TH22342A

TH22342A - Anti-obesity protein

Info

Publication number: TH22342A
Application number: TH9601000286A
Authority: TH
Inventors: จูเนียร์; จอห์น เอ็ดเวิร์ด เฮล นาย; เจมส์ อาร์เธอร์ ฮอฟฟ์แมนน์ นาย; เดวิด เบนจามิน ฟลอรา นาย; บรีกิตเตอ เอลิซาเบ็ธ โชเนอร์ นาย; มาร์เกร็ต บาร์บารา บาชินสกี นาย; ริชาร์ด เดนนิส ดีมาร์ซี นาย; วิลเลียม ฟรานซิส ฮีธ นาย; บาร์บารา บาชินสกี นายมาร์เกร็ต
Original assignee: นาย ดำเนินการเด่น; นาย ต่อพงศ์โทณะวณิก; นาย วิรัชศรีเอนกราธา; นายจักรพรรดิ์ มงคลสิทธิ์; นายดำเนิน การเด่น; นายต่อพงศ์ โทณะวณิก; นายวิรัช ศรีอเนกราธา; อีไล ลิลลี่ แอนด์ คัมปะนี
Filing date: 1996-01-29
Publication date: 1996-12-17

Abstract

การประดิษฐ์นี้ได้ให้โปรตีนต้านความอ้วนที่เมื่อให้เข้าไปในผู้ป่วยจะมีการ ควบคุมเนื้อเยื่อไขมันดังนั้นสารดังกล่าวทำให้ ผู้ป่วยเอาชนะความอ้วนและมีชีวิตเป็นปกติ โดยลดความเสี่ยง จากเบาหวานประเภท II โรคหัวใจและมะเร็งลงเป็นอย่างมาก สิทธิบัตรยาThis invention provides an anti-obesity protein that, when administered to patients, controls adipose tissue, thus enabling patients to overcome obesity and live normal lives, significantly reducing the risk of type II diabetes, heart disease, and cancer. (Drug patent)

Claims

1. Formula protein (I) (SEQ ID NO : 1) Val Pro Ile Xaa Lys Val Xaa Asp Asp Thr Lys Thr Leu Ile Lys Thr 1 5 10 15 Ile Val Thr Arg IIe Xaa Asp IIe Ser His Xaa Leu His Pro IIe 35 40 45 Leu Thr Leu Ser Lys Xaa Asp Xaa Thr Leu Ala Val Tyr Xaa Xaa IIe 50 55 60 Leu Thr Ser Xaa Pro Ser Arg Xaa Val IIe Xaa Ile Phe Ser Lys Ser Cys 85 90 95 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 100 105 110 Val Leu Glu Ala Ser Xaa Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 115 120 125 Leu Xaa Gly Ser Leu Xaa Asp Xaa Leu Trp Xaa Leu Asp Leu Ser Pro 130 135 140 Gly Cys (I) 145 where Xaa at position 4 is Gln or Glu; Xaa at position 7 is Gln or Glu; Xaa at position 22 is Gln, Asn, or Asp; Xaa at position 27 is Thr or Ala; Xaa at position 28 is Gln, Glu, or no Xaa. At position 34 is Gln or Glu; Xaa. At position 54 is Met, ethylene sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa. At position 56 is Gln or Glu; Xaa. At position 62 is Gln or Glu; Xaa. At position 63 is Gln or Glu; Xaa. At position 68 is Met, methionine sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa. At position 72 is Gln, Asp, or Glu; Xaa. At position 75 is Gln or Glu; Xaa. At position 77 is Ser or Ala; Xaa. At position 78 is Gln, Asn, or Asp; Xaa. At position 82 is Gln, Asn, or Asp; Xaa. Xaa at position 118 is Gly or Leu; Xaa at position 130 is Gln or Glu; Xaa at position 134 is Gln or Glu; Xaa at position 136 is Met, methionine sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa at position 139 is Gln or Glu; these proteins have at least one selective substitution. The group consisting of His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced by Arg; Gly at position 103 is replaced by Ala; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by Glu; Gly at position 111 is replaced by Asp; Or Trp at position 138 is replaced by Ala, Glu, Asp, Asn, Met, lle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; or its pharmaceutically recognized salts.

