Therapeutic compounds for immunomodulation
The present invention provides Immunosuppressive compounds capable of inhibiting the programmed cell death 1 (PD1) signalling pathway. The present invention further provides peptide based compositions for treatment of cancer or treatment of infections via immunopotentiation caused by inhibition of immunosuppressive signalling induced by PD-1, PD-L1, or PD-L2 and therapies using them, immunopotentiative substrates included as the active ingredient. Further, the invention provides pharmaceutical compositions comprising the Immunosuppressive peptide compounds or modified peptide moieties for preventive and/or therapeutic agents for cancer, cancer metastasis, immunodeficiency, an infectious disease or the like and an application of PD-1 or PD-L1 as a testing or diagnostic agent or a research agent for such a disease.
1. A peptide derivative of formula (I),
wherein, Am 1 represents 1 to 4 amino acid residues which may be same or different and each independently selected from Ser, Asn and Thr; wherein one of the peptide bond (—CONH—) between any two amino acid residues may be replaced with a modified peptide bond of
wherein Q is hydrogen, —CO(C 1 -C 20 )alkyl or —COO(C 1 -C 20 )alkyl;
Am 2 is comprising of dipeptide selected from Ser-Phe or Phe-Ser, wherein Phe may be optionally substituted with amino(C 1 -C 20 )alkyl, —NHCOCH 3 or —NHCONH 2 ;
X is Glu which may optionally form amide bonds with its alpha carboxylic acid group, delta carboxylic acid group or amino group;
L is a linker selected from —NH(CH 2 ) n NH—, —NH(CH 2 ) n CH(NH 2 )CO—, —OOC(CH 2 ) m COO—, —NH(CH 2 ) n CO—, —NH(CH 2 CH 2 O) n NH—, —NH(CH 2 CH 2 O) n CO— or —CO(CH 2 CH 2 O) n CO—;
R 1 is free C-terminal, amidated C-terminal or N-terminal of Am 1 ; or is (C 1 -C 20 )acyl substitution;
R 2 is free C-terminal, amidated C-terminal or N-terminal of Am 2 ; or Y—R 5 ;
Y is an optional linker selected from —OOC(CH 2 ) m COO—, —CO(CH 2 ) n NH—, —CO(CH 2 CH 2 O) n NH— or —COCH 2 (OCH 2 CH 2 ) n NH—;
R 5 is an albumin binding moiety such as maleimido propionic acid;
R 3 is free alpha C-terminal, amidated alpha C-terminal or N-terminal of Glu;
‘n’ is an integer selected from 2 to 10, both inclusive;
‘m’ is an integer selected from 0 to 8, both inclusive; wherein one or more or all amino acids may be in a D-configuration;
or its retro analogue or a pharmaceutically acceptable stereoisomer or a pharmaceutically acceptable salt thereof.
2. A peptide derivative of claim 1 having the formula (Ia):
wherein,
R 1 is N-terminal of Ser; or (C 1 -C 20 )acyl substituted with either hydroxyl group or amino group of Ser
L is a linker selected from —NH(CH 2 ) n NH—, —NH(CH 2 ) n CH(NH 2 )CO—, —OOC(CH 2 ) m COO—, —NH(CH 2 ) n CO—, —NH(CH 2 CH 2 O) n NH—, —NH(CH 2 CH 2 O) n CO— or —CO(CH 2 CH 2 O) n CO—;
R 2 is free C-terminal, amidated C-terminal or N-terminal of Am 2 ; or Y—R 5 ;
Y is an optional linker selected from —OOC(CH 2 ) m COO—, —CO(CH 2 ) n NH—, —CO(CH 2 CH 2 O) n NH— or —COCH 2 (OCH 2 CH 2 ) n NH—;
R 5 is an albumin binding moiety such as maleimido propionic acid;
R 3 is OH or NH 2 ;
R 4 is a substituent on phenyl group of Phe and is selected from hydrogen, amino(C 1 -C 20 )alkyl, —NHCOCH 3 or —NHCONH 2 ;
‘n’ is an integer having values selected from 2 to 10, both inclusive;
‘m’ is an integer having values selected from 0 to 8, both inclusive; and
one of the peptide bond (—CONH—) of Ser-Asn, Asn-Thr or Thr-Ser may be replaced with a modified peptide bond of
wherein Q is hydrogen, —CO(C 1 -C 20 )alkyl or —COO(C 1 -C 20 )alkyl group; wherein one or more or all amino acids may be in the D-configuration;
or retro analogue or a pharmaceutically acceptable stereoisomer or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , wherein one or more or all amino acids are in the D-configuration.
