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                                     Editorial          


Low Molecular Weight Antagonists of Plasminogen Activator Inhibitor-1: Therapeutic Potential in Cardiovascular Disease




Tessa M. Simone and Paul J. Higgins*

Center for Cell Biology & Cancer Research
Albany Medical College
Albany, New York 12208




*Corresponding Author:  Dr. Paul J. Higgins
                                           Center for Cell Biology & Cancer Research
                                           Albany Medical College
                                           47 New Scotland Avenue
                                           Albany, New York 12208
                                           Tel:  518-262-5168
                                           FAX: 518-262-5669
                                           e-mail:  HYPERLINK "mailto:higginp@mail.amc.edu" higginp@mail.amc.edu



Acknowledgements:  Supported by NIH grant GM057242

                                            






Abbreviations:  PAI-1, plasminogen activator inhibitor-1; SERPINE1, serine protease inhibitor clade E member 1; RCL, reactive center loop; LMW, low molecular weight;  uPA, urokinase plasminogen activator; tPA, tissue-type plasminogen activator; LRP1, low density lipoprotein receptor-related protein 1 

Introduction

     PAI-1 is a member of the serine protease inhibitor (SERPIN) superfamily, consisting of over 40 proteins with approximately 35% homology and representing more than 10% of the total plasma protein  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Andreasen, 1986 #46" 1-7].  PAI-1 is a single-chain, glycosylated polypeptide, similar in tertiary structure to most other SERPINs and is comprised of three �-sheets (A, B, C), �-helicies (A-I) and a reactive center loop (RCL)  situated in the carboxy terminus  ADDIN EN.CITE <EndNote><Cite><Author>Huber</Author><Year>1989</Year><RecNum>63</RecNum><DisplayText>[7]</DisplayText><record><rec-number>63</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">63</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huber, R.</author><author>Carrell, R. W.</author></authors></contributors><auth-address>Max-Planck-Institut fur Biochemie, Martinsried, FRG.</auth-address><titles><title>Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins</title><secondary-title>Biochemistry</secondary-title><alt-title>Biochemistry</alt-title></titles><periodical><full-title>Biochemistry</full-title><abbr-1>Biochemistry</abbr-1></periodical><alt-periodical><full-title>Biochemistry</full-title><abbr-1>Biochemistry</abbr-1></alt-periodical><pages>8951-66</pages><volume>28</volume><number>23</number><edition>1989/11/14</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Conformation</keyword><keyword>*Serpins/physiology</keyword><keyword>Structure-Activity Relationship</keyword><keyword>*alpha 1-Antitrypsin/physiology</keyword></keywords><dates><year>1989</year><pub-dates><date>Nov 14</date></pub-dates></dates><isbn>0006-2960 (Print)&#xD;0006-2960 (Linking)</isbn><accession-num>2690952</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/2690952</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Huber, 1989 #63" 7].  PAI-1 inhibits serine protease activity by forming a reversible Michaelis-like 1:1 stoichiometric complex with the target proteinase, followed by creation of a non-covalent acyl intermediate, and ultimately the formation of covalent ester bond between the carboxyl group the active SERPIN and the hydroxyl group of the serine protease, mimicking the normal substrate to proteinase interaction  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Laskowski, 1980 #68" 8,  HYPERLINK \l "_ENREF_9" \o "Egelund, 1998 #69" 9].  Upon formation of the covalent inhibitory complex, the peptide bond in the reactive center loop that joins Arg346 and Met347 (P1-P1�), mimics the normal substrate of the proteinase and is cleaved rendering PAI-1 inactive, an event that has aptly led to the designation of PAI-1 as a �suicide inhibitor�  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Wilczynska, 1995 #21" 10, HYPERLINK \l "_ENREF_11" \o "Lawrence, 1995 #70" 11].  


