Discovery of a Small Molecule PDI Inhibitor That Inhibits Reduction of HIV-1 Envelope Glycoprotein gp120
Protein disulfide isomerase (PDI) is a promiscuous protein with multifunctional properties. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction. The entry of HIV-1 into cells is facilitated by the PDI-catalyzed reductive cleavage of disulfide b...
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| Veröffentlicht in: | ACS chemical biology 2011-03, Vol.6 (3), p.245-251 |
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| creator | Khan, Maola M. G Simizu, Siro Lai, Ngit Shin Kawatani, Makoto Shimizu, Takeshi Osada, Hiroyuki |
| description | Protein disulfide isomerase (PDI) is a promiscuous protein with multifunctional properties. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction. The entry of HIV-1 into cells is facilitated by the PDI-catalyzed reductive cleavage of disulfide bonds in gp120. PDI is regarded as a potential drug target because of its reduction activity. We screened a chemical library of natural products for PDI-specific inhibitors in a high-throughput fashion and identified the natural compound juniferdin as the most potent inhibitor of PDI. Derivatives of juniferdin were synthesized, with compound 13 showing inhibitory activities comparable to those of juniferdin but reduced cytotoxicity. Both juniferdin and compound 13 inhibited PDI reductase activity in a dose-dependent manner, with IC50 values of 156 and 167 nM, respectively. Our results also indicated that juniferdin and compound 13 exert their inhibitory activities specifically on PDI but do not significantly inhibit homologues of this protein family. Moreover, we found that both compounds can inhibit PDI-mediated reduction of HIV-1 envelope glycoprotein gp120. |
| doi_str_mv | 10.1021/cb100387r |
| format | Article |
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G ; Simizu, Siro ; Lai, Ngit Shin ; Kawatani, Makoto ; Shimizu, Takeshi ; Osada, Hiroyuki</creator><creatorcontrib>Khan, Maola M. G ; Simizu, Siro ; Lai, Ngit Shin ; Kawatani, Makoto ; Shimizu, Takeshi ; Osada, Hiroyuki</creatorcontrib><description>Protein disulfide isomerase (PDI) is a promiscuous protein with multifunctional properties. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction. The entry of HIV-1 into cells is facilitated by the PDI-catalyzed reductive cleavage of disulfide bonds in gp120. PDI is regarded as a potential drug target because of its reduction activity. We screened a chemical library of natural products for PDI-specific inhibitors in a high-throughput fashion and identified the natural compound juniferdin as the most potent inhibitor of PDI. Derivatives of juniferdin were synthesized, with compound 13 showing inhibitory activities comparable to those of juniferdin but reduced cytotoxicity. Both juniferdin and compound 13 inhibited PDI reductase activity in a dose-dependent manner, with IC50 values of 156 and 167 nM, respectively. Our results also indicated that juniferdin and compound 13 exert their inhibitory activities specifically on PDI but do not significantly inhibit homologues of this protein family. 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We screened a chemical library of natural products for PDI-specific inhibitors in a high-throughput fashion and identified the natural compound juniferdin as the most potent inhibitor of PDI. Derivatives of juniferdin were synthesized, with compound 13 showing inhibitory activities comparable to those of juniferdin but reduced cytotoxicity. Both juniferdin and compound 13 inhibited PDI reductase activity in a dose-dependent manner, with IC50 values of 156 and 167 nM, respectively. Our results also indicated that juniferdin and compound 13 exert their inhibitory activities specifically on PDI but do not significantly inhibit homologues of this protein family. Moreover, we found that both compounds can inhibit PDI-mediated reduction of HIV-1 envelope glycoprotein gp120.