Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G

Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have re...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Daniel K. Afosah [verfasserIn] Rawan M. Fayyad [verfasserIn] Valerie R. Puliafico [verfasserIn] Spencer Merrell [verfasserIn] Eltice K. Langmia [verfasserIn] Sophie R. Diagne [verfasserIn] Rami A. Al-Horani [verfasserIn] Umesh R. Desai [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	allosterism cathepsin G glycosaminoglycans mimetics inflammation

Übergeordnetes Werk:	In: Biomolecules - MDPI AG, 2013, 13(2023), 5, p 760
Übergeordnetes Werk:	volume:13 ; year:2023 ; number:5, p 760

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/biom13050760

Katalog-ID:	DOAJ09441257X

Internformat


LEADER	01000naa a22002652 4500
001	DOAJ09441257X
003	DE-627
005	20240413034600.0
007	cr uuu---uuuuu
008	240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.3390/biom13050760 \|2 doi
035			\|a (DE-627)DOAJ09441257X
035			\|a (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
050		0	\|a QR1-502
100	0		\|a Daniel K. Afosah \|e verfasserin \|4 aut
245	1	0	\|a Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
264		1	\|c 2023
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.
650		4	\|a allosterism
650		4	\|a cathepsin G
650		4	\|a glycosaminoglycans
650		4	\|a mimetics
650		4	\|a inflammation
653		0	\|a Microbiology
700	0		\|a Rawan M. Fayyad \|e verfasserin \|4 aut
700	0		\|a Valerie R. Puliafico \|e verfasserin \|4 aut
700	0		\|a Spencer Merrell \|e verfasserin \|4 aut
700	0		\|a Eltice K. Langmia \|e verfasserin \|4 aut
700	0		\|a Sophie R. Diagne \|e verfasserin \|4 aut
700	0		\|a Rami A. Al-Horani \|e verfasserin \|4 aut
700	0		\|a Umesh R. Desai \|e verfasserin \|4 aut
773	0	8	\|i In \|t Biomolecules \|d MDPI AG, 2013 \|g 13(2023), 5, p 760 \|w (DE-627)735688915 \|w (DE-600)2701262-1 \|x 2218273X \|7 nnns
773	1	8	\|g volume:13 \|g year:2023 \|g number:5, p 760
856	4	0	\|u https://doi.org/10.3390/biom13050760 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 \|z kostenfrei
856	4	0	\|u https://www.mdpi.com/2218-273X/13/5/760 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/2218-273X \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 13 \|j 2023 \|e 5, p 760