PAI-1 Structure and Conformations

     PAI-1 exists in three structurally and functionally distinct conformations, active, latent, and cleaved (substrate)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_12" \o "Declerck, 1992 #71" 12-14].  The active conformation interacts with the target proteinase and is unstable (half-life approximately 2 hours at 37p C, pH 7.4) and converts spontaneously into the latent form, which cannot bind its protease targets  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_13" \o "Hekman, 1985 #72" 13,  HYPERLINK \l "_ENREF_15" \o "Levin, 1987 #74" 15,  HYPERLINK \l "_ENREF_16" \o "Lindahl, 1989 #76" 16]. PAI-1 is cleaved by proteinases at the P1-P1� site in the reactive center loop, a reaction that can occur in the absence of a covalent complex  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Patston, 1991 #78" 17-19].  In the latent form, the N-terminus of the reactive center loop inserts into �-sheet A forming a new �-strand (s4A) producing an unusual loop structure and conformational change in the reactive center disrupting the peptide bond between Arg346 and Met347 (P1-P1 )   ADDIN EN.CITE <EndNote><Cite><Author>Mottonen</Author><Year>1992</Year><RecNum>33</RecNum><DisplayText>[20]</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mottonen, J.</author><author>Strand, A.</author><author>Symersky, J.</author><author>Sweet, R. M.</author><author>Danley, D. E.</author><author>Geoghegan, K. F.</author><author>Gerard, R. D.</author><author>Goldsmith, E. J.</author></authors></contributors><auth-address>Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9050.</auth-address><titles><title>Structural basis of latency in plasminogen activator inhibitor-1</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>270-3</pages><volume>355</volume><number>6357</number><edition>1992/01/16</edition><keywords><keyword>Binding Sites</keyword><keyword>Humans</keyword><keyword>Models, Molecular</keyword><keyword>Plasminogen Inactivators/*chemistry</keyword><keyword>Protein Conformation</keyword><keyword>Recombinant Proteins/chemistry</keyword><keyword>X-Ray Diffraction</keyword></keywords><dates><year>1992</year><pub-dates><date>Jan 16</date></pub-dates></dates><isbn>0028-0836 (Print)&#xD;0028-0836 (Linking)</isbn><accession-num>1731226</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Research Support, U.S. Gov&apos;t, P.H.S.</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/1731226</url></related-urls></urls><electronic-resource-num>10.1038/355270a0</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Mottonen, 1992 #33" 20].  Alternatively, PAI-1 can be cleaved by target proteases at the peptide bond between Arg346 and Met347 (P1-P1�), resulting in the insertion of the N-terminal end of the reactive center loop into �-sheet A. The C-terminus of the reactive site loop forms strand s1C in �-sheet C producing a 70� separation of the P1 and P1  residues  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_19" \o "Aertgeerts, 1995 #34" 19, HYPERLINK \l "_ENREF_21" \o "Stein, 1991 #84" 21-23].  Clarification of these PAI-1 conformational crystal structures has driven the effort to design low molecular weight PAI-1 antagonists. 


PAI-1 Function and Role in Pathological States

PAI-1 can be found in platelets and in the plasma. Tissue injury results in an approximate 10-fold increase in plasma PAI-1 upon platelet activation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_24" \o "Juhan-Vague, 1984 #87" 24-26]. PAI-1 rapidly inhibits tPA and uPA (tissue type and urokinase-like plasminogen activators, respectively) with second order rate constants approximately 3.5x107 M-1s-1  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "Lindahl, 1989 #76" 16,  HYPERLINK \l "_ENREF_27" \o "Lawrence, 1994 #91" 27,  HYPERLINK \l "_ENREF_28" \o "Seiffert, 1991 #92" 28].  The primary role of the plasminogen activator system is to generate the active enzyme plasmin from its precursor, plasminogen, a key step in the fibrinolytic casacade.  
Indeed, PAI-1 deficiency in humans results in a hyperfibrinolytic state and abnormal bleeding after trauma or surgery  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_29" \o "Schleef, 1989 #93" 29-33].  Moreover, the generation of plasmin leads to the activation of matrix metalloproteinases and extracellular matrix (ECM) degradation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_34" \o "Myohanen, 2004 #81" 34-36]. PAI-1 (SERPINE1) is the major physiologic regulator of the plasmin-based pericellular proteolytic cascade, a modulator of vascular smooth muscle cell (VSMC) migration and a causative factor in cardiovascular disease and restenosis, particularly in the setting of increased TGF-�1  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_37" \o "DeYoung, 2001 #148" 37].  Inhibition of the fibrinolytic system by PAI-1 overexpression in transgenic mice results in the spontaneous development of thrombi and perviovascular fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_38" \o "Eren, 2002 #5" 38,  HYPERLINK \l "_ENREF_39" \o "Erickson, 1990 #6" 39]. PAI-1-/- mice exhibit significantly reduced VSMC density in the neointima (compared to wild type counterparts) in response to oxidative stress-induced vessel injury and in the balloon-catheterized carotid artery as well as  in atherosclerosis prone ApoE-/- mice  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_37" \o "DeYoung, 2001 #148" 37,  HYPERLINK \l "_ENREF_40" \o "Zhu, 2001 #8" 40,  HYPERLINK \l "_ENREF_41" \o "Ploplis, 2001 #9" 41].  Importantly, clinical findings are in agreement with these data, as post-transluminal coronary angioplasty PAI-1 activity was significantly greater in patients with restenosis compared to those without clinical recurrence  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_42" \o "Prisco, 2001 #11" 42]. This has significant translational ramifications. Atherosclerosis and arterial restenosis are associated with a dysregulation of physiological reconstruction. While it is well-accepted that medial smooth muscle cell migration and proliferation, followed by ECM synthesis are critical in the development of vascular lesions, there remains the need for a better understanding of molecular mechanisms that contribute to smooth muscle cell migration and neointimal development  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_43" \o "Ruiz-Ortega, 2007 #1" 43-46].

