Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a K$_i$ of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-5...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 1990-12, Vol.250 (4986), p.1411-1413 |
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| creator | Merluzzi, Vincent J. Hargrave, Karl D. Labadia, Mark Grozinger, Karl Skoog, Mark Wu, Joseph C. Shih, Cheng-Kon Eckner, Kristine Hattox, Susan Adams, Julian Rosehthal, Alan S. Faanes, Ronald Eckner, Robert J. Koup, Richard A. Sullivan, John L. |
| description | A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a K$_i$ of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (>8000) in culture. |
| doi_str_mv | 10.1126/science.1701568 |
| format | Article |
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One compound, BI-RG-587, had a K$_i$ of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (>8000) in culture.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1701568</identifier><identifier>PMID: 1701568</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Society for the Advancement of Science</publisher><subject>Acquired immune deficiency syndrome ; Action of physical and chemical agents ; AIDS ; AIDS/HIV ; Animals ; Antiviral Agents - pharmacology ; Antivirals ; Biological and medical sciences ; Cell Line ; Cell lines ; Cellular biology ; Cultured cells ; DNA ; Drug therapy ; Enzymes ; Fundamental and applied biological sciences. Psychology ; Health aspects ; HIV ; HIV (Viruses) ; HIV 1 ; HIV infection ; HIV infections ; HIV-1 - drug effects ; HIV-1 - enzymology ; HIV-1 - physiology ; human immunodeficiency virus 1 ; Humans ; Inhibitory concentration 50 ; Kinetics ; Medical research ; Microbiology ; Molecular Structure ; Nevirapine ; Nucleic Acid Synthesis Inhibitors ; Pyridines - chemical synthesis ; Pyridines - pharmacology ; Reproduction ; Reverse Transcriptase Inhibitors ; T lymphocytes ; Virology ; Virus inhibitors ; Virus Replication - drug effects ; Viruses</subject><ispartof>Science (American Association for the Advancement of Science), 1990-12, Vol.250 (4986), p.1411-1413</ispartof><rights>Copyright 1990 American Association for the Advancement of Science</rights><rights>1991 INIST-CNRS</rights><rights>COPYRIGHT 1990 American Association for the Advancement of Science</rights><rights>COPYRIGHT 1990 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Dec 7, 1990</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c767t-a06024ff47a192269f8d1c6b2648c48a88d51dc764105e44883277d949ef47c63</citedby><cites>FETCH-LOGICAL-c767t-a06024ff47a192269f8d1c6b2648c48a88d51dc764105e44883277d949ef47c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2878396$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2878396$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,777,781,800,2871,2872,27905,27906,57998,58231</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19623269$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1701568$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Merluzzi, Vincent J.</creatorcontrib><creatorcontrib>Hargrave, Karl D.</creatorcontrib><creatorcontrib>Labadia, Mark</creatorcontrib><creatorcontrib>Grozinger, Karl</creatorcontrib><creatorcontrib>Skoog, Mark</creatorcontrib><creatorcontrib>Wu, Joseph C.</creatorcontrib><creatorcontrib>Shih, Cheng-Kon</creatorcontrib><creatorcontrib>Eckner, Kristine</creatorcontrib><creatorcontrib>Hattox, Susan</creatorcontrib><creatorcontrib>Adams, Julian</creatorcontrib><creatorcontrib>Rosehthal, Alan S.</creatorcontrib><creatorcontrib>Faanes, Ronald</creatorcontrib><creatorcontrib>Eckner, Robert J.</creatorcontrib><creatorcontrib>Koup, Richard A.</creatorcontrib><creatorcontrib>Sullivan, John L.</creatorcontrib><title>Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a K$_i$ of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (>8000) in culture.</description><subject>Acquired immune deficiency syndrome</subject><subject>Action of physical and chemical agents</subject><subject>AIDS</subject><subject>AIDS/HIV</subject><subject>Animals</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antivirals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Cultured cells</subject><subject>DNA</subject><subject>Drug therapy</subject><subject>Enzymes</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Health aspects</subject><subject>HIV</subject><subject>HIV (Viruses)</subject><subject>HIV 1</subject><subject>HIV infection</subject><subject>HIV infections</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - enzymology</subject><subject>HIV-1 - physiology</subject><subject>human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Inhibitory concentration 50</subject><subject>Kinetics</subject><subject>Medical research</subject><subject>Microbiology</subject><subject>Molecular Structure</subject><subject>Nevirapine</subject><subject>Nucleic Acid Synthesis Inhibitors</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacology</subject><subject>Reproduction</subject><subject>Reverse Transcriptase Inhibitors</subject><subject>T lymphocytes</subject><subject>Virology</subject><subject>Virus inhibitors</subject><subject>Virus Replication - drug 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of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor</title><author>Merluzzi, Vincent J. ; Hargrave, Karl D. ; Labadia, Mark ; Grozinger, Karl ; Skoog, Mark ; Wu, Joseph C. ; Shih, Cheng-Kon ; Eckner, Kristine ; Hattox, Susan ; Adams, Julian ; Rosehthal, Alan S. ; Faanes, Ronald ; Eckner, Robert J. ; Koup, Richard A. ; Sullivan, John L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c767t-a06024ff47a192269f8d1c6b2648c48a88d51dc764105e44883277d949ef47c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>Action of physical and chemical agents</topic><topic>AIDS</topic><topic>AIDS/HIV</topic><topic>Animals</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antivirals</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell lines</topic><topic>Cellular biology</topic><topic>Cultured cells</topic><topic>DNA</topic><topic>Drug therapy</topic><topic>Enzymes</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Health aspects</topic><topic>HIV</topic><topic>HIV (Viruses)</topic><topic>HIV 1</topic><topic>HIV infection</topic><topic>HIV infections</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - enzymology</topic><topic>HIV-1 - physiology</topic><topic>human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Inhibitory concentration 50</topic><topic>Kinetics</topic><topic>Medical research</topic><topic>Microbiology</topic><topic>Molecular Structure</topic><topic>Nevirapine</topic><topic>Nucleic Acid Synthesis Inhibitors</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacology</topic><topic>Reproduction</topic><topic>Reverse Transcriptase Inhibitors</topic><topic>T lymphocytes</topic><topic>Virology</topic><topic>Virus inhibitors</topic><topic>Virus Replication - drug effects</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Merluzzi, Vincent 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(American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>1990-12-07</date><risdate>1990</risdate><volume>250</volume><issue>4986</issue><spage>1411</spage><epage>1413</epage><pages>1411-1413</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a K$_i$ of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (>8000) in culture.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>1701568</pmid><doi>10.1126/science.1701568</doi><tpages>3</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 1990-12, Vol.250 (4986), p.1411-1413 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_80170009 |
| source | MEDLINE; Science Magazine; Jstor Complete Legacy |
| subjects | Acquired immune deficiency syndrome Action of physical and chemical agents AIDS AIDS/HIV Animals Antiviral Agents - pharmacology Antivirals Biological and medical sciences Cell Line Cell lines Cellular biology Cultured cells DNA Drug therapy Enzymes Fundamental and applied biological sciences. Psychology Health aspects HIV HIV (Viruses) HIV 1 HIV infection HIV infections HIV-1 - drug effects HIV-1 - enzymology HIV-1 - physiology human immunodeficiency virus 1 Humans Inhibitory concentration 50 Kinetics Medical research Microbiology Molecular Structure Nevirapine Nucleic Acid Synthesis Inhibitors Pyridines - chemical synthesis Pyridines - pharmacology Reproduction Reverse Transcriptase Inhibitors T lymphocytes Virology Virus inhibitors Virus Replication - drug effects Viruses |
| title | Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T11%3A44%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20HIV-1%20Replication%20by%20a%20Nonnucleoside%20Reverse%20Transcriptase%20Inhibitor&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Merluzzi,%20Vincent%20J.&rft.date=1990-12-07&rft.volume=250&rft.issue=4986&rft.spage=1411&rft.epage=1413&rft.pages=1411-1413&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.1701568&rft_dat=%3Cgale_proqu%3EA9269298%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213541460&rft_id=info:pmid/1701568&rft_galeid=A9269298&rft_jstor_id=2878396&rfr_iscdi=true |