Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds
HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weak...
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| Veröffentlicht in: | Archives of biochemistry and biophysics 1997-05, Vol.341 (1), p.62-69 |
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| creator | Weber, Jan Majer, Pavel Litera, Jaroslav Urban, Jan Souček, Milan Vondrášek, Jiřı́ Konvalinka, Jan Novek, Petr Sedláček, Juraj Štrop, Petr Kräusslich, Hans-Georg Pichová, Iva |
| description | HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subnanomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1′, and P2′ side chains. While inhibitors containing reduced amide, hydroxyethylamine and statine isosteres hadKivalues in the range of 10−10–10−9magainst HIV-1 PR; their activities against HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2′ residue for both PRs. HIV-2 PR was shown to be more sensitive to P2′ Glu→Gln replacement. Using this data set we were able to design and prepare hydroxyethylene isostere containing inhibitors that were equipotent against both PRs. |
| doi_str_mv | 10.1006/abbi.1997.9945 |
| format | Article |
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PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subnanomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1′, and P2′ side chains. While inhibitors containing reduced amide, hydroxyethylamine and statine isosteres hadKivalues in the range of 10−10–10−9magainst HIV-1 PR; their activities against HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2′ residue for both PRs. HIV-2 PR was shown to be more sensitive to P2′ Glu→Gln replacement. Using this data set we were able to design and prepare hydroxyethylene isostere containing inhibitors that were equipotent against both PRs.</description><identifier>ISSN: 0003-9861</identifier><identifier>EISSN: 1096-0384</identifier><identifier>DOI: 10.1006/abbi.1997.9945</identifier><identifier>PMID: 9143353</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>AIDS/HIV ; Aspartic Acid Endopeptidases - metabolism ; Binding Sites ; Drug Design ; drug resistance ; enzyme kinetics ; Escherichia coli - genetics ; HIV Protease - metabolism ; HIV Protease Inhibitors - chemical synthesis ; HIV Protease Inhibitors - chemistry ; HIV Protease Inhibitors - pharmacology ; HIV-1 proteinase ; HIV-2 proteinase ; Models, Molecular ; Molecular Structure ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; peptide inhibitors ; subsite specificity</subject><ispartof>Archives of biochemistry and biophysics, 1997-05, Vol.341 (1), p.62-69</ispartof><rights>1997 Academic Press</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c339t-1c3ee7e58d463a2528bae67181fe5630469c203075f3beba04ae66e3267171103</citedby><cites>FETCH-LOGICAL-c339t-1c3ee7e58d463a2528bae67181fe5630469c203075f3beba04ae66e3267171103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0003986197999458$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9143353$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weber, Jan</creatorcontrib><creatorcontrib>Majer, Pavel</creatorcontrib><creatorcontrib>Litera, Jaroslav</creatorcontrib><creatorcontrib>Urban, Jan</creatorcontrib><creatorcontrib>Souček, Milan</creatorcontrib><creatorcontrib>Vondrášek, Jiřı́</creatorcontrib><creatorcontrib>Konvalinka, Jan</creatorcontrib><creatorcontrib>Novek, Petr</creatorcontrib><creatorcontrib>Sedláček, Juraj</creatorcontrib><creatorcontrib>Štrop, Petr</creatorcontrib><creatorcontrib>Kräusslich, Hans-Georg</creatorcontrib><creatorcontrib>Pichová, Iva</creatorcontrib><title>Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds</title><title>Archives of biochemistry and biophysics</title><addtitle>Arch Biochem Biophys</addtitle><description>HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. 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Using this data set we were able to design and prepare hydroxyethylene isostere containing inhibitors that were equipotent against both PRs.