Literature summary for 3.4.21.75 extracted from

Van Lam van, T.; Ivanova, T.; Hardes, K.; Heindl, M.R.; Morty, R.E.; Boettcher-Friebertshaeuser, E.; Lindberg, I.; Than, M.E.; Dahms, S.O.; Steinmetzer, T.
Design, synthesis, and characterization of macrocyclic inhibitors of the proprotein convertase furin (2019), ChemMedChem, 14, 673-685 .

Search for more literature for 3.4.21.75

Application

Application	Comment	Organism
drug development	the activation of viral glycoproteins by the host protease furin is an essential step in the replipation of numerous pathogenic viruses. Thus, effective inhibitors of furin can serve as broad-spectrum antiviral drugs, rational design of various types of cyclic inhibitors	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified enzyme furin in complexes with inhibitors N2-phenylacetyl-L-Lys-L-Lys-L-Arg-aldehyde, N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide, N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide, N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide, diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate, diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate, and diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate, vapor diffusion method, 9.0 mg/ml glycosylated human furin in 10 mm HEPES, pH 7.5, 100 mm NaCl, and 2 mm CaCl2 is mixed with an equal volume of crystallization solution containing 100 mm MES, 200 mm K/NaH2PO4, pH 5.5-6.0, and 2m NaCl, and equilibrated against reservoir solution with 3.0-3.6m NaCl, at 20°C, crystals are soaked for 16 h in soaking solution containing 3.13 M NaCl, 100 mM Mes/NaOH, pH 5.5, 200 mM NaH2PO4, 1 mM CaCl2, and 20% DMSO supplemented with inhibitor N2-phenylacetyl-L-Lys-L-Lys-L-Arg-aldehyde (5 mM), N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide (5 mM), N2-(4-[(Z)-[3-(cyclohexylmethyl)-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl]benzoyl)-L-lysyl-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-L-lysinamide (5 mM), N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide (5 mM), diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate (5 mM), diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate (1 mM), or diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate (1 mM), X-ray diffraction structure determination and analysis	Homo sapiens

Crystallization (Comment)

Organism

purified enzyme furin in complexes with inhibitors N2-phenylacetyl-L-Lys-L-Lys-L-Arg-aldehyde, N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide, N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide, N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide, diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate, diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate, and diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate, vapor diffusion method, 9.0 mg/ml glycosylated human furin in 10 mm HEPES, pH 7.5, 100 mm NaCl, and 2 mm CaCl2 is mixed with an equal volume of crystallization solution containing 100 mm MES, 200 mm K/NaH2PO4, pH 5.5-6.0, and 2m NaCl, and equilibrated against reservoir solution with 3.0-3.6m NaCl, at 20°C, crystals are soaked for 16 h in soaking solution containing 3.13 M NaCl, 100 mM Mes/NaOH, pH 5.5, 200 mM NaH2PO4, 1 mM CaCl2, and 20% DMSO supplemented with inhibitor N2-phenylacetyl-L-Lys-L-Lys-L-Arg-aldehyde (5 mM), N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide (5 mM), N2-(4-[(Z)-[3-(cyclohexylmethyl)-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl]benzoyl)-L-lysyl-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-L-lysinamide (5 mM), N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide (5 mM), diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate (5 mM), diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate (1 mM), or diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate (1 mM), X-ray diffraction structure determination and analysis

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(1S,14S,17S,20S,23S,26S,33r)-26-amino-N-(4-carbamimidoylbenzyl)-20,23-bis(3-guanidinopropyl)-17-neopentyl-4,8,16,19,22,25,32-heptaoxo-3,9,15,18,21,24,31-heptaazabicyclo[31.2.2]heptatriacontane-14-carboxamide	-	Homo sapiens
Ac-Ac-RQIKIWFQNRRMKWKKRVR 4-amidinobenzylamide	-	Homo sapiens
Ac-AGYLLGKINLKALAALAKKILRVR 4-amidinobenzylamide	-	Homo sapiens
Ac-RRRRRRRVR 4-amidinobenzylamide	-	Homo sapiens
Ac-YGRKKRRQRRRVR 4-amidinobenzylamide	-	Homo sapiens
Arg-Arg-Arg-Arg-Arg-Arg	-	Homo sapiens
Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg	-	Homo sapiens
Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg	-	Homo sapiens
Arg-Arg-Arg-Val-Arg-4-amidinobenzylamide	-	Homo sapiens
cyclo[(Arg)10]	-	Homo sapiens
cyclo[(Arg)6]	-	Homo sapiens
cyclo[(Arg)8]	-	Homo sapiens
cyclo[glutaryl-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	-	Homo sapiens
cyclo[glutaryl-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	-	Homo sapiens
cyclo[glutaryl-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	-	Homo sapiens
cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	-	Homo sapiens
Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]butanamide bridged)	-	Homo sapiens
Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 N1-[[4-(2-amino-2-oxoethyl)phenyl]methyl]butanediamide bridged)	-	Homo sapiens
Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 N1-[[4-(2-amino-2-oxoethyl)phenyl]methyl]pentanediamide bridged)	-	Homo sapiens
additional information	development of specific inhibitors of furin, synthesis of several truncated analogues of the bicyclic sunflower trypsin inhibitor (SFTI-1), or of compounds by various head-to-tail, head-to-side chain, and side-chain-to-tail cyclizations within multibasic octapeptides, or of several cationic cyclized peptides with cell-penetrating properties, overview. Inhibitory potency of these compounds is determined in enzyme kinetic assays with furin. Inhibitor docking study, crystal structure determination, and structure-function analysis. Modeling of furin in complex with inhibitors N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide, diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate, diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate, and diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate. Inhibition of respiratory syncytial virus propagation in A549 cells	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
nucleus	-	Homo sapiens	5634	-