Beyond regulating fibrinolysis, PAI-1 functions in a signaling capacity to impact low density lipoprotein receptor-related protein 1 (LRP1)-dependent cell migration.  PAI-1 is forms a complex that consists of PAI-1/uPA/uPAR (uPA receptor)/LRPI/integrin which, in turn, is endocytosed resulting in uPAR/LRP1/integrin redistribution to the leading edge leading front of the cell, causing an �adhesion-deadhesion-readhesion� cycle that promotes cell migration.  Redistribution of integrins is not required for deadhesion, but for migration upon redistribution at the leading edge, while uPAR and uPA are not required for migration, but instead deadhesion  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_47" \o "Degryse, 2004 #77" 47-52].  Furthermore, recycling of uPAR to the leading edge allows for induction of matrix degradation, which supports the motile phenotype ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_53" \o "Wilkins-Port, 2009 #110" 53]. PAI-1 can also bind to LRP1 in a uPA/uPAR-independent manner and activates Jak/Stat1 signaling inducing cell migration through Stat1-mediated transcriptional regulation of genes required for cell motility  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_47" \o "Degryse, 2004 #77" 47,  HYPERLINK \l "_ENREF_49" \o "Kamikubo, 2009 #104" 49,  HYPERLINK \l "_ENREF_54" \o "Hou, 2002 #119" 54]. Importantly, all three forms of PAI-1 (active, cleaved, latent) are able to interact with LRP1 and increase LRP1-mediated cell migration through activation of Jak/Stat1 signaling at low concentrations  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_47" \o "Degryse, 2004 #77" 47].
.  
Clearly, the implications of plasminogen activation go beyond just fibrinolytic control and extend to processes including cell migration and adhesion.  This cascade has been functionally implicated in various disease states including thrombosis, atherosclerosis, restenosis, fibrosis, and cancer and has driven the effort to design small molecular weight antagonists of PAI-1.Early studies on PAI-1 inhibition focused on (a) utilizing monoclonal antibodies that convert PAI-1 to the latent or cleaved form and (b) peptides that correspond to the reactive site of PAI-1.  While initial investigations provided important data regarding the utilization of PAI-1 inhibition in various disease states and facilitated the mapping sites of LMW antagonist binding, their poor oral bioavailability precluded clinical adaptability.  Therefore, there is growing interest in investigating the efficacy of specific, potent, low molecular weight compounds on the inhibition of PAI-1.


Low Molecular Weight Antagonists

Several low molecular weight antagonists of PAI-1 have been discovered and characterized (Table 1).  The first were diketopiperazines (XR330 and XR334) and, from that template, more potent antagonists were designed (XR1853, XR5082, XR5967, XR1121) which inhibit PAI-1 by inducing the transition from active PAI-1 to non-reactive PAI-1  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_55" \o "Charlton, 1996 #131" 55-58].  By inhibiting the interaction of tPA/uPA and PAI-1 in a rat carotid artery thrombus model, XR334, XR5082 and XR1853 effectively increased fibrinolysis in vivo  ADDIN EN.CITE <EndNote><Cite><Author>Charlton</Author><Year>1996</Year><RecNum>131</RecNum><DisplayText>[55]</DisplayText><record><rec-number>131</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">131</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Charlton, P. A.</author><author>Faint, R. W.</author><author>Bent, F.</author><author>Bryans, J.</author><author>Chicarelli-Robinson, I.</author><author>Mackie, I.</author><author>Machin, S.</author><author>Bevan, P.</author></authors></contributors><auth-address>Xenova Limited, Slough, Berkshire, UK.</auth-address><titles><title>Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity</title><secondary-title>Thromb Haemost</secondary-title><alt-title>Thrombosis and haemostasis</alt-title></titles><periodical><full-title>Thromb Haemost</full-title><abbr-1>Thrombosis and haemostasis</abbr-1></periodical><alt-periodical><full-title>Thromb Haemost</full-title><abbr-1>Thrombosis and haemostasis</abbr-1></alt-periodical><pages>808-15</pages><volume>75</volume><number>5</number><edition>1996/05/01</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Peptides/*isolation &amp; purification/metabolism</keyword><keyword>Piperazines/*isolation &amp; purification</keyword><keyword>Plasminogen Activator Inhibitor 1/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Recombinant Proteins/metabolism</keyword><keyword>Tissue Plasminogen Activator/metabolism</keyword></keywords><dates><year>1996</year><pub-dates><date>May</date></pub-dates></dates><isbn>0340-6245 (Print)&#xD;0340-6245 (Linking)</isbn><accession-num>8725728</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8725728</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_55" \o "Charlton, 1996 #131" 55].  

Other antagonists that act similarly include AR-H2029953XX and fendosal.  AR-H2029953XX is an anthranalic acid derivative of the known fibrinolysis antagonist flufenamic acid [44-47].  The acidic function of AR-H2029953XX was required for its function . AR-H2029953XX binds PAI-1 in the vicinity of Arg76, Arg115 and Arg118, which are above and behind helix E and between � sheet A and helix D, a region implicated in the binding of LRP  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_2" \o "Durand, 2004 #136" 2,  HYPERLINK \l "_ENREF_47" \o "Degryse, 2004 #77" 47,  HYPERLINK \l "_ENREF_59" \o "Horn, 1998 #135" 59].  

