BRENDA - Enzyme Database
show all sequences of 3.4.22.69

Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus

Goetz, D.H.; Choe, Y.; Hansell, E.; Chen, Y.T.; McDowell, M.; Jonsson, C.B.; Roush, B.C.; McKerrow, J.; Craik, C.S.; Biochemistry 46, 8744-8752 (2007)

Data extracted from this reference:

Cloned(Commentary)
Cloned (Commentary)
Organism
-
SARS coronavirus
Crystallization (Commentary)
Crystallization (Commentary)
Organism
1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor, an alpha,beta-epoxyketone
SARS coronavirus
Inhibitors
Inhibitors
Commentary
Organism
Structure
4,5-anhydro-2-([N-[(benzyloxy)carbonyl]-L-phenylalanyl]amino)-1,2-dideoxy-D-erythro-pent-3-ulose
-
SARS coronavirus
Organism
Organism
UniProt
Commentary
Textmining
SARS coronavirus
-
-
-
Purification (Commentary)
Purification (Commentary)
Organism
-
SARS coronavirus
Substrates and Products (Substrate)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
Substrate Product ID
acetyl-TSAVLH-7-amido-4-carbamoyl-coumarin + H2O
SARS-CoV 3Clpro prefers Gln over His in P1 position. Unlike SARS-CoV 3Clpro, His is strongly preferred in the P1 position by 3C-like proteases from infectious bronchitis virus murine hepatitis virus
678313
SARS coronavirus
acetyl-TSAVLH + 7-amino-4-carbamoyl-coumarin
-
-
-
?
acetyl-TSTKLQ-7-amido-4-carbamoyl-coumarin + H2O
optimized fluorogenic peptide substrate. The enzyme exhibits a strong preference for P1 Gln containing substrates and P2 Leu containing substrates
678313
SARS coronavirus
acetyl-TSTKLQ + 7-amino-4-carbamoyl-coumarin
-
-
-
?
additional information
complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160 000 possible naturally occurring tetrapeptides. P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln
678313
SARS coronavirus
?
-
-
-
-
additional information
a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160000 possible naturally occurring tetrapeptides. The enzyme exhibits a strong preference for P1 Gln containing substrates and P2 Leu containing substrates. The enzyme also shows a strong preference for P1 histidine containing substrates. 3Clpro has extended substrate specificity at P5 and P6 preferring hydrophobic amino acids such as Leu
678313
SARS coronavirus
?
-
-
-
-
Ki Value [mM]
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0022
-
4,5-anhydro-2-([N-[(benzyloxy)carbonyl]-L-phenylalanyl]amino)-1,2-dideoxy-D-erythro-pent-3-ulose
-
SARS coronavirus
Cloned(Commentary) (protein specific)
Commentary
Organism
-
SARS coronavirus
Crystallization (Commentary) (protein specific)
Crystallization
Organism
1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor, an alpha,beta-epoxyketone
SARS coronavirus
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
4,5-anhydro-2-([N-[(benzyloxy)carbonyl]-L-phenylalanyl]amino)-1,2-dideoxy-D-erythro-pent-3-ulose
-
SARS coronavirus
Ki Value [mM] (protein specific)
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0022
-
4,5-anhydro-2-([N-[(benzyloxy)carbonyl]-L-phenylalanyl]amino)-1,2-dideoxy-D-erythro-pent-3-ulose
-
SARS coronavirus
Purification (Commentary) (protein specific)
Commentary
Organism
-
SARS coronavirus
Substrates and Products (Substrate) (protein specific)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
ID
acetyl-TSAVLH-7-amido-4-carbamoyl-coumarin + H2O
SARS-CoV 3Clpro prefers Gln over His in P1 position. Unlike SARS-CoV 3Clpro, His is strongly preferred in the P1 position by 3C-like proteases from infectious bronchitis virus murine hepatitis virus
678313
SARS coronavirus
acetyl-TSAVLH + 7-amino-4-carbamoyl-coumarin
-
-
-
?
acetyl-TSTKLQ-7-amido-4-carbamoyl-coumarin + H2O
optimized fluorogenic peptide substrate. The enzyme exhibits a strong preference for P1 Gln containing substrates and P2 Leu containing substrates
678313
SARS coronavirus
acetyl-TSTKLQ + 7-amino-4-carbamoyl-coumarin
-
-
-
?
additional information
complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160 000 possible naturally occurring tetrapeptides. P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln
678313
SARS coronavirus
?