</description><subject>AIDS/HIV</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>Binding Sites</subject><subject>Drug Design</subject><subject>drug resistance</subject><subject>enzyme kinetics</subject><subject>Escherichia coli - genetics</subject><subject>HIV Protease - metabolism</subject><subject>HIV Protease Inhibitors - chemical synthesis</subject><subject>HIV Protease Inhibitors - chemistry</subject><subject>HIV Protease Inhibitors - pharmacology</subject><subject>HIV-1 proteinase</subject><subject>HIV-2 proteinase</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>peptide inhibitors</subject><subject>subsite specificity</subject><issn>0003-9861</issn><issn>1096-0384</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEFv1DAQRq0KVJbSa29IPnHLMo4TJ-aGtoWutBJ7AK6W40zaQZs4tZ2K_nuS3RW3nmak7_Mb-TF2I2AtANRn2zS0FlpXa62L8oKtBGiVgayLN2wFADLTtRLv2PsY_wAIUaj8kl1qUUhZyhX7u_cJB_fCN74fbaDoB-47vscxUet76jGR49vhkRpKPkRuHywNMfH77e9McDu0xy3n-zCDaLAR4xd-i5EejqC7p4nG5UTiO7Tt8YyfhjZ-YG87e4h4fZ5X7Ne3u5-b-2z34_t283WXOSl1yoSTiBWWdVsoafMyrxuLqhK16LBUEgqlXQ4SqrKTDTYWijlWKPO5UwkB8op9OnHH4J8mjMn0FB0eDnZAP0VTaYCiqsVcXJ-KLvgYA3ZmDNTb8GIEmEW1WVSbRbVZVM8PPp7JU9Nj-79-djvn9SnH-XvPhMFER7NrbCmgS6b19Br6HybLjOw</recordid><startdate>19970501</startdate><enddate>19970501</enddate><creator>Weber, Jan</creator><creator>Majer, Pavel</creator><creator>Litera, Jaroslav</creator><creator>Urban, Jan</creator><creator>Souček, Milan</creator><creator>Vondrášek, Jiřı́</creator><creator>Konvalinka, Jan</creator><creator>Novek, Petr</creator><creator>Sedláček, Juraj</creator><creator>Štrop, Petr</creator><creator>Kräusslich, Hans-Georg</creator><creator>Pichová, Iva</creator><general>Elsevier Inc</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></search><sort><creationdate>19970501</creationdate><title>Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds</title><author>Weber, Jan ; Majer, Pavel ; Litera, Jaroslav ; Urban, Jan ; Souček, Milan ; Vondrášek, Jiřı́ ; Konvalinka, Jan ; Novek, Petr ; Sedláček, Juraj ; Štrop, Petr ; Kräusslich, Hans-Georg ; Pichová, Iva</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c339t-1c3ee7e58d463a2528bae67181fe5630469c203075f3beba04ae66e3267171103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>AIDS/HIV</topic><topic>Aspartic Acid Endopeptidases - metabolism</topic><topic>Binding Sites</topic><topic>Drug Design</topic><topic>drug resistance</topic><topic>enzyme kinetics</topic><topic>Escherichia coli - genetics</topic><topic>HIV Protease - metabolism</topic><topic>HIV Protease Inhibitors - chemical synthesis</topic><topic>HIV Protease Inhibitors - chemistry</topic><topic>HIV Protease Inhibitors - pharmacology</topic><topic>HIV-1 proteinase</topic><topic>HIV-2 proteinase</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacology</topic><topic>peptide inhibitors</topic><topic>subsite specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weber, Jan</creatorcontrib><creatorcontrib>Majer, Pavel</creatorcontrib><creatorcontrib>Litera, Jaroslav</creatorcontrib><creatorcontrib>Urban, Jan</creatorcontrib><creatorcontrib>Souček, Milan</creatorcontrib><creatorcontrib>Vondrášek, Jiřı́</creatorcontrib><creatorcontrib>Konvalinka, Jan</creatorcontrib><creatorcontrib>Novek, Petr</creatorcontrib><creatorcontrib>Sedláček, Juraj</creatorcontrib><creatorcontrib>Štrop, Petr</creatorcontrib><creatorcontrib>Kräusslich, Hans-Georg</creatorcontrib><creatorcontrib>Pichová, Iva</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Archives of biochemistry and biophysics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weber, Jan</au><au>Majer, Pavel</au><au>Litera, Jaroslav</au><au>Urban, Jan</au><au>Souček, Milan</au><au>Vondrášek, Jiřı́</au><au>Konvalinka, Jan</au><au>Novek, Petr</au><au>Sedláček, Juraj</au><au>Štrop, Petr</au><au>Kräusslich, Hans-Georg</au><au>Pichová, Iva</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds</atitle><jtitle>Archives of biochemistry and biophysics</jtitle><addtitle>Arch Biochem Biophys</addtitle><date>1997-05-01</date><risdate>1997</risdate><volume>341</volume><issue>1</issue><spage>62</spage><epage>69</epage><pages>62-69</pages><issn>0003-9861</issn><eissn>1096-0384</eissn><abstract>HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subnanomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1′, and P2′ side chains. While inhibitors containing reduced amide, hydroxyethylamine and statine isosteres hadKivalues in the range of 10−10–10−9magainst HIV-1 PR; their activities against HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2′ residue for both PRs. HIV-2 PR was shown to be more sensitive to P2′ Glu→Gln replacement. 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| subjects | AIDS/HIV Aspartic Acid Endopeptidases - metabolism Binding Sites Drug Design drug resistance enzyme kinetics Escherichia coli - genetics HIV Protease - metabolism HIV Protease Inhibitors - chemical synthesis HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - pharmacology HIV-1 proteinase HIV-2 proteinase Models, Molecular Molecular Structure Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacology peptide inhibitors subsite specificity |
| title | Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds |
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