2. The protein of claim 1 that has at least one substitution selected from... The group containing His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced by Arg; Gly at position 103 is replaced by Ala; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by Glu or Gly; and at position 111, it is replaced by Asp. Or its pharmaceutically recognized salt.

3. Protein of Formula (II) (SEQ ID NO : 2) 5 10 15 Val Pro IIe Gln Lys Val Gln Asp Asp Thr Lys Thr Leu IIe Lys THr 20 25 30 IIe Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 145 Gly Cys (II) where Asn at position 22 may be selected as Gln or Asp; Thr at position 27 may be selected as Ala; Gln at position 28 may be selected as Glu or none; Met at position 54 may be selected as Ala; Met at position 68 may be selected as Leu; Asn at position 72 may be selected as Glu, or Asp; Ser at position 77 may be replaced by Ala; Gly at position 118 may be replaced by Leu; His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced by Arg; Gly at position 103 is replaced by Ala; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by... GluGly at position 111 is replaced by Asp; or Trp at position 138 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; or its pharmaceutically recognized salts.

4. Protein of claim 3, where Trp at position 100 is Gln, Tyr, Phe, Ile, Val, or Leu; or Trp at position 138 is Gln, Tyr, Phe, Ile, Val, or Leu;

5. Protein of formula (III) (SEQ ID NO : 3) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 145 Gly Cys His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position Position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced by Arg; Gly at position 103 is replaced by Ala; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by Glu; Gly at position 111 is replaced by Asp; or Trp at position 138 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; or its pharmaceutically recognized salts.

6. Proteins of claim 5, where His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by Glu; Gly at position 111 is replaced by Asp; Or Trp at position 138 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu;

7. Proteins of claim 6 where His at position 97 is replaced by Ser or Pro Trp at position 100 is replaced by Ala, Gly, Gln, Val, Tle, or Leu; Ala at position 101 is replaced by Thr, or Trp at position 138 is Ala, Ile, Gly, Gln, Val, or Leu.

8. A protein of any of the claims 1 through 7 where Cys at position 96 is linked by a disulfide bond to Cys at position 146.

9. Proteins of SEQ ID NO : 4 : (SEQ ID NO : 4) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Ala Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 145 Gly Cys, where Cys at position 96 is linked by a disulfide bond to Cys at position 146 or its pharmaceutically recognized salt.

10. Protein SEQ ID NO : 5 : (SEQ ID NO : 5) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Gln Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 145 Gly Cys, where Cys at position 96 is linked by a disulfide bond to Cys at position 146; or its pharmaceutically recognized salt.

11. Proteins of SEQ ID NO : 6 : (SEQ ID NO : 6) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Gln Gln Leu Asp Leu Ser Pro 145 Gly Cys, where Cys at position 96 is linked by a disulfide bond to Cys at position 146 or its pharmaceutically recognized salt.

12. Proteins of SEQ ID NO : 7 : (SEQ ID NO : 7) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Thr Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Gln Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Gln Gln Leu Asp Leu Ser Pro 145 Gly Cys, where Cys at position 96 is linked by a disulfide bond to Cys at position 146 or its pharmaceutically recognized salt.