-
-
-
-
additional information
a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160000 possible naturally occurring tetrapeptides. The enzyme exhibits a strong preference for P1 Gln containing substrates and P2 Leu containing substrates. The enzyme also shows a strong preference for P1 histidine containing substrates. 3Clpro has extended substrate specificity at P5 and P6 preferring hydrophobic amino acids such as Leu
678313
SARS coronavirus
?
-
-
-
-
Other publictions for EC 3.4.22.69
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Synonyms
Temperature Optimum [°C]
Temperature Range [°C]
Temperature Stability [°C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [°C] (protein specific)
Temperature Range [°C] (protein specific)
Temperature Stability [°C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
752729
Krichel
Processing of the SARS-CoV pp ...
SARS coronavirus
Biochem. J.
477
1009-1019
2020
-
-
-
-
-
-
-
-
-
-
-
1
-
4
-
-
-
-
-
-
-
-
2
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
752975
Yoshizawa
Evaluation of an octahydroiso ...
SARS coronavirus
Bioorg. Med. Chem.
28
115273
2020
-
-
-
-
-
-
8
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
7
-
-
-
-
-
-
-
7
8
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
753268
Morse
Learning from the Past Possib ...
SARS coronavirus
ChemBioChem
21
730-738
2020
-
-
-
-
-
-
5
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
5
-
-
-
-
-
-
-
5
5
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
753527
Chen
Prediction of the SARS-CoV-2 ...
Severe acute respiratory syndrome coronavirus 2
F1000Res.
9
129
2020
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
2
-
-
-
754293
Jo
Inhibition of SARS-CoV 3CL pr ...
SARS coronavirus
J. Enzyme Inhib. Med. Chem.
35
145-151
2020
-
-
1
-
-
-
3
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
-
2
-
-
-
-
-
-
-
-
-
-
3
-
-
1
-
-
-
-
3
3
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
754405
Dong
A guideline for homology mode ...
Severe acute respiratory syndrome coronavirus 2
J. Med. Virol.
FEHLT
0000
2020
-
-
-
-
-
-
-
-
-
-
-
-
-
7
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
754752
Ton
Rapid identification of poten ...
Severe acute respiratory syndrome coronavirus 2
Mol. Inform.
FEHLT
0000
2020
-
-
-
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
755546
Zhang
Crystal structure of SARS-CoV ...
SARS coronavirus, Severe acute respiratory syndrome coronavirus 2
Science
FEHLT
0000
2020
-
-
-
1
-
-
2
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
1
-
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4
4
-
-
-
752974
Ohnishi
Evaluation of a non-prime sit ...
SARS coronavirus
Bioorg. Med. Chem.
27
425-435
2019
-
-
-
-
-
-
2
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
753344
Rahman
Lead molecule prediction and ...
Middle East respiratory syndrome-related coronavirus
Curr. Comput. Aided Drug Des.
15
82-88
2019
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
2
-
-
-
753538
Zhou
Identification of novel prote ...
porcine epidemic diarrhea virus
FASEB J.
33
14575-14587
2019
-
-
-
-
4
-
-
-
-
-
-
-
-
6
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
755284
Lim
Structurally- and dynamically ...
SARS coronavirus
Prog. Biophys. Mol. Biol.
143
52-66
2019
-
-
-
-
2
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
755639
Perera
Characterization of amino aci ...
feline coronavirus
Vet. Microbiol.
