                         SEQUENCE LISTING

<110>  National Research Council of Canada
       Ni, Feng
       Tolkatchev, Dmitri
       Tonan, Kenji
       Xu, Ping
       Hossain, Sazzad
 
<120>  LOCALLY-ACTIVE ANTICOAGULANTS AND ANTI-INFLAMMATORY AGENTS

<130>  12024-98

<150>  US 61/477,343
<151>  2011-04-20

<160>  87    

<170>  PatentIn version 3.5

<210>  1
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  (GS)8 linker

<400>  1

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 
1               5                   10                  15      


<210>  2
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  gb1 linker

<400>  2

Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu 
1               5                   10                  15      


<210>  3
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  trpzip6 linker

<400>  3

Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr Trp Thr Val Thr Glu 
1               5                   10                  15      


<210>  4
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  trpzip5 linker

<400>  4

Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Trp Thr Glu 
1               5                   10                  15      


<210>  5
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  trpzip4 linker

<400>  5

Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr Trp Thr Trp Thr Glu 
1               5                   10                  15      


<210>  6
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  GEGT(GS)4 linker

<400>  6

Gly Glu Gly Thr Gly Ser Gly Ser Gly Ser Gly Ser 
1               5                   10          


<210>  7
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting the active site of thrombin

<400>  7

Ile Arg Phe Thr Asp 
1               5   


<210>  8
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting the fibrinogen-specific exosite I of 
       thrombin

<400>  8

Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
1               5                   10          


<210>  9
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BTI1 bivalent thrombin inhibitor


<220>
<221>  misc_feature
<222>  (1)..(1)
<223>  Xaa is 4-tert-butyl-benzenesulfonyl

<220>
<221>  misc_feature
<222>  (3)..(3)
<223>  Xaa is D-pipecolic acid

<400>  9

Xaa Arg Xaa Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly 
1               5                   10                  15      


Ser Gly Ser Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30      


<210>  10
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BTI2 bivalent thrombin inhibitor


<220>
<221>  misc_feature
<222>  (1)..(1)
<223>  Xaa is 4-tert-butyl-benzenesulfonyl

<220>
<221>  misc_feature
<222>  (3)..(3)
<223>  Xaa is D-pipecolic acid

<400>  10

Xaa Arg Xaa Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr 
1               5                   10                  15      


Val Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30      


<210>  11
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BTI3 bivalent thrmobin inhibitor


<220>
<221>  misc_feature
<222>  (1)..(1)
<223>  Xaa is 4-tert-butyl-benzenesulfonyl

<220>
<221>  misc_feature
<222>  (3)..(3)
<223>  Xaa is D-pipecolic acid

<400>  11

Xaa Arg Xaa Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr Trp Thr 
1               5                   10                  15      


Val Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30      


<210>  12
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BTI4 bivalent thrombin inhibitor


<220>
<221>  misc_feature
<222>  (1)..(1)
<223>  Xaa is 4-tert-butyl-benzenesulfonyl

<220>
<221>  misc_feature
<222>  (3)..(3)
<223>  Xaa is D-pipecolic acid

<400>  12

Xaa Arg Xaa Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr 
1               5                   10                  15      


Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30      


<210>  13
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BTI5 bivalent thrombin inhibitor


<220>
<221>  misc_feature
<222>  (1)..(1)
<223>  Xaa is 4-tert-butyl-benzenesulfonyl

<220>
<221>  misc_feature
<222>  (3)..(3)
<223>  Xaa is D-pipecolic acid

<400>  13

Xaa Arg Xaa Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr Trp Thr 
1               5                   10                  15      


Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30      


<210>  14
<211>  29
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-GS bivalent thrombin inhibitor

<400>  14

Ile Arg Phe Thr Asp Gly Glu Gly Thr Gly Ser Gly Ser Gly Ser Gly 
1               5                   10                  15      


Ser Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  


<210>  15
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-gb1 bivalent thrombin inhibitor

<400>  15

Ile Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Phe Thr Val Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  16
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-trpzip6 bivalent thrombin inhibitor

<400>  16

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Val Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  17
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-trpzip5 bivalent thrombin inhibitor

<400>  17

Ile Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  18
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-trpzip4 bivalent thrombin inhibitor

<400>  18

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  19
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker


<220>
<221>  misc_feature
<222>  (5)..(5)
<223>  Xaa is any amino acid.

<220>
<221>  misc_feature
<222>  (12)..(12)
<223>  Xaa is any amino acid.

<220>
<221>  misc_feature
<222>  (14)..(14)
<223>  Xaa is any amino acid.

