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Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine
Polyarginine-containing peptides represent potent inhibitors of furin, a mammalian endoprotease that plays an important role in metabolism, activation of pathogenic toxins, and viral proliferation. The therapeutic use of D-polyarginines is especially interesting because they are not cleaved by furin...
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Published in: | The Journal of biological chemistry 2004-08, Vol.279 (35), p.36788-36794 |
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creator | Kacprzak, Magdalena M Peinado, Juan R Than, Manuel E Appel, Jon Henrich, Stefan Lipkind, Gregory Houghten, Richard A Bode, Wolfram Lindberg, Iris |
description | Polyarginine-containing peptides represent potent inhibitors of furin, a mammalian endoprotease that plays an important role in metabolism, activation of pathogenic toxins, and viral proliferation. The therapeutic use of D-polyarginines is especially interesting because they are not cleaved by furin and possess inhibitory potency almost equal to L-polyarginines. In this study we attempted to determine the important elements within polyarginines that contribute to effective inhibition. Structure-function analyses of polyarginine peptides showed that inhibition by polyarginine-containing peptides appeared to depend on the total number of basic charges of the positively charged inhibitors bound to the negatively charged substrate binding pocket; peptide positioning did not appear to be rigorously determined. Screening of L- and D-decapeptide positional scanning combinatorial peptide libraries indicated a preference for basic residues in nearly all positions, similar to previous results with hexapeptide libraries. Length and terminal modification studies showed that the most potent D-polyarginine tested was nona-D-arginine (D9R) amide with a K(i) of 1.3 nm. D9R amide was shown to protect RAW264.7 cells against anthrax toxemia with an IC(50) of 3.7 microm. Because of its high stability, specificity, low toxicity, small molecular weight, and extremely low K(i) against furin, D9R amide or its derivatives may represent promising compounds for therapeutic use. |
doi_str_mv | 10.1074/jbc.M400484200 |
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The therapeutic use of D-polyarginines is especially interesting because they are not cleaved by furin and possess inhibitory potency almost equal to L-polyarginines. In this study we attempted to determine the important elements within polyarginines that contribute to effective inhibition. Structure-function analyses of polyarginine peptides showed that inhibition by polyarginine-containing peptides appeared to depend on the total number of basic charges of the positively charged inhibitors bound to the negatively charged substrate binding pocket; peptide positioning did not appear to be rigorously determined. Screening of L- and D-decapeptide positional scanning combinatorial peptide libraries indicated a preference for basic residues in nearly all positions, similar to previous results with hexapeptide libraries. Length and terminal modification studies showed that the most potent D-polyarginine tested was nona-D-arginine (D9R) amide with a K(i) of 1.3 nm. D9R amide was shown to protect RAW264.7 cells against anthrax toxemia with an IC(50) of 3.7 microm. Because of its high stability, specificity, low toxicity, small molecular weight, and extremely low K(i) against furin, D9R amide or its derivatives may represent promising compounds for therapeutic use.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M400484200</identifier><identifier>PMID: 15197180</identifier><language>eng</language><publisher>United States</publisher><subject>Alanine - chemistry ; Animals ; Antigens, Bacterial - metabolism ; Arginine - chemistry ; Bacterial Toxins - metabolism ; CHO Cells ; Cricetinae ; Crystallography, X-Ray ; DNA, Complementary - metabolism ; Dose-Response Relationship, Drug ; Furin - antagonists & inhibitors ; Humans ; Hydrolysis ; Inhibitory Concentration 50 ; Ions ; Kinetics ; Lysine - chemistry ; Mice ; Models, Molecular ; Oligopeptides - pharmacology ; Peptide Library ; Peptides - chemistry ; Protein Binding ; Structure-Activity Relationship ; Substrate Specificity</subject><ispartof>The Journal of biological chemistry, 2004-08, Vol.279 (35), p.36788-36794</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></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/15197180$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kacprzak, Magdalena M</creatorcontrib><creatorcontrib>Peinado, Juan R</creatorcontrib><creatorcontrib>Than, Manuel E</creatorcontrib><creatorcontrib>Appel, Jon</creatorcontrib><creatorcontrib>Henrich, Stefan</creatorcontrib><creatorcontrib>Lipkind, Gregory</creatorcontrib><creatorcontrib>Houghten, Richard A</creatorcontrib><creatorcontrib>Bode, Wolfram</creatorcontrib><creatorcontrib>Lindberg, Iris</creatorcontrib><title>Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Polyarginine-containing peptides represent potent inhibitors of furin, a mammalian endoprotease that plays an important role in metabolism, activation of pathogenic toxins, and viral proliferation. The therapeutic use of D-polyarginines is especially interesting because they are not cleaved by furin and possess inhibitory potency almost equal to L-polyarginines. In this study we attempted to determine the important elements within polyarginines that contribute to effective inhibition. Structure-function analyses of polyarginine peptides showed that inhibition by polyarginine-containing peptides appeared to depend on the total number of basic charges of the positively charged inhibitors bound to the negatively charged substrate binding pocket; peptide positioning did not appear to be rigorously determined. Screening of L- and D-decapeptide positional scanning combinatorial peptide libraries indicated a preference for basic residues in nearly all positions, similar to previous results with hexapeptide libraries. Length and terminal modification studies showed that the most potent D-polyarginine tested was nona-D-arginine (D9R) amide with a K(i) of 1.3 nm. D9R amide was shown to protect RAW264.7 cells against anthrax toxemia with an IC(50) of 3.7 microm. Because of its high stability, specificity, low toxicity, small molecular weight, and extremely low K(i) against furin, D9R amide or its derivatives may represent promising compounds for therapeutic use.