237
108398
2019
-
-
-
-
6
-
2
-
-
-
-
-
-
5
-
-
-
-
-
-
-
-
1
-
2
1
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
6
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
-
-
-
1
-
-
-
-
-
-
-
-
-
755651
Kanitz
Structural basis for catalysi ...
Alphamesonivirus 1
Virology
533
21-33
2019
-
-
-
1
-
-
1
-
-
-
-
-
-
1
-
-
1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
1
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
752992
Konno
Synthesis and evaluation of p ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
27
2746-2751
2017
-
-
-
-
1
-
3
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
1
-
3
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
753488
Wang
Discovery of unsymmetrical ar ...
SARS coronavirus
Eur. J. Med. Chem.
137
450-461
2017
-
-
-
-
-
-
2
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
753022
Teruya
Structural basis for the deve ...
SARS coronavirus
Biopolymers
106
391-403
2016
-
-
1
1
1
-
2
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
2
-
-
1
-
1
1
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
755253
Muramatsu
SARS-CoV 3CL protease cleaves ...
SARS coronavirus
Proc. Natl. Acad. Sci. USA
113
12997-13002
2016
-
-
-
1
1
-
3
1
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
3
-
-
-
-
-
-
1
1
-
-
3
3
1
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
1
1
-
-
-
755419
Li
Conformational flexibility of ...
SARS coronavirus
Sci. Rep.
6
20918
2016
-
-
1
-
2
-
-
2
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
1
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
-
-
2
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
2
-
-
-
-
-
-
-
-
-
-
752951
Shimamoto
Fused-ring structure of decah ...
SARS coronavirus
Bioorg. Med. Chem.
23
876-890
2015
-
-
-
1
-
-
12
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
1
-
-
-
-
-
-
-
-
-
-
11
-
-
-
-
1
-
-
11
12
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
731320
Paasche
Evidence for substrate binding ...
SARS coronavirus
Biochemistry
53
5930-5946
2014
-
1
-
-
-
-
1
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
3
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
2
-
-
-
731060
Wu
Mechanism for controlling the ...
SARS coronavirus
Acta Crystallogr. Sect. D
69
747-755
2013
-
1
1
1
1
-
-
-
1
-
-
-
-
2
-
-
1
-
-
-
-
-
3
2
7
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
1
1
-
-
-
-
-
1
-
-
-
-
-
-
1
-
-
-
-
3
2
-
-
-
-
-
-
-
-
-
1
1
-
-
-
731443
Turlington
Discovery of N-(benzo[1,2,3]tr ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
23
6172-6177
2013
-
-
-
1
-
-
44
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
31
-
-
-
-
1
-
-
31
44
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
731748
Thanigaimalai
Design, synthesis, and biologi ...
SARS coronavirus
Eur. J. Med. Chem.
65
436-447
2013
-
-
-
-
-
-
45
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
34
-
14
-
-
-
-
-
-
-
14
45
34
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
731749
Thanigaimalai
Development of potent dipeptid ...
SARS coronavirus
Eur. J. Med. Chem.
68
372-384
2013
-
-
-
-
-
-
23
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
21
-
3
-
-
-
-
-
-
-
3
23
21
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
731790
Muramatsu
Autoprocessing mechanism of se ...
SARS coronavirus
FEBS J.
280
2002-2013
2013
1
-
-
-
3
-
-
-
-
-
1
-
-
3
-
1
-
-
-
-
-
-
1
1
7
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
3
-
-
-
-
-
-
-
1
-
-
-
1
-
-
-
-
-
1
1
1
-
-
-
-
-
-
-
-
1
1
-
-
-
717101
Zhu
Peptide aldehyde inhibitors ch ...
SARS coronavirus
Antiviral Res.