<400>  19

Gly Glu Trp Thr Xaa Asp Asp Ala Thr Lys Thr Xaa Thr Xaa Thr Glu 
1               5                   10                  15      


<210>  20
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Xaa is any amino acid

<220>
<221>  MISC_FEATURE
<222>  (5)..(8)
<223>  Xaa is any amino acid

<220>
<221>  MISC_FEATURE
<222>  (12)..(12)
<223>  Xaa is any amino acid

<400>  20

Xaa Trp Thr Trp Xaa Xaa Xaa Xaa Trp Thr Trp Xaa 
1               5                   10          


<210>  21
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker

<400>  21

Ser Trp Thr Trp Glu Gly Asn Lys Trp Thr Trp Lys 
1               5                   10          


<210>  22
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker

<400>  22

Thr Trp Thr Trp Asn Gly Ser Ala Trp Thr Trp Asn 
1               5                   10          


<210>  23
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker

<400>  23

Ser Trp Thr Trp Glu Asn Gly Lys Trp Thr Trp Lys 
1               5                   10          


<210>  24
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker


<220>
<221>  MISC_FEATURE
<222>  (6)..(6)
<223>  Pro is D-proline

<400>  24

Ser Trp Thr Trp Glu Pro Asn Lys Trp Thr Trp Lys 
1               5                   10          


<210>  25
<211>  11
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting fibrinogen-specific exosite I of thrombin

<400>  25

Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
1               5                   10      


<210>  26
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting active site of thrombin

<400>  26

Phe Gln Pro Arg 
1               


<210>  27
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting active site of thrombin

<400>  27

Trp Asp Pro Arg 
1               


<210>  28
<211>  29
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker + tbm2 from BTI1

<400>  28

Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly 
1               5                   10                  15      


Ser Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  


<210>  29
<211>  6
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting active site of thrombin

<400>  29

Ile Arg Phe Thr Asp Gly 
1               5       


<210>  30
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker fragment from mini-huridin 2

<400>  30

Gly Glu Gly Thr Pro Asn Pro Glu Ser His Asn Asn 
1               5                   10          


<210>  31
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker

<400>  31

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 
1               5                   10          


<210>  32
<211>  16
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker

<400>  32

Gly Glu Gly Thr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 
1               5                   10                  15      


<210>  33
<211>  29
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH1 - bivalent thrombin inhibitor

<400>  33

Val Arg Phe Thr Asp Gly Glu Gly Thr Pro Lys Pro Gln Ser His Asp 
1               5                   10                  15      


Asn Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  


<210>  34
<211>  29
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2 - bivalent thrombin inhibitor

<400>  34

Ile Arg Phe Thr Asp Gly Glu Gly Thr Pro Asn Pro Glu Ser His Asn 
1               5                   10                  15      


Asn Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  


<210>  35
<211>  29
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-allGS - bivalent thrombin inhibitor

<400>  35

Ile Arg Phe Thr Asp Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly 
1               5                   10                  15      


Ser Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  


<210>  36
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  MH2-longGS - bivalent thrombin inhibitor

<400>  36

Ile Arg Phe Thr Asp Gly Glu Gly Thr Gly Ser Gly Ser Gly Ser Gly 
1               5                   10                  15      


Ser Gly Ser Gly Ser Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  37
<211>  18
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Linker


<220>
<221>  DISULFID
<222>  (1)..(2)
<223>  Cysteine residues linked by disulfide bond

<400>  37

Cys Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 
1               5                   10                  15      


Gly Ser 
        


<210>  38
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  4 aa polypeptide

<400>  38

Ile Gln Pro Arg 
1               


<210>  39
<211>  11
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  11 aa polypeptide segment of SEQ ID NO: 8

<400>  39

Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
1               5                   10      


<210>  40
<211>  37
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Covalently blocked MH2-trpzip4


<220>
<221>  MISC_FEATURE
<222>  (1)..(4)
<223>  Xaa is any amino acid

<400>  40

Xaa Xaa Xaa Xaa Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu Gln 
        35          


<210>  41
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Polypeptide targeting active site of thrombin

<400>  41

Pro Arg Phe Thr Asp 
1               5   


<210>  42
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  5 aa polypeptide

<400>  42

Val Arg Phe Thr Asp 
1               5   


<210>  43
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  4 aa polypeptide

<400>  43

Ile Glu Gly Arg 
1               


<210>  44
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T207 bivalent thrombin inhibitor