4. The compound according to claim 2 , wherein L is —NH(CH 2 ) 4 NH—.
5. The compound according to claim 2 , wherein L is —NH(CH 2 ) 4 CH(NH 2 )CO—.
6. The compound according to claim 2 , wherein R 2 is N-terminal of Ser.
7. The compound according to claim 2 , wherein the peptide bond (—CONH—) of Ser-Asn is replaced with a modified peptide bond of
wherein Q is hydrogen, —CO(C 1 -C 20 )alkyl or —COO(C 1 -C 20 )alkyl group.
8. The compound according to claim 2 , wherein the peptide bond (—CONH—) of Asn-Thr is replaced with a modified peptide bond of
wherein Q is hydrogen, —CO(C 1 -C 20 )alkyl or —COO(C 1 -C 20 )alkyl group.
9. A peptide derivative of claim 1 having the formula (Ib):
wherein,
R 1 is free C-terminal or amidated C-terminal of Ser;
L is a linker selected from —NH(CH 2 ) n NH— or —NH(CH 2 CH 2 O) n NH—;
R 4 is selected from hydrogen, amino(C 1 -C 20 )alkyl, —NHCOCH 3 or —NHCONH 2 ;
wherein one or more or all amino acids may be in D-configuration;
or retro analogue or a pharmaceutically acceptable stereoisomer or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 , wherein one or more or all amino acids are in D-configuration.
11. The compound according to claim 9 , wherein L is —NH(CH 2 ) 4 NH—.
12. The compound according to claim 9 , wherein R 1 is amidated C-terminal of Ser.
13. A compound selected from
Comp
No.
Structure
001
(SEQ ID NO: 3)
002
(SEQ ID NO: 4)
003
(SEQ ID NO: 5)
004
(SEQ ID NO: 6)
005
(SEQ ID NO: 7)
006
(SEQ ID NO: 8)
007
(SEQ ID NO: 9)
008
(SEQ ID NO: 10)
009
(SEQ ID NO: 11)
010
*D-Phe (SEQ ID NO: 12)
011
(SEQ ID NO: 13)
012
*D-Glu (SEQ ID NO: 14)
013
*D-Phe urea (SEQ ID NO: 15)
014
(SEQ ID NO: 16)
015
*D-Glu (SEQ ID NO: 17)
016
*All D-amino acids (SEQ ID NO: 18)
017
(SEQ ID NO: 19)
018
(SEQ ID NO: 20)
019
(SEQ ID NO: 21)
020
(SEQ ID NO: 22)
021
(SEQ ID NO: 23)
022
(SEQ ID NO: 24)
023
(SEQ ID NO: 25)
024
(SEQ ID NO: 26)
025
(SEQ ID NO: 27)
026
(SEQ ID NO: 28)
027
(SEQ ID NO: 29)
028
(SEQ ID NO: 30)
029
(SEQ ID NO: 31)
030
(SEQ ID NO: 32)
031
(SEQ ID NO: 33)
14. A compound according to claim 1 , for use as a medicament for the treatment of cancer or infectious disease.
15. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable diluent or carrier.
16. method of inhibiting growth of tumour cells and/or metastasis in a subject, comprising administering to the subject a therapeutically effective amount of compound according to claim 1 , capable of inhibiting the programmed cell death 1 (PD1) signaling pathway.
17. The method of claim 16 , wherein the tumour cells are of a cancer selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer.
18. A method of treating an infectious disease in a subject comprising administering to the subject a therapeutically effective amount of compound according to claim 1 , capable of inhibiting the programmed cell death 1 (PD1) signaling pathway such that the subject is treated for the infectious disease.
19. A method of treating bacterial and viral infections in a subject comprising administering to the subject a therapeutically effective amount of compound according to claim 1 , capable of inhibiting the programmed cell death 1 (PD1) signaling pathway such that the subject is treated for the bacterial, fungal and viral infections.
20. A method for treating sepsis in a subject comprising administering to the subject a therapeutically effective amount of compound according to claim 1 , capable of inhibiting the programmed cell death 1 (PD1) signaling pathway such that the subject is treated for the bacterial, fungal and viral infections.