Indexfelder

author_variant	d k a dka r m f rmf v r p vrp s m sm e k l ekl s r d srd r a a h raah u r d urd
matchkey_str	article:2218273X:2023----::ooeeusnhtcoschrdgyoaiolcnieissoetn
hierarchy_sort_str	2023
callnumber-subject-code	QR
publishDate	2023
allfields	10.3390/biom13050760 doi (DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17 DE-627 ger DE-627 rakwb eng QR1-502 Daniel K. Afosah verfasserin aut Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk. allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology Rawan M. Fayyad verfasserin aut Valerie R. Puliafico verfasserin aut Spencer Merrell verfasserin aut Eltice K. Langmia verfasserin aut Sophie R. Diagne verfasserin aut Rami A. Al-Horani verfasserin aut Umesh R. Desai verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 5, p 760 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:5, p 760 https://doi.org/10.3390/biom13050760 kostenfrei https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 kostenfrei https://www.mdpi.com/2218-273X/13/5/760 kostenfrei https://doaj.org/toc/2218-273X 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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 13 2023 5, p 760
spelling	10.3390/biom13050760 doi (DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17 DE-627 ger DE-627 rakwb eng QR1-502 Daniel K. Afosah verfasserin aut Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk. allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology Rawan M. Fayyad verfasserin aut Valerie R. Puliafico verfasserin aut Spencer Merrell verfasserin aut Eltice K. Langmia verfasserin aut Sophie R. Diagne verfasserin aut Rami A. Al-Horani verfasserin aut Umesh R. Desai verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 5, p 760 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:5, p 760 https://doi.org/10.3390/biom13050760 kostenfrei https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 kostenfrei https://www.mdpi.com/2218-273X/13/5/760 kostenfrei https://doaj.org/toc/2218-273X 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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 13 2023 5, p 760
allfields_unstemmed	10.3390/biom13050760 doi (DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17 DE-627 ger DE-627 rakwb eng QR1-502 Daniel K. Afosah verfasserin aut Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk. allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology Rawan M. Fayyad verfasserin aut Valerie R. Puliafico verfasserin aut Spencer Merrell verfasserin aut Eltice K. Langmia verfasserin aut Sophie R. Diagne verfasserin aut Rami A. Al-Horani verfasserin aut Umesh R. Desai verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 5, p 760 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:5, p 760 https://doi.org/10.3390/biom13050760 kostenfrei https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 kostenfrei https://www.mdpi.com/2218-273X/13/5/760 kostenfrei https://doaj.org/toc/2218-273X 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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 13 2023 5, p 760
allfieldsGer	10.3390/biom13050760 doi (DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17 DE-627 ger DE-627 rakwb eng QR1-502 Daniel K. Afosah verfasserin aut Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk. allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology Rawan M. Fayyad verfasserin aut Valerie R. Puliafico verfasserin aut Spencer Merrell verfasserin aut Eltice K. Langmia verfasserin aut Sophie R. Diagne verfasserin aut Rami A. Al-Horani verfasserin aut Umesh R. Desai verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 5, p 760 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:5, p 760 https://doi.org/10.3390/biom13050760 kostenfrei https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 kostenfrei https://www.mdpi.com/2218-273X/13/5/760 kostenfrei https://doaj.org/toc/2218-273X 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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 13 2023 5, p 760
allfieldsSound	10.3390/biom13050760 doi (DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17 DE-627 ger DE-627 rakwb eng QR1-502 Daniel K. Afosah verfasserin aut Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk. allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology Rawan M. Fayyad verfasserin aut Valerie R. Puliafico verfasserin aut Spencer Merrell verfasserin aut Eltice K. Langmia verfasserin aut Sophie R. Diagne verfasserin aut Rami A. Al-Horani verfasserin aut Umesh R. Desai verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 5, p 760 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:5, p 760 https://doi.org/10.3390/biom13050760 kostenfrei https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 kostenfrei https://www.mdpi.com/2218-273X/13/5/760 kostenfrei https://doaj.org/toc/2218-273X 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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 13 2023 5, p 760
language	English
source	In Biomolecules 13(2023), 5, p 760 volume:13 year:2023 number:5, p 760
sourceStr	In Biomolecules 13(2023), 5, p 760 volume:13 year:2023 number:5, p 760
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	allosterism cathepsin G glycosaminoglycans mimetics inflammation Microbiology
isfreeaccess_bool	true
container_title	Biomolecules
authorswithroles_txt_mv	Daniel K. Afosah @@aut@@ Rawan M. Fayyad @@aut@@ Valerie R. Puliafico @@aut@@ Spencer Merrell @@aut@@ Eltice K. Langmia @@aut@@ Sophie R. Diagne @@aut@@ Rami A. Al-Horani @@aut@@ Umesh R. Desai @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	735688915
id	DOAJ09441257X
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ09441257X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240413034600.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biom13050760</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ09441257X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QR1-502</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Daniel K. Afosah</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">allosterism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cathepsin G</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">glycosaminoglycans</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mimetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">inflammation</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Microbiology</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rawan M. Fayyad</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Valerie R. Puliafico</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Spencer Merrell</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eltice K. Langmia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sophie R. Diagne</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rami A. Al-Horani</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Umesh R. Desai</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomolecules</subfield><subfield code="d">MDPI AG, 2013</subfield><subfield code="g">13(2023), 5, p 760</subfield><subfield code="w">(DE-627)735688915</subfield><subfield code="w">(DE-600)2701262-1</subfield><subfield code="x">2218273X</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:13</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:5, p 760</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biom13050760</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2218-273X/13/5/760</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2218-273X</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">13</subfield><subfield code="j">2023</subfield><subfield code="e">5, p 760</subfield></datafield></record></collection>