92
204-212
2011
-
-
-
1
-
-
5
1
-
-
-
-
-
2
-
-
-
-
-
-
-
-
18
-
2
-
-
-
-
-
-
-
-
5
-
-
-
-
-
-
1
-
-
-
5
5
1
-
-
-
-
-
-
-
-
-
-
-
-
18
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
717343
Nguyen
Virtual screening identificati ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
21
3088-3091
2011
-
-
-
-
-
-
7
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
2
-
-
-
-
-
-
-
-
-
-
7
-
-
-
-
-
-
-
7
7
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
717978
Akaji
Structure-based design, synthe ...
SARS coronavirus
J. Med. Chem.
54
7962-7973
2011
-
-
-
1
1
-
15
-
-
-
-
-
-
1
-
-
1
-
-
-
-
-
1
-
3
-
-
-
-
-
-
-
-
-
-
13
-
-
-
-
1
1
-
13
15
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707696
Ryu
SARS-CoV 3CLpro inhibitory eff ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
20
1873-1876
2010
-
-
-
-
-
-
6
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
4
-
6
-
-
-
-
-
-
-
6
6
4
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707708
Ramajayam
Synthesis, docking studies, an ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
20
3569-3572
2010
-
-
-
-
-
-
14
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
14
-
-
-
-
-
-
-
14
14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707753
Cheng
Mutation of Glu-166 blocks the ...
SARS coronavirus
Biophys. J.
98
1327-1336
2010
-
-
1
-
5
-
-
2
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
1
1
-
-
-
4
-
-
-
-
-
-
-
-
-
1
-
-
5
-
-
-
-
2
-
-
-
-
-
-
-
1
-
-
-
-
1
1
-
-
-
4
-
-
-
-
-
-
-
-
2
2
709130
Li
Maturation mechanism of severe ...
SARS coronavirus
J. Biol. Chem.
285
28134-28140
2010
-
-
1
-
-
-
1
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
1
2
-
-
-
-
-
-
-
-
-
-
1
-
-
1
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
3
3
717244
Barrila
Mutation of Asn28 disrupts the ...
SARS coronavirus
Biochemistry
49
4308-4317
2010
-
-
1
1
1
-
-
2
-
-
1
1
-
6
-
-
1
-
-
-
-
-
1
1
2
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
1
-
-
-
-
2
-
-
1
1
-
-
-
1
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
2
2
717308
Okamoto
Increase of SARS-CoV 3CL pepti ...
SARS coronavirus
Biol. Chem.
391
1461-1468
2010
3
-
1
-
-
-
-
13
-
-
-
-
1
3
-
-
1
-
-
-
-
-
9
-
2
-
-
-
13
1
1
-
-
-
-
-
3
-
1
-
-
-
-
-
-
-
13
-
-
-
-
1
-
-
1
-
-
-
-
9
-
-
-
-
13
1
1
-
-
-
-
-
-
13
13
717450
Ahn
-
Synthesis and evaluation of be ...
SARS coronavirus
Bull. Korean Chem. Soc.
31
87-91
2010
-
-
-
-
-
-
10
-
-
-
-
-
-
1
-
-
1
-
-
-
-
-
1
-
3
-
-
-
-
-
-
-
-
-
-
10
-
-
-
-
-
-
-
10
10
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
718259
Chuck
Profiling of substrate specifi ...
SARS coronavirus
PLoS ONE
5
e13197
2010
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
10
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
10
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691480
Phakthanakanok
A computational analysis of SA ...
SARS coronavirus
BMC Bioinformatics
10 Suppl 1
S48
2009
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
4
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
692371
Kuo
Individual and common inhibito ...
SARS coronavirus
FEBS Lett.
583
549-555
2009
-
-
-
-
-
-
9
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
9
-
-
-
-
-
-
-
9
9
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
693255
Lee
Structural basis of inhibition ...