The negatively charged LMW antagonists ANS, bis-ANS and 1-dodecyl sulphurc acid and the positively charged XR-5118 overlap and localize around hD and hE and �-sheet A in the flexible joint region of PAI-1, which becomes accessible for the reactive center loop to insert during the reaction with proteinases  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_58" \o "Bryans, 1996 #142" 58,  HYPERLINK \l "_ENREF_60" \o "Egelund, 2001 #122" 60,  HYPERLINK \l "_ENREF_61" \o "Einholm, 2003 #141" 61].  This conformational rearrangement causes the reactive site to become inaccessible, thereby preventing tPA and uPA from binding potentially resulting in the inhibition of LRP binding due to the location of the binding site  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_61" \o "Einholm, 2003 #141" 61].  Of these compounds only XR-5118 has shown in vivo efficacy by increasing tPA activity and reduced rat arterial thrombus growth  ADDIN EN.CITE <EndNote><Cite><Author>Charlton</Author><Year>1997</Year><RecNum>144</RecNum><DisplayText>[62]</DisplayText><record><rec-number>144</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">144</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Charlton, P., Faint R, Barnes C, et al.</author></authors></contributors><titles><title>XR5118, a novel modulator of plasminogen activator inhibitor 1 (PAI-1), increases endogenous tPA activity in the rat.</title><secondary-title>Fibrinolysis and Proteolysis</secondary-title></titles><periodical><full-title>Fibrinolysis and Proteolysis</full-title></periodical><volume>11</volume><number>51-56</number><section>&#xD;</section><dates><year>1997</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_62" \o "Charlton, 1997 #144" 62].

Comounds that insert into the s4A position of �-sheet A as a mock molecule that prevents the activity of PAI-1 have also been designed.   Tiplaxtinin and TM5007, indole oxoacetic acid derivatives insert in the s4A position and effectively inhibit PAI-1 activity  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_63" \o "Izuhara, 2008 #146" 63,  HYPERLINK \l "_ENREF_64" \o "Elokdah, 2004 #145" 64]. Furthermore, these compounds inhibit the PAI-1/tPA complex formation and importantly, both Tiplaxtinin and TM5007 are metabolically stable, non-toxic and showed good oral bioavailability and in vivo efficacy in a rat thrombosis model  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_63" \o "Izuhara, 2008 #146" 63].  Finally, high concentrations of non-ionic amphlilic compounds, such as Triton X-100 cause an inhibition of PAI-1 and a butadiene derivative, T-686 was found to inhibit PAI-1 synthesis and augment PAI-1 activity induced by vascular injury and reduced atherosclerotic lesions in rabbits  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_65" \o "Andreasen, 1999 #127" 65-67].