callnumber-first	Q - Science
author	Daniel K. Afosah
spellingShingle	Daniel K. Afosah misc QR1-502 misc allosterism misc cathepsin G misc glycosaminoglycans misc mimetics misc inflammation misc Microbiology Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
authorStr	Daniel K. Afosah
ppnlink_with_tag_str_mv	@@773@@(DE-627)735688915
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut aut aut aut aut
collection	DOAJ
remote_str	true
callnumber-label	QR1-502
illustrated	Not Illustrated
issn	2218273X
topic_title	QR1-502 Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G allosterism cathepsin G glycosaminoglycans mimetics inflammation
topic	misc QR1-502 misc allosterism misc cathepsin G misc glycosaminoglycans misc mimetics misc inflammation misc Microbiology
topic_unstemmed	misc QR1-502 misc allosterism misc cathepsin G misc glycosaminoglycans misc mimetics misc inflammation misc Microbiology
topic_browse	misc QR1-502 misc allosterism misc cathepsin G misc glycosaminoglycans misc mimetics misc inflammation misc Microbiology
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Biomolecules
hierarchy_parent_id	735688915
hierarchy_top_title	Biomolecules
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)735688915 (DE-600)2701262-1
title	Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
ctrlnum	(DE-627)DOAJ09441257X (DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17
title_full	Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
author_sort	Daniel K. Afosah
journal	Biomolecules
journalStr	Biomolecules
callnumber-first-code	Q
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2023
contenttype_str_mv	txt
author_browse	Daniel K. Afosah Rawan M. Fayyad Valerie R. Puliafico Spencer Merrell Eltice K. Langmia Sophie R. Diagne Rami A. Al-Horani Umesh R. Desai
container_volume	13
class	QR1-502
format_se	Elektronische Aufsätze
author-letter	Daniel K. Afosah
doi_str_mv	10.3390/biom13050760
author2-role	verfasserin
title_sort	homogeneous, synthetic, non-saccharide glycosaminoglycan mimetics as potent inhibitors of human cathepsin g
callnumber	QR1-502
title_auth	Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
abstract	Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.
abstractGer	Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.
abstract_unstemmed	Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.
collection_details	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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 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_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
container_issue	5, p 760
title_short	Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G
url	https://doi.org/10.3390/biom13050760 https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17 https://www.mdpi.com/2218-273X/13/5/760 https://doaj.org/toc/2218-273X
remote_bool	true
author2	Rawan M. Fayyad Valerie R. Puliafico Spencer Merrell Eltice K. Langmia Sophie R. Diagne Rami A. Al-Horani Umesh R. Desai
author2Str	Rawan M. Fayyad Valerie R. Puliafico Spencer Merrell Eltice K. Langmia Sophie R. Diagne Rami A. Al-Horani Umesh R. Desai
ppnlink	735688915
callnumber-subject	QR - Microbiology
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.3390/biom13050760
callnumber-a	QR1-502
up_date	2024-07-03T23:01:03.155Z
_version_	1803600698442514432
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ09441257X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240413034600.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biom13050760</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ09441257X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ1097e4fa5d0a43ee96427a13d0f7ae17</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QR1-502</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Daniel K. Afosah</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM <b<25</b< inhibited CatG with a potency of ~50 nM. NSGM <b<25</b< binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated <b<25</b< exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated <b<25</b< also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">allosterism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cathepsin G</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">glycosaminoglycans</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">mimetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">inflammation</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Microbiology</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rawan M. Fayyad</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Valerie R. Puliafico</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Spencer Merrell</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eltice K. Langmia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sophie R. Diagne</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Rami A. Al-Horani</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Umesh R. Desai</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomolecules</subfield><subfield code="d">MDPI AG, 2013</subfield><subfield code="g">13(2023), 5, p 760</subfield><subfield code="w">(DE-627)735688915</subfield><subfield code="w">(DE-600)2701262-1</subfield><subfield code="x">2218273X</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:13</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:5, p 760</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biom13050760</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/1097e4fa5d0a43ee96427a13d0f7ae17</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2218-273X/13/5/760</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2218-273X</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">13</subfield><subfield code="j">2023</subfield><subfield code="e">5, p 760</subfield></datafield></record></collection>
score	7.402011

Nicht das Richtige dabei?

Schreiben Sie uns!

Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?