Rational design of the first difluorostatone-based PfSUB1 inhibitors
The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease su...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (15), p.3582-3586 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Giovani, Simone Penzo, Maria Brogi, Simone Brindisi, Margherita Gemma, Sandra Novellino, Ettore Savini, Luisa Blackman, Michael J Campiani, Giuseppe Butini, Stefania |
| description | The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.044 |
| format | Article |
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Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.05.044</identifier><identifier>PMID: 24909083</identifier><language>eng</language><publisher>England</publisher><subject>Dose-Response Relationship, Drug ; Drug Design ; Models, Molecular ; Molecular Conformation ; Oligopeptides - chemical synthesis ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - enzymology ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - metabolism ; Structure-Activity Relationship ; Subtilisins - antagonists & inhibitors ; Subtilisins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-08, Vol.24 (15), p.3582-3586</ispartof><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-fb4e5582167f0f3650fe6b65707722efaa9ce6b02112b1b837c0d49ca42478a33</citedby><cites>FETCH-LOGICAL-c385t-fb4e5582167f0f3650fe6b65707722efaa9ce6b02112b1b837c0d49ca42478a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24909083$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Giovani, Simone</creatorcontrib><creatorcontrib>Penzo, Maria</creatorcontrib><creatorcontrib>Brogi, Simone</creatorcontrib><creatorcontrib>Brindisi, Margherita</creatorcontrib><creatorcontrib>Gemma, Sandra</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Savini, Luisa</creatorcontrib><creatorcontrib>Blackman, Michael J</creatorcontrib><creatorcontrib>Campiani, Giuseppe</creatorcontrib><creatorcontrib>Butini, Stefania</creatorcontrib><title>Rational design of the first difluorostatone-based PfSUB1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors.</description><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - enzymology</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Protozoan Proteins - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Subtilisins - antagonists & inhibitors</subject><subject>Subtilisins - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kEtLxDAUhYMozjj6B1xIl25ab55tlzo-YUBRB9yFpE2cDG0zNunCf2_LqKsLh-8cLh9C5xgyDFhcbTPdVk1GALMMeAaMHaA5ZoKllAE_RHMoBaRFyT5m6CSELYzgCB2jGWEllFDQObp9VdH5TjVJbYL77BJvk7gxiXV9iEntbDP43oeoou9MqlUwdfJi39Y3OHHdxmkXfR9O0ZFVTTBnv3eB1vd378vHdPX88LS8XqUVLXhMrWaG84JgkVuwVHCwRmjBc8hzQoxVqqzGAAjGRGNd0LyCmpWVYoTlhaJ0gS73u7vefw0mRNm6UJmmUZ3xQ5CYcyxIydiEkj1ajd-H3li5612r-m-JQU725FZO9uRkTwKXo5ixdPG7P-jW1P-VP130B-xBa2E</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Giovani, Simone</creator><creator>Penzo, Maria</creator><creator>Brogi, Simone</creator><creator>Brindisi, Margherita</creator><creator>Gemma, Sandra</creator><creator>Novellino, Ettore</creator><creator>Savini, Luisa</creator><creator>Blackman, Michael J</creator><creator>Campiani, Giuseppe</creator><creator>Butini, Stefania</creator><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>7QO</scope><scope>8FD</scope><scope>C1K</scope><scope>F1W</scope><scope>FR3</scope><scope>H95</scope><scope>H97</scope><scope>L.G</scope><scope>P64</scope></search><sort><creationdate>20140801</creationdate><title>Rational design of the first difluorostatone-based PfSUB1 inhibitors</title><author>Giovani, Simone ; 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| subjects | Dose-Response Relationship, Drug Drug Design Models, Molecular Molecular Conformation Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacology Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - enzymology Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - metabolism Structure-Activity Relationship Subtilisins - antagonists & inhibitors Subtilisins - metabolism |
| title | Rational design of the first difluorostatone-based PfSUB1 inhibitors |
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