SARS coronavirus
J. Biol. Chem.
284
7646-7655
2009
-
-
1
1
-
-
9
-
-
-
-
-
-
1
-
-
1
-
-
-
-
-
2
1
3
-
-
-
-
-
-
-
-
8
-
-
-
-
1
-
1
-
-
-
9
8
-
-
-
-
-
-
-
-
1
-
-
-
-
2
1
-
-
-
-
-
-
-
-
-
1
1
-
-
-
695025
Zhong
C-terminal domain of SARS-CoV ...
SARS coronavirus
Protein Sci.
18
839-844
2009
-
-
-
1
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707665
Regnier
New developments for the desig ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
19
2722-2727
2009
-
-
-
-
-
-
15
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
2
-
-
-
-
-
-
-
-
15
-
-
-
-
-
-
-
-
-
-
15
15
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707798
Luo
Anti-SARS coronavirus 3C-like ...
SARS coronavirus
Biosci. Trends
3
124-126
2009
-
-
1
-
-
-
2
-
-
-
-
-
-
5
-
-
1
-
-
-
-
-
2
-
3
-
-
-
-
-
-
-
-
-
-
1
-
-
1
-
-
-
-
1
2
-
-
-
-
-
-
-
-
-
1
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
707802
Kuo
Engineering a novel endopeptid ...
SARS coronavirus
Biotechniques
47
1029-1032
2009
-
-
1
-
2
-
-
4
-
-
-
1
-
1
-
-
1
-
-
-
-
-
16
-
3
-
-
-
4
-
-
-
-
-
-
-
-
-
1
-
-
2
-
-
-
-
4
-
-
-
1
-
-
-
1
-
-
-
-
16
-
-
-
-
4
-
-
-
-
-
1
1
-
-
-
710675
Hu
Two adjacent mutations on the ...
SARS coronavirus Tor2
Virology
388
324-334
2009
-
-
1
1
2
-
-
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
-
1
2
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
2
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
1
1
-
-
-
678335
Solowiej
Steady-state and pre-steady-st ...
SARS coronavirus
Biochemistry
47
2617-2630
2008
-
-
-
-
-
-
-
5
-
-
-
-
-
1
-
-
-
-
-
-
-
-
5
-
1
-
-
-
5
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
5
-
-
-
-
-
-
-
-
-
-
-
-
5
-
-
-
-
5
-
-
-
-
-
-
-
-
-
-
678619
Niu
Molecular docking identifies t ...
SARS coronavirus
Bioorg. Med. Chem.
16
293-302
2008
-
-
-
-
-
-
13
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12
-
-
-
-
-
-
-
12
13
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
680920
Chen
Mutation of Gly-11 on the dime ...
Alphacoronavirus
J. Biol. Chem.
283
554-564
2008
-
-
1
1
1
-
-
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
690620
Lin
Correlation between dissociati ...
SARS coronavirus
Arch. Biochem. Biophys.
472
34-42
2008
-
-
1
-
12
-
-
15
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
2
1
-
-
-
20
-
-
-
-
-
-
-
-
-
1
-
-
12
-
-
-
-
15
-
-
-
-
-
-
-
1
-
-
-
-
1
2
-
-
-
20
-
-
-
-
-
-
-
-
-
-
691200
Zhang
Aryl methylene ketones and flu ...
SARS coronavirus
Bioorg. Chem.
36
229-240
2008
-
1
-
-
-
-
9
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
2
-
1
-
-
-
-
-
-
-
-
-
-
4
-
1
-
-
-
-
-
4
9
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691218
Mukherjee
Structure-based virtual screen ...
SARS coronavirus
Bioorg. Med. Chem.
16
4138-4149
2008
-
1
-
-
-
-
2
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
-
1
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691222
Shao
Design, synthesis, and evaluat ...
SARS coronavirus
Bioorg. Med. Chem.
16
4652-4660
2008
-
-
-
-
-
-
7
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
7
-
-
-
-
-
-
-
7
7
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691242
Akaji
Evaluation of peptide-aldehyde ...
SARS coronavirus
Bioorg. Med. Chem.