Mechanism of actionDesignationIC50AssayReferenceInduces reactive center loop inaccessibility1-dodecyl sulfuric acid15.1 � 3.4  �M Direct uPA assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_60" \o "Egelund, 2001 #122" 60,  HYPERLINK \l "_ENREF_68" \o "Pedersen, 2003 #121" 68]ANS116 �MDirect uPA assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_57" \o "Gils, 2002 #124" 57,  HYPERLINK \l "_ENREF_60" \o "Egelund, 2001 #122" 60,  HYPERLINK \l "_ENREF_68" \o "Pedersen, 2003 #121" 68,  HYPERLINK \l "_ENREF_69" \o "Bjorquist, 1998 #41" 69]Bis-ANS0.57 �MDirect uPA assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_60" \o "Egelund, 2001 #122" 60,  HYPERLINK \l "_ENREF_68" \o "Pedersen, 2003 #121" 68,  HYPERLINK \l "_ENREF_69" \o "Bjorquist, 1998 #41" 69]�Tiplaxtinin40 � 7  �M tPA-mediated plasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_63" \o "Izuhara, 2008 #146" 63]TM500729.2 � 4.2 �MtPA-mediated plasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_63" \o "Izuhara, 2008 #146" 63]XR511815  �  1 �MPlasmin generation assay ADDIN EN.CITE <EndNote><Cite><Author>Charlton</Author><Year>1997</Year><RecNum>144</RecNum><DisplayText>[62]</DisplayText><record><rec-number>144</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">144</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Charlton, P., Faint R, Barnes C, et al.</author></authors></contributors><titles><title>XR5118, a novel modulator of plasminogen activator inhibitor 1 (PAI-1), increases endogenous tPA activity in the rat.</title><secondary-title>Fibrinolysis and Proteolysis</secondary-title></titles><periodical><full-title>Fibrinolysis and Proteolysis</full-title></periodical><volume>11</volume><number>51-56</number><section>&#xD;</section><dates><year>1997</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_62" \o "Charlton, 1997 #144" 62]InactivatingAR-H2029953XX54  �  18 �M�Plasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_57" \o "Gils, 2002 #124" 57,  HYPERLINK \l "_ENREF_60" \o "Egelund, 2001 #122" 60,  HYPERLINK \l "_ENREF_69" \o "Bjorquist, 1998 #41" 69]Fendosal36  �  1 �MPlasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_57" \o "Gils, 2002 #124" 57]XR112110.2 �  0.015 �MPlasmin generation assay ADDIN EN.CITE <EndNote><Cite><Author>Folkes</Author><Year>2001</Year><RecNum>40</RecNum><DisplayText>[56]</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Folkes, A.</author><author>Roe, M. B.</author><author>Sohal, S.</author><author>Golec, J.</author><author>Faint, R.</author><author>Brooks, T.</author><author>Charlton, P.</author></authors></contributors><auth-address>Xenova Limited, 957 Buckingham Avenue, Slough, Berks SL1 4NL, UK. adrian_folkes@xenova.co.uk</auth-address><titles><title>Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1</title><secondary-title>Bioorg Med Chem Lett</secondary-title><alt-title>Bioorganic &amp; medicinal chemistry letters</alt-title></titles><periodical><full-title>Bioorg Med Chem Lett</full-title><abbr-1>Bioorganic &amp; medicinal chemistry letters</abbr-1></periodical><alt-periodical><full-title>Bioorg Med Chem Lett</full-title><abbr-1>Bioorganic &amp; medicinal chemistry letters</abbr-1></alt-periodical><pages>2589-92</pages><volume>11</volume><number>19</number><edition>2001/09/12</edition><keywords><keyword>Diketopiperazines</keyword><keyword>Piperazines/*chemical synthesis/chemistry/pharmacology</keyword><keyword>Plasminogen Activator Inhibitor 1/*metabolism</keyword><keyword>Structure-Activity Relationship</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct 8</date></pub-dates></dates><isbn>0960-894X (Print)&#xD;0960-894X (Linking)</isbn><accession-num>11551756</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11551756</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_56" \o "Folkes, 2001 #40" 56]XR185362  �  10 �MPlasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_55" \o "Charlton, 1996 #131" 55,  HYPERLINK \l "_ENREF_57" \o "Gils, 2002 #124" 57]XR33030 ��MtPA-mediated plasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_58" \o "Bryans, 1996 #142" 58]XR33451 �  7 �MtPA-mediated plasmin generation assay  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_55" \o "Charlton, 1996 #131" 55,  HYPERLINK \l "_ENREF_58" \o "Bryans, 1996 #142" 58] XR508214.5 �  0.5 �MtPA-mediated plasmin generation assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_55" \o "Charlton, 1996 #131" 55,  HYPERLINK \l "_ENREF_57" \o "Gils, 2002 #124" 57]XR5967800 nMDirect uPA assay ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_70" \o "Brooks, 2004 #128" 70]Inhibits PAI-1 synthesisT-686Not reportedN/A ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_67" \o "Vinogradsky, 1997 #147" 67]Non-ionic detergentTriton X-100Not reportedN/A ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_65" \o "Andreasen, 1999 #127" 65,  HYPERLINK \l "_ENREF_66" \o "Gils, 1998 #126" 66]


Clinical Implications

PAI-1 is the major physiological regulator of the plasmin proteolysis system and a critical component of the cell migratory machinery.  High levels of PAI-1 have been implicated in several pathophysiological disease states, including fibroproliferative diseases of the cardiovascular system.  Significant effort has gone into the design, synthesis and characterization of PAI-1 antagonists, however, there are no clinically applicable inhibitors available to date.  As PAI-1 regulates cardiovascular disease largely through fibrinolysis and LRP1-dependent cell migration, it is important to determine the mechanism through which PAI-1 inhibitors abrogate cardiovascular pathogenesis.  This Editorial describes several low molecular weight inhibitors with clinical potential including the diketopiperazine derivatives (XR330, XR334, XR1853, XR5082, XR5967, and XR1121), indole oxoacetic acid derivatives (TM5007 and Tiplaxtinin) and several others (AR-H2029953XX, fendosal, ANS, bis-ANS and 1-dodecyl sulphuric acid).  Of these only XR334, XR5082, XR1853, XR5118, Tiplaxtinin and TM5007 have shown in vivo efficacy and only XR5118 has the potential to inhibit LRP1-dependent migration. Cell motility is a major contributor of pathological diseases including, but not limited to, cancer, fibrosis, restenosis and atherosclerosis. In this regard, it would appear prudent to continue to assess the translational impact of LMW PAI-1 inhibitors  that specifically interfere with LRP1 binding.  