<400>  44

Phe Gln Pro Arg Pro Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  45
<211>  33
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T109 bivalent thrombin inhibitor

<400>  45

Pro Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


Gln 
    


<210>  46
<211>  32
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T110 bivalent thrombin inhibitor

<400>  46

Pro Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


<210>  47
<211>  32
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T111 bivalent thrombin inhibitor

<400>  47

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30          


<210>  48
<211>  31
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T113 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  48

Phe Pro Arg Pro Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr Trp 
1               5                   10                  15      


Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu 
            20                  25                  30      


<210>  49
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T204 bivalent thrombin inhibitor

<400>  49

Ile Glu Gly Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  50
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T205 bivalent thrombin inhibitor

<400>  50

Ile Glu Gly Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  51
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T217 bivalent thrombin inhibitor

<400>  51

Phe Gln Pro Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  52
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T227 bivalent thrombin inhibitor

<400>  52

Phe Gln Pro Arg Val Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  53
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T237 bivalent thrombin inhibitor

<400>  53

Phe Gln Pro Arg Leu Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  54
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T247 bivalent thrombin inhibitor

<400>  54

Phe Gln Pro Arg Phe Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  55
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T208 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  55

Phe Pro Arg Pro Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  56
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T218 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  56

Phe Pro Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  57
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T228 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  57

Phe Pro Arg Val Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  58
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T238 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  58

Phe Pro Arg Leu Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  59
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T248 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  59

Phe Pro Arg Phe Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  60
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T209 bivalent thrombin inhibitor

<400>  60

Trp Asp Pro Arg Pro Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  61
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T219 bivalent thrombin inhibitor

<400>  61

Trp Asp Pro Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  62
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T229 bivalent thrombin inhibitor

<400>  62

Trp Asp Pro Arg Val Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  63
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T239 bivalent thrombin inhibitor

<400>  63

Trp Asp Pro Arg Leu Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  64
<211>  36
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T249 bivalent thrombin inhibitor

<400>  64

Trp Asp Pro Arg Phe Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp 
1               5                   10                  15      


Ala Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro 
            20                  25                  30          


Glu Glu Tyr Leu 
        35      


<210>  65
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T210 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  65

Phe Pro Arg Pro Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  66
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T220 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  66

Phe Pro Arg Ile Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  67
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T230 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  67

Phe Pro Arg Val Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  68
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T240 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  68

Phe Pro Arg Leu Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  69
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T250 bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Phe is D-phenylalanine

<400>  69

Phe Pro Arg Phe Arg Phe Thr Asp Gly Glu Trp Thr Tyr Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Phe Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  70
<211>  4
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  4 aa polypeptide

<400>  70

Phe Asn Pro Arg 
1               


<210>  71
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  5 aa linker segment (Gly)4-Asn

<400>  71

Gly Gly Gly Gly Asn 
1               5   


<210>  72
<211>  5
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  5 aa polypeptide targeting active site of thrombin


<220>
<221>  MISC_FEATURE
<222>  (1)..(1)
<223>  Xaa is isoleucine, valine, leucine or phenylalanine

<400>  72

Xaa Arg Phe Thr Asp 
1               5   


<210>  73
<211>  8
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  8 aa polypeptide targeting active site of thrombin


<220>
<221>  MISC_FEATURE
<222>  (4)..(4)
<223>  Xaa is isoleucine, valine, leucine or phenylalanine

<400>  73

Phe Pro Arg Xaa Arg Phe Thr Asp 
1               5               


<210>  74
<211>  35
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  bivalent thrombin inhibitor


<220>
<221>  MISC_FEATURE
<222>  (4)..(4)
<223>  Xaa is isoleucine, valine, leucine or phenylalanine

<400>  74

Phe Pro Arg Xaa Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala 
1               5                   10                  15      


Thr Lys Thr Trp Thr Trp Thr Glu Gly Asp Phe Glu Glu Ile Pro Glu 
            20                  25                  30          


Glu Tyr Leu 
        35  


<210>  75
<211>  21
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  Fragment of bivalent thrombin inhibitor

<400>  75

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu 
            20      


<210>  76
<211>  12
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  12 aa haemadin C-terminus specific for AB2 of thrombin

<400>  76

Glu Phe Glu Glu Phe Glu Ile Asp Glu Glu Glu Lys 
1               5                   10          


<210>  77
<211>  131
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  PEPA1 - 131 aa human VH domain binder for PPACK-thrombin

<400>  77

Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ser Gly Asp 
1               5                   10                  15      


Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Thr Tyr 
            20                  25                  30          


Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Leu Arg Glu Phe Val 
        35                  40                  45              


Gly Val Ile Ser Ser Ser Gly Tyr Thr His Tyr Thr Asn Ser Val Arg 
    50                  55                  60                  


Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Val Tyr Leu 
65                  70                  75                  80  


Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 
                85                  90                  95      


Ala Ala Asp Arg Arg Phe Ile Ala Thr Asp Gly Lys Gln Tyr Asp Tyr 
            100                 105                 110         


Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Leu Glu His His His 
        115                 120                 125             


His His His 
    130     


<210>  78
<211>  34
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T304 bivalent thrombin inhibitor

<400>  78

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Glu Phe Glu Glu Phe Glu Ile Asp Glu Glu 
            20                  25                  30          


Glu Lys 
        


<210>  79
<211>  155
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  BRI-T404 bivalent thrombin inhibitor

<400>  79

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly Gly Ser Glu Val Gln Leu Gln Ala Ser Gly 
            20                  25                  30          


Gly Gly Leu Val Gln Ser Gly Asp Ser Leu Arg Leu Ser Cys Ala Ala 
        35                  40                  45              


Ser Gly Arg Thr Phe Ser Thr Tyr Ala Met Gly Trp Phe Arg Gln Ala 
    50                  55                  60                  


Pro Gly Lys Leu Arg Glu Phe Val Gly Val Ile Ser Ser Ser Gly Tyr 
65                  70                  75                  80  


Thr His Tyr Thr Asn Ser Val Arg Gly Arg Phe Thr Ile Ser Arg Asp 
                85                  90                  95      


Asn Ala Lys Asn Met Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu 
            100                 105                 110         


Asp Thr Ala Val Tyr Tyr Cys Ala Ala Ala Asp Arg Arg Phe Ile Ala 
        115                 120                 125             


Thr Asp Gly Lys Gln Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr 
    130                 135                 140                 


Val Ser Ser Leu Glu His His His His His His 
145                 150                 155 


<210>  80
<211>  148
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  VSL-PEPA1

<400>  80

Gly Ser Val Ser Pro Arg Pro Gln Leu His Asn Asp Gly Gly Gly Ser 
1               5                   10                  15      


Ser Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Val Gln Ser Gly 
            20                  25                  30          


Asp Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Thr 
        35                  40                  45              


Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Leu Arg Glu Phe 
    50                  55                  60                  


Val Gly Val Ile Ser Ser Ser Gly Tyr Thr His Tyr Thr Asn Ser Val 
65                  70                  75                  80  


Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Val Tyr 
                85                  90                  95      


Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 
            100                 105                 110         


Ala Ala Ala Asp Arg Arg Phe Ile Ala Thr Asp Gly Lys Gln Tyr Asp 
        115                 120                 125             


Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Leu Glu His His 
    130                 135                 140                 


His His His His 
145             


<210>  81
<211>  22
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  22 amino acid fragment of bivalent thrombin inhibitor

<400>  81

Ile Arg Phe Thr Asp Gly Glu Trp Thr Trp Asp Asp Ala Thr Lys Thr 
1               5                   10                  15      


Trp Thr Trp Thr Glu Gly 
            20          


<210>  82
<211>  32
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  bivalent thrombin inhibitor

<400>  82

Ile Arg Phe Thr Asp Gly Gly Ser Trp Thr Trp Glu Gly Asn Lys Trp 
1               5                   10                  15      


Thr Trp Lys Gly Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30          


<210>  83
<211>  30
<212>  PRT
<213>  Artificial Sequence

<220>
<223>  bivalent thrombin inhibitor

<400>  83

Ile Arg Phe Thr Asp Gly Ser Trp Thr Trp Glu Gly Asn Lys Trp Thr 
1               5                   10                  15      


Trp Lys Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln 
            20                  25                  30  


<210>  84
<211>  42
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Primer

<400>  84
acctggaccg aaggcggcag cgatgtccag ctgcaggcgt ct                          42


<210>  85
<211>  30
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Primer

<400>  85
aatcggctcg agtgaggaga cggtgacctg                                        30


<210>  86
<211>  81
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Primer

<400>  86
gcccagccgg cgatggccat tcgttttact gatggcgaat ggacctggga tgatgccacc       60

aaaacctgga cctggaccga a                                                 81


<210>  87
<211>  30
<212>  DNA
<213>  Artificial Sequence

<220>
<223>  Primer

<400>  87
aatcggctcg agtgaggaga cggtgacctg                                        30