16
9400-9408
2008
-
-
1
-
1
1
4
3
-
-
-
1
-
2
-
-
1
-
-
-
-
-
4
-
1
-
-
-
3
-
-
-
-
-
1
4
-
-
1
-
-
1
1
4
4
-
3
-
-
-
1
-
-
-
1
-
-
-
-
4
-
-
-
-
3
-
-
-
1
-
-
-
-
-
-
691304
Ghosh
Design, synthesis and antivira ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
18
5684-5688
2008
-
-
-
-
-
-
10
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
10
-
-
-
-
-
-
-
10
10
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691735
Bacha
Development of broad-spectrum ...
SARS coronavirus
Chem. Biol. Drug Des.
72
34-49
2008
-
-
-
1
-
-
5
-
-
-
-
-
-
4
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
5
-
-
-
-
-
-
1
-
-
-
5
5
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691768
Yang
Design and synthesis of cinans ...
SARS coronavirus
Chem. Pharm. Bull.
56
1400-1405
2008
-
-
-
-
-
-
9
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
9
-
-
-
-
-
-
-
9
9
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
692911
Chen
Residues on the dimer interfac ...
SARS coronavirus
J. Biochem.
143
525-536
2008
-
-
1
-
7
-
-
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
1
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
7
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
693700
Taranto
QM/QM studies for Michael reac ...
SARS coronavirus
J. Mol. Graph. Model.
27
275-285
2008
-
-
-
-
-
-
1
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
693917
Zhong
Without its N-finger, the main ...
SARS coronavirus
J. Virol.
82
4227-4234
2008
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
1
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
693918
Shi
Mechanism for controlling the ...
SARS coronavirus
J. Virol.
82
4620-4629
2008
-
-
1
1
1
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
678313
Goetz
Substrate specificity profilin ...
SARS coronavirus
Biochemistry
46
8744-8752
2007
-
-
1
1
-
-
1
-
-
-
-
-
-
1
-
-
1
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
1
-
-
-
1
1
-
-
-
-
-
-
-
-
1
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
678690
Ghosh
Structure-based design, synthe ...
SARS coronavirus
Bioorg. Med. Chem. Lett.
17
5876-5880
2007
-
-
-
-
-
-
7
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
7
-
-
-
-
-
-
-
7
7
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
678728
Chang
Reversible unfolding of the se ...
SARS coronavirus
Biophys. J.
92
1374-1383
2007
-
-
-
-
-
-
-
-
-
-
-
-
1
3
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
679216
Shao
Structure-based design and syn ...
SARS coronavirus
Chembiochem
8
1654-1657
2007
-
-
-
-
-
-
2
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
681313
Wen
Specific plant terpenoids and ...
SARS coronavirus
J. Med. Chem.
50
4087-4095
2007
-
-
-
-
-
-
4
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
4
-
-
-
-
-
-
-
4
4
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
681418
Lee
Crystal structures reveal an i ...
SARS coronavirus
J. Mol. Biol.
366
916-932
2007
-
-
-
1
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
681443
Yin
A mechanistic view of enzyme i ...
SARS coronavirus
J. Mol. Biol.
371
1060-1074
2007
-
-
1
1
-
-
2
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
-
-
-
2
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
682785
Zheng
Insight into the activity of S ...
SARS coronavirus
Proteins Struct. Funct. Bioinform.
66
467-479
2007
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
2
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
668633
Graziano
Enzymatic activity of the SARS ...
SARS coronavirus
FEBS Lett.
580
2577-2583
2006
-
-
1
-
-
-
3
1
-
-
1
-
-
3
-
-
1
-
-
-
-
-
1
-
-
1
-
-
1
1
-
-
-
-
-
-
-
-
1
-
-
-
-
-
3
-
1
-
-
1
-
-
-
-
1
-
-
-
-
1
-
1
-
-
1
1
-
-
-
-
-
-
-
-
-
678172
Graziano
SARS CoV main proteinase: The ...
