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US 2010/0144641 A1Published application
Compositions Having Antiangiogenic Activity and Uses Thereof
OwnerAleksander S. Popel, Emmanouil D. Karagiannisinventors
Life of this patent
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Abstract
The invention generally features compositions and methods that are useful for modulating blood vessel formation, as well as methods that provide for the systematic and efficient identification of angiogenesis modulators. As described in more detail below, a systematic computational methodology based on bioinformatics was used to identify novel peptide modulators of angiogenesis that have been characterized in vitro and/or in vivo.
Claims36
An isolated peptide or analog thereof comprising the amino acid sequence W-X2-C-X3-C-X2-G (SEQ ID NO:
- 161, wherein X denotes a variable amino acid;
- W is tryptophan;
- C is cysteine, G is glycine;
- and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
1 more element
8-9. (canceled)
An isolated peptide or analog thereof comprising a 20 amino acid (AA) sequence having positions AA1-AA20 (SEQ ID NO:
- 162), wherein:
- AA1 is X, S, T, G, Q, or A;
- AA2 is X, P, E, S, A, Q, or K;
- AA3 is W;
- AA4 is X, S, T, G, E, D, R, or A;
- AA5 is X, P, A, Q, D, E, K, R, or V;
- AA6 is C;
- AA7 is X, S, N, or T;
- AA8 is X, V, A, R, K, G, S, T, or E;
- AA9 is X, T, S, R, or N;
- AA10 is C;
- AA11 is X, G, S, or N;
- AA12 is X, G, K, R, M, T, L, D, S, or P;
- AA13 is G;
- AA14 is X, V, I, M, T, H, A, E, F, K, R, S, Q, W, or Y;
- AA15 is X, Q, S, R, K, Y, or A;
- AA16 is X, T, F, K, Q, S, L, E, M, N, or V;
- AA17 is X, R, S, or Q;
- AA18 is X, S, T, V, R, H, E, Q, A, or I;
- AA19 is X, R, or V;
- and
- AA20 is R;
- wherein X denotes a variable amino acid;
- W is tryptophan;
- C is cysteine, T is threonine, S is serine;
- N is asparagine;
- G is glycine;
- R is arginine;
- V is valine, P is proline, and Q is glutamine;
- and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
27 more elements
An isolated peptide or analog thereof comprising:
- (i) at least a fragment of a thrombospondin containing protein, wherein the peptide reduces blood vessel formation in a tissue or organ and comprises a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the thrombospondin containing protein listed in Table 1 (SEQ ID Nos:
- 1-76);
- or.
- (ii) a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:
- THSD-1:
- QPWSQCSATCGDGVRERRR;
- (SEQ ID NO:
- 64)
- THSD-3:
- SPWSPCSGNCSTGKQQRTR;
- (SEQ ID NO:
- 65)
- THSD-6:
- WTRCSSSCGRGVSVRSR;
- (SEQ ID NO:
- 66)
- CILP:
- SPWSKCSAACGQTGVQTRTR;
- (SEQ ID NO:
- 39)
- WISP-1:
- SPWSPCSTSCGLGVSTRI;
- (SEQ ID NO:
- 74)
- WISP-2:
- TAWGPCSTTCGLGMATRV;
- (SEQ ID NO:
- 75)
- WISP-3:
- TKWTPCSRTCGMGISNRV;
- (SEQ ID NO:
- 76)
- F-spondin:
- SEWSDCSVTCGKGMRTRQR;