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��2�������ƅM�a�d���܆��"�Ňه܇��������?�U�X��������<�s��������$�&�X�������ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ��ٹ�h�h`h�h`5�CJmHnHuh�h`h�h`6�CJmHnHuh�h`h�h`CJmHnHuh�5lhr�jh�5lhr�Uh�5lhZ <IX���ҋՋ�q�����������7�`�s�v���I�\�_�������B�Ï֏؏�ÐѐӐ�~�����Ñ�2�4�j�>�[�_������,�������ǔ$�2�4�]�ɕݕߕ�������̖�3�5�n���������A�C�����*���Ιљ�����������������������������������������������������������������������������������h�h`h�h`5�CJmHnHuh�h`h�h`CJmHnHuh�h`h�h`6�CJmHnHuS��o�%�����E�n����E����G���S�����V�,��z����[�������������������������������$���0�^��`�0�a$gd�h`љ��_�n�q���-�A�D�q����D������(�P�g�i��������$��������8�I�K�t������*�l�����֠�������O�f�i����,�/�h��������������դ�/�0�\���֥إ�r����������A���ۧݧ�`����������������������������������������������������������������������������������Uh�h`h�h`5�CJmHnHuh�h`h�h`6�CJmHnHuh�h`h�h`CJmHnHuR��ϡy�B�У��@����)���`�a�bdc!d�d�eLf`gh�h�i�i�i�i�������������������������gd�,u$a$gdP�$a$gd�h`$���0�^��`�0�a$gd�h`59.	Horn, I.R., et al., Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator. Thromb Haemost, 1998. 80(5): p. 822-8.
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61.	Einholm, A.P., et al., Biochemical mechanism of action of a diketopiperazine inactivator of plasminogen activator inhibitor-1. Biochem J, 2003. 373(Pt 3): p. 723-32.
62.	Charlton, P., Faint R, Barnes C, et al., XR5118, a novel modulator of plasminogen activator inhibitor 1 (PAI-1), increases endogenous tPA activity in the rat. Fibrinolysis and Proteolysis, 1997. 11(51-56).
63.	Izuhara, Y., et al., Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis. Arterioscler Thromb Vasc Biol, 2008. 28(4): p. 672-7.
64.	Elokdah, H., et al., Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem, 2004. 47(14): p. 3491-4.
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Table 1:  Low molecular weight PAI-1 antagonists 