</description><subject>Diethylstilbestrol - chemical synthesis</subject><subject>Diethylstilbestrol - chemistry</subject><subject>Diethylstilbestrol - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Estrone - chemical synthesis</subject><subject>Estrone - chemistry</subject><subject>Estrone - pharmacology</subject><subject>High-Throughput Screening Assays</subject><subject>HIV Envelope Protein gp120 - antagonists & inhibitors</subject><subject>HIV Envelope Protein gp120 - metabolism</subject><subject>Humans</subject><subject>Masoprocol - chemical synthesis</subject><subject>Masoprocol - chemistry</subject><subject>Masoprocol - pharmacology</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Molecular Weight</subject><subject>Oxidation-Reduction</subject><subject>Parabens - chemical synthesis</subject><subject>Parabens - chemistry</subject><subject>Parabens - pharmacology</subject><subject>Protein Disulfide-Isomerases - antagonists & inhibitors</subject><subject>Protein Disulfide-Isomerases - metabolism</subject><subject>Protein Folding - drug effects</subject><subject>Sesquiterpenes - chemical synthesis</subject><subject>Sesquiterpenes - chemistry</subject><subject>Sesquiterpenes - pharmacology</subject><subject>Small Molecule Libraries</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>1554-8929</issn><issn>1554-8937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtPwzAQhC0EoqVw4A8gXxDiEPDazuuI2tJGAoGgcI0cx6GpnDjYSaX-e1L1ceK0u9I3s5pB6BrIAxAKjzIDQlgU2hM0BN_nXhSz8PS403iALpxbEcJZEMXnaEABKAQchmg5KZ00a2U32BRY4M9KaI1fjVay0wq_TxKc1MsyK1tj8WIp2sPp8IfKO9mWpt4q58m3B3har5U2jcIzvZGmsaZVZY1_GqDkEp0VQjt1tZ8j9PU8XYzn3svbLBk_vXiCAW89kccMwCeUs1DQguaK0yjKWeYHIg9YTKkMSBhQGgglREzzHmUkpMAZiyWP2Ajd7Xz777-dcm1a9QmV1qJWpnNp5IcRcOL7PXm_I6U1zllVpI0tK2E3KZB022t67LVnb_auXVap_EgeiuyB2x0gpEtXprN1H_Ifoz9KXXvz</recordid><startdate>20110318</startdate><enddate>20110318</enddate><creator>Khan, Maola M. 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We screened a chemical library of natural products for PDI-specific inhibitors in a high-throughput fashion and identified the natural compound juniferdin as the most potent inhibitor of PDI. Derivatives of juniferdin were synthesized, with compound 13 showing inhibitory activities comparable to those of juniferdin but reduced cytotoxicity. Both juniferdin and compound 13 inhibited PDI reductase activity in a dose-dependent manner, with IC50 values of 156 and 167 nM, respectively. Our results also indicated that juniferdin and compound 13 exert their inhibitory activities specifically on PDI but do not significantly inhibit homologues of this protein family. Moreover, we found that both compounds can inhibit PDI-mediated reduction of HIV-1 envelope glycoprotein gp120.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21121641</pmid><doi>10.1021/cb100387r</doi><tpages>7</tpages></addata></record> |
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| subjects | Diethylstilbestrol - chemical synthesis Diethylstilbestrol - chemistry Diethylstilbestrol - pharmacology Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Estrone - chemical synthesis Estrone - chemistry Estrone - pharmacology High-Throughput Screening Assays HIV Envelope Protein gp120 - antagonists & inhibitors HIV Envelope Protein gp120 - metabolism Humans Masoprocol - chemical synthesis Masoprocol - chemistry Masoprocol - pharmacology Models, Molecular Molecular Structure Molecular Weight Oxidation-Reduction Parabens - chemical synthesis Parabens - chemistry Parabens - pharmacology Protein Disulfide-Isomerases - antagonists & inhibitors Protein Disulfide-Isomerases - metabolism Protein Folding - drug effects Sesquiterpenes - chemical synthesis Sesquiterpenes - chemistry Sesquiterpenes - pharmacology Small Molecule Libraries Stereoisomerism Structure-Activity Relationship |
| title | Discovery of a Small Molecule PDI Inhibitor That Inhibits Reduction of HIV-1 Envelope Glycoprotein gp120 |
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