</description><subject>Alanine - chemistry</subject><subject>Animals</subject><subject>Antigens, Bacterial - metabolism</subject><subject>Arginine - chemistry</subject><subject>Bacterial Toxins - metabolism</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Crystallography, X-Ray</subject><subject>DNA, Complementary - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Furin - antagonists & inhibitors</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Inhibitory Concentration 50</subject><subject>Ions</subject><subject>Kinetics</subject><subject>Lysine - chemistry</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Oligopeptides - pharmacology</subject><subject>Peptide Library</subject><subject>Peptides - chemistry</subject><subject>Protein Binding</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNpFkLtPwzAYxC0EoqWwMqJMbC6fH3EdNlRelYpYQGILnx2nuErskMeQ_54iWnHL3fC7G46QSwZzBgt5szV2_iIBpJYc4IhMGWhBRco-jskUgDOa8VRPyFnXbWEnmbFTMmEpyxZMw5R8rsKXN773MSSxTMqh9SExY9LEasR244MPjtoYevyNm6RxTe8L190mAUOsY4Vt4v8nds0QA9J7eiifk5MSq85d7H1G3h8f3pbPdP36tFrerWnDhe4p00VZWIEI1qkStRASnLEZBwFOKYdSoTWF0RwtT5XRSilAY0vnhGTciBm5_ttt2vg9uK7Pa99ZV1UYXBy6nGWaLdJU7sCrPTiY2hV50_oa2zE_fCJ-AJVoZjE</recordid><startdate>20040827</startdate><enddate>20040827</enddate><creator>Kacprzak, Magdalena M</creator><creator>Peinado, Juan R</creator><creator>Than, Manuel E</creator><creator>Appel, Jon</creator><creator>Henrich, Stefan</creator><creator>Lipkind, Gregory</creator><creator>Houghten, Richard A</creator><creator>Bode, Wolfram</creator><creator>Lindberg, Iris</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20040827</creationdate><title>Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine</title><author>Kacprzak, Magdalena M ; Peinado, Juan R ; Than, Manuel E ; Appel, Jon ; Henrich, Stefan ; Lipkind, Gregory ; Houghten, Richard A ; Bode, Wolfram ; Lindberg, Iris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p238t-18dfdc3aa0ce6fa83340ebc92030e66ea46acbdb82ac256b86660abcfee3412b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Alanine - chemistry</topic><topic>Animals</topic><topic>Antigens, Bacterial - metabolism</topic><topic>Arginine - chemistry</topic><topic>Bacterial Toxins - metabolism</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Crystallography, X-Ray</topic><topic>DNA, Complementary - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Furin - antagonists & inhibitors</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Inhibitory Concentration 50</topic><topic>Ions</topic><topic>Kinetics</topic><topic>Lysine - chemistry</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Oligopeptides - pharmacology</topic><topic>Peptide Library</topic><topic>Peptides - chemistry</topic><topic>Protein Binding</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kacprzak, Magdalena M</creatorcontrib><creatorcontrib>Peinado, Juan R</creatorcontrib><creatorcontrib>Than, Manuel E</creatorcontrib><creatorcontrib>Appel, Jon</creatorcontrib><creatorcontrib>Henrich, Stefan</creatorcontrib><creatorcontrib>Lipkind, Gregory</creatorcontrib><creatorcontrib>Houghten, Richard A</creatorcontrib><creatorcontrib>Bode, Wolfram</creatorcontrib><creatorcontrib>Lindberg, Iris</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kacprzak, Magdalena M</au><au>Peinado, Juan R</au><au>Than, Manuel E</au><au>Appel, Jon</au><au>Henrich, Stefan</au><au>Lipkind, Gregory</au><au>Houghten, Richard A</au><au>Bode, Wolfram</au><au>Lindberg, Iris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-08-27</date><risdate>2004</risdate><volume>279</volume><issue>35</issue><spage>36788</spage><epage>36794</epage><pages>36788-36794</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Polyarginine-containing peptides represent potent inhibitors of furin, a mammalian endoprotease that plays an important role in metabolism, activation of pathogenic toxins, and viral proliferation. The therapeutic use of D-polyarginines is especially interesting because they are not cleaved by furin and possess inhibitory potency almost equal to L-polyarginines. In this study we attempted to determine the important elements within polyarginines that contribute to effective inhibition. Structure-function analyses of polyarginine peptides showed that inhibition by polyarginine-containing peptides appeared to depend on the total number of basic charges of the positively charged inhibitors bound to the negatively charged substrate binding pocket; peptide positioning did not appear to be rigorously determined. Screening of L- and D-decapeptide positional scanning combinatorial peptide libraries indicated a preference for basic residues in nearly all positions, similar to previous results with hexapeptide libraries. Length and terminal modification studies showed that the most potent D-polyarginine tested was nona-D-arginine (D9R) amide with a K(i) of 1.3 nm. D9R amide was shown to protect RAW264.7 cells against anthrax toxemia with an IC(50) of 3.7 microm. Because of its high stability, specificity, low toxicity, small molecular weight, and extremely low K(i) against furin, D9R amide or its derivatives may represent promising compounds for therapeutic use.</abstract><cop>United States</cop><pmid>15197180</pmid><doi>10.1074/jbc.M400484200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Alanine - chemistry Animals Antigens, Bacterial - metabolism Arginine - chemistry Bacterial Toxins - metabolism CHO Cells Cricetinae Crystallography, X-Ray DNA, Complementary - metabolism Dose-Response Relationship, Drug Furin - antagonists & inhibitors Humans Hydrolysis Inhibitory Concentration 50 Ions Kinetics Lysine - chemistry Mice Models, Molecular Oligopeptides - pharmacology Peptide Library Peptides - chemistry Protein Binding Structure-Activity Relationship Substrate Specificity |
title | Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine |
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