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S.</author><author>Oppenheimer, C.</author><author>Blasi, F.</author><author>Dano, K.</author></authors></contributors><titles><title>Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing</title><secondary-title>FEBS Lett</secondary-title><alt-title>FEBS letters</alt-title></titles><periodical><full-title>FEBS Lett</full-title><abbr-1>FEBS letters</abbr-1></periodical><alt-periodical><full-title>FEBS Lett</full-title><abbr-1>FEBS letters</abbr-1></alt-periodical><pages>213-8</pages><volume>209</volume><number>2</number><edition>1986/12/15</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Base Sequence</keyword><keyword>Binding Sites</keyword><keyword>DNA/*analysis</keyword><keyword>DNA Restriction Enzymes</keyword><keyword>Humans</keyword><keyword>Plasminogen/*metabolism</keyword><keyword>Protease Inhibitors/pharmacology</keyword><keyword>Substrate Specificity</keyword><keyword>*Tissue Plasminogen Activator/genetics</keyword><keyword>*Urokinase-Type Plasminogen Activator/genetics</keyword></keywords><dates><year>1986</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>0014-5793 (Print)&#xD;0014-5793 (Linking)</isbn><accession-num>3025016</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/3025016</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Ginsburg</Author><Year>1986</Year><RecNum>45</RecNum><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ginsburg, D.</author><author>Zeheb, R.</author><author>Yang, A. Y.</author><author>Rafferty, U. M.</author><author>Andreasen, P. A.</author><author>Nielsen, L.</author><author>Dano, K.</author><author>Lebo, R. V.</author><author>Gelehrter, T. D.</author></authors></contributors><titles><title>cDNA cloning of human plasminogen activator-inhibitor from endothelial cells</title><secondary-title>J Clin Invest</secondary-title><alt-title>The Journal of clinical investigation</alt-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><alt-periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></alt-periodical><pages>1673-80</pages><volume>78</volume><number>6</number><edition>1986/12/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Base Sequence</keyword><keyword>Chromosome Mapping</keyword><keyword>*Cloning, Molecular</keyword><keyword>Codon</keyword><keyword>DNA/*analysis</keyword><keyword>Endothelium/*analysis</keyword><keyword>Glycoproteins/analysis/*genetics/immunology</keyword><keyword>Humans</keyword><keyword>Plasminogen Activators/*antagonists &amp; inhibitors</keyword><keyword>*Plasminogen Inactivators</keyword><keyword>RNA, Messenger/analysis</keyword></keywords><dates><year>1986</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0021-9738 (Print)&#xD;0021-9738 (Linking)</isbn><accession-num>3097076</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Research Support, U.S. Gov&apos;t, P.H.S.</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/3097076</url></related-urls></urls><custom2>423941</custom2><electronic-resource-num>10.1172/JCI112761</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Ny</Author><Year>1986</Year><RecNum>44</RecNum><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ny, T.</author><author>Sawdey, M.</author><author>Lawrence, D.</author><author>Millan, J. L.</author><author>Loskutoff, D. J.</author></authors></contributors><titles><title>Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></periodical><alt-periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></alt-periodical><pages>6776-80</pages><volume>83</volume><number>18</number><edition>1986/09/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Antithrombin III/analysis</keyword><keyword>Base Sequence</keyword><keyword>*Cloning, Molecular</keyword><keyword>DNA/*analysis/isolation &amp; purification</keyword><keyword>Glycoproteins/analysis/*genetics</keyword><keyword>Humans</keyword><keyword>Placenta/analysis</keyword><keyword>Plasminogen Activators/*antagonists &amp; inhibitors</keyword><keyword>*Plasminogen Inactivators</keyword><keyword>alpha 1-Antitrypsin/analysis</keyword></keywords><dates><year>1986</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>3092219</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Research Support, U.S. Gov&apos;t, Non-P.H.S.&#xD;Research Support, U.S. Gov&apos;t, P.H.S.</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/3092219</url></related-urls></urls><custom2>386592</custom2><language>eng</language></record></Cite><Cite><Author>Pannekoek</Author><Year>1986</Year><RecNum>42</RecNum><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pannekoek, H.</author><author>Veerman, H.</author><author>Lambers, H.</author><author>Diergaarde, P.</author><author>Verweij, C. L.</author><author>van Zonneveld, A. J.</author><author>van Mourik, J. 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�/��������a���p�2����������ytX:pD<EndNote><Cite><Author>Pedersen</Author><Year>2003</Year><RecNum>121</RecNum><DisplayText>[60, 68]</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pedersen, K. E.</author><author>Einholm, A. P.</author><author>Christensen, A.</author><author>Schack, L.</author><author>Wind, T.</author><author>Kenney, J. M.</author><author>Andreasen, P. A.</author></authors></contributors><auth-address>Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, Denmark. kep@mb.au.dk</auth-address><titles><title>Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>747-55</pages><volume>372</volume><number>Pt 3</number><edition>2003/03/27</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Binding Sites</keyword><keyword>Biopolymers/chemistry/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Heparin Cofactor II/pharmacology</keyword><keyword>Hot Temperature</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Papain/metabolism</keyword><keyword>Plasminogen Activator Inhibitor 1/chemistry/*metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Recombinant Proteins/chemistry/metabolism</keyword><keyword>Serpins/metabolism</keyword><keyword>Spectrometry, Fluorescence/methods</keyword><keyword>Urokinase-Type Plasminogen Activator/pharmacology</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0264-6021 (Print)&#xD;0264-6021 (Linking)</isbn><accession-num>12656676</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12656676</url></related-urls></urls><custom2>1223451</custom2><electronic-resource-num>10.1042/BJ20021868</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Egelund</Author><Year>2001</Year><RecNum>122</RecNum><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Egelund, R.</author><author>Einholm, A. P.</author><author>Pedersen, K. E.</author><author>Nielsen, R. W.</author><author>Christensen, A.</author><author>Deinum, J.</author><author>Andreasen, P. A.</author></authors></contributors><auth-address>Laboratory of Cellular Protein Science, Department of Molecular and Structural Biology, Aarhus University, 8000 Aarhus C, Denmark.</auth-address><titles><title>A regulatory hydrophobic area in the flexible joint region of plasminogen activator inhibitor-1, defined with fluorescent activity-neutralizing ligands. Ligand-induced serpin polymerization</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>13077-86</pages><volume>276</volume><number>16</number><edition>2001/03/30</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Anilino Naphthalenesulfonates</keyword><keyword>Binding, Competitive</keyword><keyword>Fluorescent Dyes</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Ligands</keyword><keyword>Macromolecular Substances</keyword><keyword>Models, Molecular</keyword><keyword>Peptide Fragments/chemistry</keyword><keyword>Plasminogen Activator Inhibitor 1/*chemistry/*metabolism</keyword><keyword>Protein Structure, Secondary</keyword><keyword>Serpins/*chemistry/*metabolism</keyword><keyword>Spectrometry, Fluorescence</keyword><keyword>Urokinase-Type Plasminogen Activator/*chemistry/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 20</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>11278457</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11278457</url></related-urls></urls><electronic-resource-num>10.1074/jbc.M009024200</electronic-resource-num><language>eng</language></record></Cite></EndNote>uD���y������K�
