</subject><subject>DNA Primers</subject><subject>Drug Design</subject><subject>HIV Reverse Transcriptase - chemistry</subject><subject>HIV Reverse Transcriptase - isolation & purification</subject><subject>HIV Reverse Transcriptase - metabolism</subject><subject>HIV-1 - drug effects</subject><subject>Humans</subject><subject>Indicators and Reagents</subject><subject>Mass Spectrometry</subject><subject>Models, Molecular</subject><subject>Oligonucleotides - chemistry</subject><subject>Oligonucleotides - isolation & purification</subject><subject>Polyethylene Glycols - pharmacology</subject><subject>Reverse Transcriptase Inhibitors - chemical synthesis</subject><subject>Reverse Transcriptase Inhibitors - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Virus Replication - drug effects</subject><subject>X-Ray Diffraction</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkduKFDEQhoMo7rh64QtIbgS9aM2hj14s6HjYgfWAjt6G6qQyk6E7aZPugXkWX9YeZh0UhIKiqI-_fuon5DFnLzgT_OWuzxnjJUt3yIIXgmV5zfK7ZMGYEJkohbwgD1LaMcYkF_I-uRCyLBpeywX59cbZyevRBQ8dXfmta91xoMHS66kHT1d9P_lg0Drt0OsD_eHilOj6MCDl9CvuMSak6wg-6eiGERK-oh9Rb8G71FPwhn6JIdhsrmXwGoeRQqJAP4U9dnS9xQgDTqPT9C0mt_H02xhhxM3hIblnoUv46LZfku_v362X19nN5w-r5eubDPKKjxmvGmNbrIW20FhubFHkvG2xEQhNgwYZomF1o03b8soya0wx_6FsbAWmqCt5Sa5OusPU9mg0-tlAp4boeogHFcCpfzfebdUm7JWspBT5UeDZrUAMPydMo-pd0th14DFMSXE5W6oqURYz-vyE6hhSimjPZzhTxzDVOcyZffK3rzP5J70ZeHoCQCe1C1OcM0z_EfoNaQ6rKg</recordid><startdate>20130523</startdate><enddate>20130523</enddate><creator>Bailey, Christopher M</creator><creator>Sullivan, Todd J</creator><creator>Iyidogan, Pinar</creator><creator>Tirado-Rives, Julian</creator><creator>Chung, Raymond</creator><creator>Ruiz-Caro, Juliana</creator><creator>Mohamed, Ebrahim</creator><creator>Jorgensen, William</creator><creator>Hunter, Roger</creator><creator>Anderson, Karen S</creator><general>American Chemical Society</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130523</creationdate><title>Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy</title><author>Bailey, Christopher M ; 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Med. Chem</addtitle><date>2013-05-23</date><risdate>2013</risdate><volume>56</volume><issue>10</issue><spage>3959</spage><epage>3968</epage><pages>3959-3968</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23659183</pmid><doi>10.1021/jm400160s</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2013-05, Vol.56 (10), p.3959-3968 |
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| source | ACS Publications; MEDLINE |
| subjects | Anti-HIV Agents - chemical synthesis Anti-HIV Agents - pharmacology Dinucleoside Phosphates - chemistry Dinucleoside Phosphates - isolation & purification DNA Primers Drug Design HIV Reverse Transcriptase - chemistry HIV Reverse Transcriptase - isolation & purification HIV Reverse Transcriptase - metabolism HIV-1 - drug effects Humans Indicators and Reagents Mass Spectrometry Models, Molecular Oligonucleotides - chemistry Oligonucleotides - isolation & purification Polyethylene Glycols - pharmacology Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - pharmacology Structure-Activity Relationship Virus Replication - drug effects X-Ray Diffraction |
| title | Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy |
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