Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an...
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Autor*in:	Rami A. Al-Horani [verfasserIn] Rajesh Karuturi [verfasserIn] Domonique T. White [verfasserIn] Umesh R. Desai [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	allosteric inhibitors library screening plasmin sulfated glycosaminoglycan mimetics

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 20(2015), 1, Seite 608-624
Übergeordnetes Werk:	volume:20 ; year:2015 ; number:1 ; pages:608-624

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules20010608

Katalog-ID:	DOAJ028710169

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allfieldsSound	10.3390/molecules20010608 doi (DE-627)DOAJ028710169 (DE-599)DOAJ6f3de1d2b5bd45059d35dcbfd2c2b3ed DE-627 ger DE-627 rakwb eng QD241-441 Rami A. Al-Horani verfasserin aut Plasmin Regulation through Allosteric, Sulfated, Small Molecules 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design. allosteric inhibitors library screening plasmin sulfated glycosaminoglycan mimetics Organic chemistry Rajesh Karuturi verfasserin aut Domonique T. White verfasserin aut Umesh R. Desai verfasserin aut In Molecules MDPI AG, 2003 20(2015), 1, Seite 608-624 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:20 year:2015 number:1 pages:608-624 https://doi.org/10.3390/molecules20010608 kostenfrei https://doaj.org/article/6f3de1d2b5bd45059d35dcbfd2c2b3ed kostenfrei http://www.mdpi.com/1420-3049/20/1/608 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2015 1 608-624
language	English
source	In Molecules 20(2015), 1, Seite 608-624 volume:20 year:2015 number:1 pages:608-624
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topic_facet	allosteric inhibitors library screening plasmin sulfated glycosaminoglycan mimetics Organic chemistry
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authorswithroles_txt_mv	Rami A. Al-Horani @@aut@@ Rajesh Karuturi @@aut@@ Domonique T. White @@aut@@ Umesh R. Desai @@aut@@
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callnumber-first	Q - Science
author	Rami A. Al-Horani
spellingShingle	Rami A. Al-Horani misc QD241-441 misc allosteric inhibitors misc library screening misc plasmin misc sulfated glycosaminoglycan mimetics misc Organic chemistry Plasmin Regulation through Allosteric, Sulfated, Small Molecules
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topic_title	QD241-441 Plasmin Regulation through Allosteric, Sulfated, Small Molecules allosteric inhibitors library screening plasmin sulfated glycosaminoglycan mimetics
topic	misc QD241-441 misc allosteric inhibitors misc library screening misc plasmin misc sulfated glycosaminoglycan mimetics misc Organic chemistry
topic_unstemmed	misc QD241-441 misc allosteric inhibitors misc library screening misc plasmin misc sulfated glycosaminoglycan mimetics misc Organic chemistry
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title	Plasmin Regulation through Allosteric, Sulfated, Small Molecules
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title_sort	plasmin regulation through allosteric, sulfated, small molecules
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title_auth	Plasmin Regulation through Allosteric, Sulfated, Small Molecules
abstract	Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.
abstractGer	Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.
abstract_unstemmed	Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%–100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.
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title_short	Plasmin Regulation through Allosteric, Sulfated, Small Molecules
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Plasmin Regulation through Allosteric, Sulfated, Small Molecules

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