Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance
HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-08, Vol.51 (15), p.4839-4843 |
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| container_end_page | 4843 |
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| container_issue | 15 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Kožíšek, Milan Cígler, Petr Lepšík, Martin Fanfrlík, Jindřich Řezáčová, Pavlína Brynda, Jiří Pokorná, Jana Plešek, Jaromír Grüner, Bohumír Grantz Šašková, Klára Václavíková, Jana Král, Vladimír Konvalinka, Jan |
| description | HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode. |
| doi_str_mv | 10.1021/jm8002334 |
| format | Article |
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We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm8002334</identifier><identifier>PMID: 18598016</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Boron Compounds - chemistry ; Boron Compounds - pharmacology ; Crystallography, X-Ray ; Drug Resistance, Viral - drug effects ; HIV Protease - chemistry ; HIV Protease - genetics ; HIV Protease - metabolism ; HIV Protease Inhibitors - chemistry ; HIV Protease Inhibitors - pharmacology ; HIV-1 - drug effects ; HIV-1 - enzymology ; Medical sciences ; Metals - chemistry ; Models, Molecular ; Molecular Structure ; Mutation - genetics ; Pharmacology. 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Med. Chem</addtitle><description>HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Boron Compounds - chemistry</subject><subject>Boron Compounds - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>Drug Resistance, Viral - drug effects</subject><subject>HIV Protease - chemistry</subject><subject>HIV Protease - genetics</subject><subject>HIV Protease - metabolism</subject><subject>HIV Protease Inhibitors - chemistry</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - enzymology</subject><subject>Medical sciences</subject><subject>Metals - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Mutation - genetics</subject><subject>Pharmacology. Drug treatments</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1Lw0AQBuBFFK3Vg39A9uLBQ3S_stl4C8WPQv1A1GuYbid2S5oNu2nFf2_E0l48DQwP7zAvIWecXXEm-PViaRgTUqo9MuCpYIkyTO2TQb8UidBCHpHjGBeMMcmFPCRH3KS5YVwPSBw3PnxC4yx98fX3HGcBavqIHdQ1WAhTH6BBOm7mbuo6HyL1FX0Yf9CX4DuEiDe0oE_4RYu2DR7snHaePq8xWL90zSctms6t3W_mK0YXO2gsnpCDCuqIp5s5JO93t2-jh2TyfD8eFZMElFJdYkyaAstQaFZpmVlmq1zZ3ADPZzITNkWtBTdGc4WoLFRZbkReoYSZ1jBN5ZBc_uXa4GMMWJVtcEsI3yVn5W9x5ba43p7_2XY1XeJsJzdN9eBiAyBaqKu-Fuvi1gmWZnnGzM6BjeXCr0LTv_jPwR-pWoF4</recordid><startdate>20080814</startdate><enddate>20080814</enddate><creator>Kožíšek, Milan</creator><creator>Cígler, Petr</creator><creator>Lepšík, Martin</creator><creator>Fanfrlík, Jindřich</creator><creator>Řezáčová, Pavlína</creator><creator>Brynda, Jiří</creator><creator>Pokorná, Jana</creator><creator>Plešek, Jaromír</creator><creator>Grüner, Bohumír</creator><creator>Grantz Šašková, Klára</creator><creator>Václavíková, Jana</creator><creator>Král, Vladimír</creator><creator>Konvalinka, Jan</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20080814</creationdate><title>Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance</title><author>Kožíšek, Milan ; Cígler, Petr ; Lepšík, Martin ; Fanfrlík, Jindřich ; Řezáčová, Pavlína ; Brynda, Jiří ; Pokorná, Jana ; Plešek, Jaromír ; Grüner, Bohumír ; Grantz Šašková, Klára ; Václavíková, Jana ; Král, Vladimír ; Konvalinka, Jan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a444t-8855a07e260f637c0cf94c98a19d372c5e662188614ee4caf79829fe3ad66ab53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Boron Compounds - chemistry</topic><topic>Boron Compounds - pharmacology</topic><topic>Crystallography, X-Ray</topic><topic>Drug Resistance, Viral - drug effects</topic><topic>HIV Protease - chemistry</topic><topic>HIV Protease - genetics</topic><topic>HIV Protease - metabolism</topic><topic>HIV Protease Inhibitors - chemistry</topic><topic>HIV Protease Inhibitors - pharmacology</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - enzymology</topic><topic>Medical sciences</topic><topic>Metals - chemistry</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Mutation - genetics</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>2008-08-14</date><risdate>2008</risdate><volume>51</volume><issue>15</issue><spage>4839</spage><epage>4843</epage><pages>4839-4843</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18598016</pmid><doi>10.1021/jm8002334</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-08, Vol.51 (15), p.4839-4843 |
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| source | ACS Publications; MEDLINE |
| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Boron Compounds - chemistry Boron Compounds - pharmacology Crystallography, X-Ray Drug Resistance, Viral - drug effects HIV Protease - chemistry HIV Protease - genetics HIV Protease - metabolism HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - pharmacology HIV-1 - drug effects HIV-1 - enzymology Medical sciences Metals - chemistry Models, Molecular Molecular Structure Mutation - genetics Pharmacology. Drug treatments |
| title | Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance |
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