SARS coronavirus
Biochemistry
45
14632-14641
2006
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
678512
Hamill
Development of a red-shifted f ...
SARS coronavirus
Biol. Chem.
387
1063-1074
2006
-
1
1
-
-
-
1
1
-
-
-
-
-
2
-
-
1
-
-
-
-
-
2
-
1
-
-
-
1
-
-
-
-
-
-
1
-
1
1
-
-
-
-
1
1
-
1
-
-
-
-
-
-
-
1
-
-
-
-
2
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
678590
Chen
Binding interaction of quercet ...
SARS coronavirus
Bioorg. Med. Chem.
14
8295-8306
2006
-
-
-
-
1
-
7
2
-
-
-
-
-
1
-
-
-
-
-
-
-
-
1
-
1
-
-
-
2
-
-
-
-
-
-
5
-
-
-
-
-
1
-
5
7
-
2
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
679164
Wu
Stable benzotriazole esters as ...
SARS coronavirus
Chem. Biol.
13
261-268
2006
-
-
-
-
1
-
8
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
8
-
-
-
-
-
-
-
1
-
-
8
8
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
679402
Lai
Quaternary structure, substrat ...
SARS coronavirus
Curr. Pharm. Des.
12
4555-4564
2006
-
-
-
-
-
-
15
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
44
-
1
-
-
-
-
2
2
-
-
5
-
10
-
-
-
-
-
-
-
10
15
5
-
-
-
-
-
-
-
-
-
-
-
-
-
44
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
679408
Liang
Characterization and inhibitio ...
SARS coronavirus
Curr. Top. Med. Chem.
6
361-376
2006
-
-
-
-
-
-
24
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
2
2
-
-
-
-
-
-
-
-
17
-
7
-
-
-
-
-
-
-
7
24
17
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
679734
Shi
The catalysis of the SARS 3C-l ...
SARS coronavirus
FEBS J.
273
1035-1045
2006
-
-
1
-
16
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
16
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
680643
Chen
Only one protomer is active in ...
SARS coronavirus
J. Biol. Chem.
281
13894-13898
2006
-
-
-
-
-
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
681287
Yang
Synthesis, crystal structure, ...
SARS coronavirus
J. Med. Chem.
49
4971-4980
2006
-
-
1
1
-
-
4
-
-
-
-
-
-
4
-
-
1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
5
-
-
-
-
1
-
1
-
-
-
4
5
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
681289
Lu
Structure-based drug design an ...
SARS coronavirus
J. Med. Chem.
49
5154-5161
2006
-
-
-
1
-
-
21
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
21
-
-
-
-
1
-
-
21
21
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
694999
Chu
Rapid peptide-based screening ...
SARS coronavirus
Protein Sci.
15
699-709
2006
-
-
-
-
-
-
-
-
-
-
-
1
-
3
-
-
-
-
-
-
-
-
2
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
667075
Xu
Structure of the SARS coronavi ...
SARS coronavirus
Acta Crystallogr. Sect. F
61
964-966
2005
-
-
1
1
-
-
-
-
-
-
-
-
-
2
-
-
1
-
-
-
-
-
-
1
1
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
669868
Tan
pH-dependent conformational fl ...
SARS coronavirus
J. Mol. Biol.
354
25-40
2005
-
-
-
1
-
-
-
1
-
-
-
-
-
2
-
-
-
-
-
-
-
-
1
-
1
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
667918
Zhang
Old drugs as lead compounds fo ...
SARS coronavirus
Bioorg. Med. Chem.
12
2517-2521
2004
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
691145
Fan
Biosynthesis, purification, an ...
SARS coronavirus
Biol. Chem.
279
1637-1642
2004
-
-
1
-
-
-
-
6
-
-
-
-
-
3
-
-
1
-
-
-
-
-
12
2
1
-
-
1
6
1
1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
6
-
-
-
-
-
-
-
1
-
-
-
-
12
2
-
-
1
6
1
1
-
-
-
-
-
-
-
-