| 摘要 |
The present invention provides immunosuppression compounds to inhibit 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 signaling induced by PD-1, PD-L1, or PD-L2 and therapies using them, immunopotentiative substrates included as the active ingredient. Further, the invention provides an application of the compositions containing the peptide moieties for preventive and/or therapeutic agents for cancer, cancer metastasis, immunodeficiency, an infectious disease or the like and an application of peptide moieties as a testing or diagnostic agent or a research agent for such a disease. |
| 主权项 |
1. A compound of formula (I)or pharmaceutically acceptable salt thereof;wherein;
A is an amino acid sequence of from three amino acids to the full length of a peptide sequence of mammalian PD1 ectodomain fragments selected from FG loop, BC loop, C-C′ loop, C strand, C′ strand to C′-C″ loop, or is Glu-Asp; B is an amino acid sequence of from three amino acids to the full length of a peptide sequence of mammalian PD1 ectodomain fragments selected from BC loop, FG loop, C C′ loop to C′ strand, C strand, D strand, C′ strand to C′-C″ loop, or is Glu-Asp, or is absent; with the proviso that if A is the amino acid sequence SNTSESF and X is lysine then B cannot be the amino acid sequence SNTSESF; Z is
(i) from one to four peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from BC loop, D strand, FG loop, G strand, C strand, F strand, C′ strand, C″ strand, C″-D loop, C′ strand to C′-C″ loop, C′ strand to C″ strand or D strand to DE loop;(ii) G-L-Z′
G is an amino acid sequence of from three amino acids to the full length of a peptide sequence of mammalian PD1 ectodomain fragments from D-strand or is absent;L is selected from —CO(CH2)n—NH—, or PEG 2-20 KD;‘n’ is an integer selected from 2 to 10, both inclusive; andZ′ is one to three peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from FG loop and G-strand; or(iii) from one to four peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from D-strand, FG loop and G strand, wherein two or more amino acids of the peptide sequence combine together to form a lactam bond between any of the two fragments or within the fragment; D is up to two peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from BC loop, FG loop, C C′ loop to C′ strand or is absent; E is up to four peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from BC loop, D strand, FG loop, C C′ loop to C′ strand, G strand, FG loop to G strand or is absent; X and X′ are independently selected from lysine, ornithine, diaminopropionic acid, diaminobutyric acid or olefinic amino acid of formula which is optionally linked with an additional lysine; or
X and X′ combine together forming a ring with olefinic amino acid which is optionally linked with an additional lysine; orX′ is absent;‘m’ is an integer selected from 1 to 6, both inclusive; R1 is selected from group consisting of C2-C20 acyl, PEG 2-20 KD moiety; or absent, R2 and R3 are independently selected from group consisting of C2-C20 acyl, PEG 2-20 KD, absent or Ra-L′;
Ra is selected from biotin or maleimido propionic acid;L′ is selected from linkers —CO(CH2)n—NH—, —CO(CH2—CH2—O—)nNH or —COCH2(—OCH2—CH2)nNH—; and‘n’ is an integer selected from 2 to 10, both inclusive; R4 and R5 are independently NH2, or one or both of R4 or R5 are absent, with the proviso to the compound of Formula I, that in a compound of Formula I as above defined:
a) up to 5 but not more than 25% of the amino acids may be substituted with other natural or unnatural amino acids;b) not more than 30% of the amino acids may be omitted;c) in each said peptide sequence up to 2 amino acids may be added individually at any position;d) up to 5 but not more than 25% of the peptide bonds may instead be replaced by reduced amide bond (—CH2NH—);e) up to 100% of the amino acids may be D-amino acids;f) up to 100% of the amino acids may be in reverse order. |