13. Protein SEQ ID NO : 8 : (SEQ ID NO ; 7) 5 10 15 Val Pro lle Gln Lys Val Gln Asp Asp Thr Lys Thr Leu lle Lys Thr 20 25 30 lle Val Thr Arg lle Asn Asp lle Ser His Ala Gln Ser Val Ser Ser 35 40 45 Lys Gln Lys Val Thr Gly Leu Asp Phe lle Pro Gly Leu His Pro lle 50 55 60 Leu Thr Leu Ser Lys Met Asp Gln Thr Leu Ala Val Tyr Gln Gln lle 65 70 75 80 Leu Thr Ser Met Pro Ser Arg Asn Val lle Gln lle Ser Asn Asp Leu 85 90 95 Glu Asn Leu Arg Asp Leu Leu His Val Leu Ala Phe Ser Lys Ser Cys 100 105 110 His Leu Pro Ala Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu Gly Gly 115 120 125 Val Leu Glu Ala Ser Gly Tyr Ser Thr Glu Val Val Ala Leu Ser Arg 130 135 140 Leu Gln Gly Ser Leu Gln Asp Met Leu Trp Gln Leu Asp Leu Ser Pro 145 Gly Cys, where Cys at position 96 is linked by a disulfide bond to Cys at position 146 or its pharmaceutically recognized salt.

14. Proteins of the formula Met-R1-Val Pro lle Xaa Lys Val Xaa Asp Asp Thr Lys Thr Leu lle 1 5 10 Lys Thr lle Val Thr Arg lle Leu His 35 40 45 Pro lle Leu Thr Leu Ser Lys Xaa Asp Xaa Thr Leu Ala Val Tyr Xaa 50 55 60 Xaa lle Leu Thr Ser Xaa Pro Ser Arg Ala Phe Ser Lys 80 85 90 Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu Thr Leu Asp Ser Leu 95 100 105 110 Gly Gly Val Leu Glu Ala Ser Xaa Tyr Ser Thr Glu Val Val Ala Leu 115 120 125 Ser Arg Leu Xaa Gly Ser Leu Xaa Asp Xaa Leu Trp Xaa Leu Asp Leu 130 135 140 Ser Pro Gly Cys 145 where R1 is any amino acid except Pro; Xaa at position 4 is Gln or Glu; Xaa at position 7 is Gln or Glu; Xaa at position 22 is Asn, Asp or Glu; Xaa at position 27 is Thr or Ala; Xaa at position 28 is ln, Xaa at position 34 is Gln or Glu; Xaa at position 54 is Met, methionine sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa at position 56 is Gln or Glu; Xaa at position 62 is Gln or Glu; Xaa at position 63 is Gln or Glu; Xaa at position 68 is Met, methionine sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa at position 72 is Asn or Glu; Xaa at position 75 is Gln or Glu; Xaa at position 77 is Ser or Ala; Xaa at position 78 is Gln, Asn, or Asp; Xaa at position 82 is Gln, Asn, or Asp; Xaa at position 118 is Gly or Leu; Xaa at position 130 is Gln or Glu; Xaa at position 134 is Gln or Glu; Xaa at position 136 is Met, methionine sulfoxide, Leu, Ile, Val, Ala, or Gly; Xaa at position 139 is Gln or Glu; the protein has at least one substituted portion. The group consisting of His at position 97 is replaced by Gln, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu; Ala at position 101 is replaced by Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced by Arg; Gly at position 103 is replaced by Ala; Glu at position 105 is replaced by Gln; Thr at position 106 is replaced by Lys or Ser; Leu at position 107 is replaced by Pro; Asp at position 108 is replaced by Glu; Gly at position 111 is replaced by Asp; Or Trp at position 138 is replaced by Ala, Glu, Asp, Asn, Met, Tle, Phe, Tyr, Ser, Thr, Gly, Gln, Val, or Leu;

15. Protein of claim 14, where R1 is Arg.

16. The procedure for synthesizing a protein of any of the claims 1 through 13 shall consist of (a) transforming the host cell with DNA encoding a protein of any of the claims 1 through 13; such protein may have a guide sequence; (b) culturing the host cell and isolating the protein encoding in step (a); and may (c) cleave the guide sequence with an enzyme to synthesize a protein of any of the claims 1 through 13.

17. Procedure for Claim No. 16, where the precedent is Met-R1-.

18. Procedure of Claim No. 17, where the precedent is Met-Arg.

19. A pharmaceutical formulation containing the protein claimed in any of the claims of claims 1 through 13, together with one or more pharmaceutically acceptable diluents, carriers, or fillers.

20. Any protein under claims 1 through 12 for use as a pharmaceutical substance.