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�/��������/��������/��a���p�2����������ytX:�%D<EndNote><Cite><Author>Pedersen</Author><Year>2003</Year><RecNum>121</RecNum><DisplayText>[57, 60, 68, 69]</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pedersen, K. E.</author><author>Einholm, A. P.</author><author>Christensen, A.</author><author>Schack, L.</author><author>Wind, T.</author><author>Kenney, J. M.</author><author>Andreasen, P. A.</author></authors></contributors><auth-address>Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, Denmark. kep@mb.au.dk</auth-address><titles><title>Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>747-55</pages><volume>372</volume><number>Pt 3</number><edition>2003/03/27</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Binding Sites</keyword><keyword>Biopolymers/chemistry/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Heparin Cofactor II/pharmacology</keyword><keyword>Hot Temperature</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Papain/metabolism</keyword><keyword>Plasminogen Activator Inhibitor 1/chemistry/*metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Recombinant Proteins/chemistry/metabolism</keyword><keyword>Serpins/metabolism</keyword><keyword>Spectrometry, Fluorescence/methods</keyword><keyword>Urokinase-Type Plasminogen Activator/pharmacology</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0264-6021 (Print)&#xD;0264-6021 (Linking)</isbn><accession-num>12656676</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12656676</url></related-urls></urls><custom2>1223451</custom2><electronic-resource-num>10.1042/BJ20021868</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Egelund</Author><Year>2001</Year><RecNum>122</RecNum><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Egelund, R.</author><author>Einholm, A. 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�/��������/��������/��a���p�2������������������ytX:*D<EndNote><Cite><Author>Bjorquist</Author><Year>1998</Year><RecNum>41</RecNum><DisplayText>[60, 68, 69]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bjorquist, P.</author><author>Ehnebom, J.</author><author>Inghardt, T.</author><author>Hansson, L.</author><author>Lindberg, M.</author><author>Linschoten, M.</author><author>Stromqvist, M.</author><author>Deinum, J.</author></authors></contributors><auth-address>Preclinical R&amp;D, Astra Hassle, Molndal, Sweden.</auth-address><titles><title>Identification of the binding site for a low-molecular-weight inhibitor of plasminogen activator inhibitor type 1 by site-directed mutagenesis</title><secondary-title>Biochemistry</secondary-title><alt-title>Biochemistry</alt-title></titles><periodical><full-title>Biochemistry</full-title><abbr-1>Biochemistry</abbr-1></periodical><alt-periodical><full-title>Biochemistry</full-title><abbr-1>Biochemistry</abbr-1></alt-periodical><pages>1227-34</pages><volume>37</volume><number>5</number><edition>1998/03/07</edition><keywords><keyword>Animals</keyword><keyword>Antibodies, Monoclonal/metabolism</keyword><keyword>Binding Sites</keyword><keyword>Binding Sites, Antibody</keyword><keyword>Biosensing Techniques</keyword><keyword>CHO Cells</keyword><keyword>Chemistry Techniques, Analytical</keyword><keyword>Chlorphenamidine/*metabolism</keyword><keyword>Chromogenic Compounds</keyword><keyword>Cricetinae</keyword><keyword>Flufenamic Acid/*analogs &amp; derivatives/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Weight</keyword><keyword>*Mutagenesis, Site-Directed</keyword><keyword>Nitro Compounds/metabolism</keyword><keyword>Plasminogen Activator Inhibitor 1/chemistry/genetics/immunology/*metabolism</keyword><keyword>Plasminogen Inactivators/*metabolism</keyword><keyword>Protein Conformation</keyword><keyword>Substrate Specificity</keyword><keyword>Tissue Plasminogen Activator/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb 3</date></pub-dates></dates><isbn>0006-2960 (Print)&#xD;0006-2960 (Linking)</isbn><accession-num>9477948</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9477948</url></related-urls></urls><electronic-resource-num>10.1021/bi971554q</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Egelund</Author><Year>2001</Year><RecNum>122</RecNum><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Egelund, R.</author><author>Einholm, A. 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Ligand-induced serpin polymerization</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>13077-86</pages><volume>276</volume><number>16</number><edition>2001/03/30</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Anilino Naphthalenesulfonates</keyword><keyword>Binding, Competitive</keyword><keyword>Fluorescent Dyes</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Ligands</keyword><keyword>Macromolecular Substances</keyword><keyword>Models, Molecular</keyword><keyword>Peptide Fragments/chemistry</keyword><keyword>Plasminogen Activator Inhibitor 1/*chemistry/*metabolism</keyword><keyword>Protein Structure, Secondary</keyword><keyword>Serpins/*chemistry/*metabolism</keyword><keyword>Spectrometry, Fluorescence</keyword><keyword>Urokinase-Type Plasminogen Activator/*chemistry/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 20</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>11278457</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11278457</url></related-urls></urls><electronic-resource-num>10.1074/jbc.M009024200</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Pedersen</Author><Year>2003</Year><RecNum>121</RecNum><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="ee22vwxwn59prhefz9mxze02d2ev90vrtrdd">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pedersen, K. 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A.</author></authors></contributors><auth-address>Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, Denmark. kep@mb.au.dk</auth-address><titles><title>Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>747-55</pages><volume>372</volume><number>Pt 3</number><edition>2003/03/27</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Binding Sites</keyword><keyword>Biopolymers/chemistry/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Heparin Cofactor II/pharmacology</keyword><keyword>Hot Temperature</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Papain/metabolism</keyword><keyword>Plasminogen Activator Inhibitor 1/chemistry/*metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Recombinant Proteins/chemistry/metabolism</keyword><keyword>Serpins/metabolism</keyword><keyword>Spectrometry, Fluorescence/methods</keyword><keyword>Urokinase-Type Plasminogen Activator/pharmacology</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0264-6021 (Print)&#xD;0264-6021 (Linking)</isbn><accession-num>12656676</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12656676</url></related-urls></urls><custom2>1223451</custom2><electronic-resource-num>10.1042/BJ20021868</electronic-resource-num><language>eng</language></record></Cite></EndNote>uD���y������K�
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