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P09958	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
glycoprotein	-	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
A-549 cell	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
phenylacetyl-Arg-Val-Arg-7-amido-4-methylcoumarin + H2O	-	Homo sapiens	phenylacetyl-Arg-Val-Arg + 7-amino-4-methylcoumarin	-	?

Synonyms

Synonyms	Comment	Organism
Proprotein convertase	-	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.0000000337	-	Arg-Arg-Arg-Val-Arg-4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.0000000538	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000000136	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000000146	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000000154	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000000378	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000000491	-	Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]butanamide bridged)	pH and temperature not specified in the publication	Homo sapiens
0.000000618	-	cyclo[succinyl-Phe-2-Nal-Arg-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.00000068	-	cyclo[glutaryl-Arg-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.00000099	-	(1S,14S,17S,20S,23S,26S,33r)-26-amino-N-(4-carbamimidoylbenzyl)-20,23-bis(3-guanidinopropyl)-17-neopentyl-4,8,16,19,22,25,32-heptaoxo-3,9,15,18,21,24,31-heptaazabicyclo[31.2.2]heptatriacontane-14-carboxamide	pH and temperature not specified in the publication	Homo sapiens
0.00000105	-	cyclo[glutaryl-Arg-Arg-Lys]-Lys 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.00000117	-	Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 N1-[[4-(2-amino-2-oxoethyl)phenyl]methyl]pentanediamide bridged)	pH and temperature not specified in the publication	Homo sapiens
0.00000504	-	Lys-Arg-Arg-Tle-Lys 4-amidinobenzylamide (Lys1-Lys5 N1-[[4-(2-amino-2-oxoethyl)phenyl]methyl]butanediamide bridged)	pH and temperature not specified in the publication	Homo sapiens
0.000006	-	Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg	pH and temperature not specified in the publication	Homo sapiens
0.0000093	-	Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg	pH and temperature not specified in the publication	Homo sapiens
0.0000094	-	Arg-Arg-Arg-Arg-Arg-Arg	pH and temperature not specified in the publication	Homo sapiens
0.0000107	-	Ac-RRRRRRRVR 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000011	-	Ac-YGRKKRRQRRRVR 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.000019	-	Ac-Ac-RQIKIWFQNRRMKWKKRVR 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.0000227	-	cyclo[(Arg)8]	pH and temperature not specified in the publication	Homo sapiens
0.0000228	-	Ac-AGYLLGKINLKALAALAKKILRVR 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens
0.0000278	-	cyclo[(Arg)10]	pH and temperature not specified in the publication	Homo sapiens
0.0001104	-	cyclo[(Arg)6]	pH and temperature not specified in the publication	Homo sapiens
0.000504	-	cyclo[glutaryl-Arg-Arg-Lys]-Arg 4-amidinobenzylamide	pH and temperature not specified in the publication	Homo sapiens

General Information

General Information	Comment	Organism
evolution	furin belongs to the family of Ca2+-dependent proprotein convertases (PCs), all of which contain a subtilisin-like serine protease domain. Furin and the other six basic PCs, i.e. PC1, PC2, PC4, PACE4, PC5, and PC7, cleave their substrates at multibasic sequences mainly after arginine, whereas the nonbasic PC site-1 protease (S1P) cleaves preferentially after leucine, valine, or isoleucine	Homo sapiens
physiological function	activation of viral glycoproteins or bacterial toxins, furin and other PCs contribute to the propagation of certain pathogenic viruses and to the toxicity of some bacteria	Homo sapiens