- (SEQ ID NO:
- 73)
- F-spondin:
- WDECSATCGMGMKKRHR;
- (SEQ ID NO:
- 72)
- CTGF:
- TEWSACSKTCGMGISTRV;
- (SEQ ID NO:
- 41)
- fibulin-6:
- ASWSACSVSCGGGARQRTR;
- (SEQ ID NO:
- 45)
- fibulin-6:
- QPWGTCSESCGKGTQTRAR;
- (SEQ ID NO:
- 44)
- fibulin-6:
- SAWRACSVTCGKGIQKRSR;
- (SEQ ID NO:
- 43)
- CYR61:
- TSWSQCSKTCGTGISTRV;
- (SEQ ID NO:
- 42)
- NOVH:
- TEWTACSKSCGMGFSTRV;
- (SEQ ID NO:
- 46)
- UNC5-C:
- TEWSVCNSRCGRGYQKRTR;
- (SEQ ID NO:
- 79)
- UNC5-D:
- TEWSACNVRCGRGWQKRSR;
- (SEQ ID NO:
- 71)
- SCO-spondin:
- GPWEDCSVSCGGGEQLRSR;
- (SEQ ID NO:
- 63)
- Properdin:
- GPWEPCSVTCSKGTRTRRR;
- (SEQ ID NO:
- 49)
- C6:
- TQWTSCSKTCNSGTQSRHR;
- (SEQ ID NO:
- 38)
- ADAMTS-like-4:
- SPWSQCSVRCGRGQRSRQVR;
- (SEQ ID NO:
- 69)
- ADAMTS4:
- GPWGDCSRTCGGGVQFSSR;
- (SEQ ID NO:
- 7)
- ADAMTS-8:
- GPWGECSRTCGGGVQFSHR;
- (SEQ ID NO:
- 14)
- ADAMTS-16:
- SPWSQCTASCGGGVQTR;
- (SEQ ID NO:
- 24)
- ADAMTS-18:
- SKWSECSRTCGGGVKFQER;
- (SEQ ID NO:
- 29)
- semaphorin 5A:
- GPWERCTAQCGGGIQARRR;
- (SEQ ID NO:
- 60)
- semaphorin 5A:
- SPWTKCSATCGGGHYMRTR;
- (SEQ ID NO:
- 61)
- semaphoring 5B:
- TSWSPCSASCGGGHYQRTR;
- (SEQ ID NO:
- 62)
- papilin:
- GPWAPCSASCGGGSQSRS;
- (SEQ ID NO:
- 48)
- papilin:
- SQWSPCSRTGGGGVSFRER;
- (SEQ ID NO:
- 47)
- ADAM-9:
- KCHGHGVCNS;
- (SEQ ID NO:
- 157)
- and
- ADAM-12:
- MQCHGRGVCNNRKN,
- (SEQ ID NO:
- 2)
- wherein A is alanine;
- I is isoleucine;
- M is methionine;
- H is histidine;
- Y is tyrosine;
- K is lysine;
- W is tryptophan;
- C is cysteine, T is threonine, S is serine;
- N is asparagine;
- G is glycine;
- R is arginine;
- V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (iii) the amino acid sequence G-X3-C-L-X-P-X10-K-X-L (SEQ ID NO:
- 170), wherein X denotes a variable amino acid;
- G denotes Glycine;
- C denotes cysteine;
- L denotes leucine;
- P denotes proline;
- K is lysine;
- and the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (iv) a 22 amino acid sequence having positions AA1-AA22 (SEQ ID NO:
- 171), wherein:
- AA1 is X, N or D;
- AA2 is G;
- AA3 is X, R or K;
- AA4 is X, K, E, or Q;
- AA5 is X, A, I, L, or V;
- AA6 is C;
- AA7 is L;
- AA8 is X, D or N;
- AA9 is P;
- AA10 is X, A, E, D, or K;
- AA11 is X, A, S, or E;
- AA12 is P;
- AA13 is X, F, I, M, R, or W;
- AA14 is X, V, L, or I;
- AA15 is X, K or Q;
- AA16 is X, K or R;
- AA17 is X, I or V;
- AA18 is X, I or V;
- AA19 is X, E or Q;
- AA20 is K;
- A21 is X, I, F, K, or M;
- and
- AA22 is L;
- wherein X denotes a variable amino acid;
- A is alanine;
- I is isoleucine;
- F is phenylalanine;
- D is aspartic acid;
- M is methionine;
- H is histidine;
- Y is tyrosine;
- K is lysine;
- W is tryptophan;
- C is cysteine, T is threonine, S is serine;
- N is asparagine;
- G is glycine;
- R is arginine;
- V is valine, P is proline, and Q is glutamine;
- and wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (v) an amino acid sequence selected from the group consisting of:
- G-X3-C-L-X-P-X10-K-X-L;
- (SEQ ID NO:
- 170)
- (N/D/K)-G-X3-C-L-(D/N)-(P/L)-X5-(K/Q)-(K/R/N)-(I/V/L)-(I/V/L)-X6;
- (SEQ ID NO:
- 172)
- and
- (N/D)-G-(R/K)-X2-C-L-(N/D)-P-X2-(P/N)-X2-(K/Q)-(K/Q)-(I/V)-(I/V)-(E/Q)-K-X-L;
- (SEQ ID NO:
- 173)
- or
- (vi a sequence that has at least 85% amino acid sequence identity to a CXC Chemokine protein listed in Table 1 (SEQ ID Nos:
- 95-116);
- or
- (vii) a sequence having at 85% identity to an amino acid sequence selected from the group consisting of:
- ENA-78:
- NGKEICLDPEAPFLKKVIQKILD;
- (SEQ ID NO:
- 95)
- CXCL6:
- NGKQVCLDPEAPFLKKVIQKILDS;
- (SEQ ID NO:
- 98)
- CXCL1:
- NGRKACLNPASPIVKKIIEKMLNS;
- (SEQ ID NO:
- 102)
- Gro-γ:
- NGKKACLNPASPMVQKIIEKIL;
- (SEQ ID NO:
- 106)
- Beta thromboglobulin/CXCL7:
- DGRKICLDPDAPRIKKIVQKKL,
- (SEQ ID NO:
- 114)
- Interleukin 8(IL-8)/CXCL8:
- DGRELCLDPKENWVQRVVEKFLK,
- (SEQ ID NO:
- 110)
- GCP-2:
- NGKQVCLDPLAPFLKKVIQKILDS,
- (SEQ ID NO:
- 98)
- wherein A is alanine;
- I is isoleucine;
- F is phenylalanine;
- D is aspartic acid;
- M is methionine;
- H is histidine;
- Y is tyrosine;
- K is lysine;
- W is tryptophan;
- C is cysteine, T is threonine, S is serine;
- N is asparagine;
- G is glycine;
- R is arginine;
- V is valine, P is proline, and Q is glutamine;
- and wherein the peptide reduces blood vessel formation in a cell, tissue or organ, or
- (viii) a peptide comprises at least a fragment of a C-X-C chemokine protein of Table 1.
- (ix) an amino acid sequence C-N-X3-V-C (SEQ ID NO:
- 174) or P-F-X-E-C-X-G-X5-A-N (SEQ ID NO:
- 175), wherein X denotes a variable amino acid;
- F is phenylalanine;
- C is cysteine, N is asparagine;
- G is glycine;
- V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- (x) a sequence comprising at least a fragment of a type IV collagen C4 polypeptide, wherein the peptide reduces blood vessel formation in a cell, tissue or organ and comprises a sequence having at least 85% identity to an amino acid sequence selected from collagen proteins listed in Table 1;
- (xi) one of the following amino acid sequences,
- C-N-X3-V-C-X2-A-X-R-N-D-X-S-Y-W-L (SEQ ID NO:
- 176);
- or
- L-X2-F-S-T-X-P-F-X2-C-N-X3-V-C (SEQ ID NO:
- 177), wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (xii) an amino acid sequence P-F-(I/L)-E-C-X-G-X-(R/G)-X-(Y/F)-(Y/F)-A-N (SEQ ID NO:
- 178), wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- (xiii) a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of
- Alpha 6 fibril of type 4 collagen:
- YCNINEVCHYARRNDKSYWL;
- (SEQ ID NO:
- 93)
- Alpha 5 fibril of type 4 collagen:
- LRRFSTMPFMFCNINNVCNF;
- (SEQ ID NO:
- 89)
- Alpha 4 fibril of type 4 collagen:
- AAPFLECQGRQGTCHFFAN;
- (SEQ ID NO. 87)
- Alpha 4 fibril of type 4 collagen:
- LPVFSTLPFAYCNIHQVCHY;
- (SEQ ID NO:
- 85)
- and
- Alpha 4 fibril of type 4 collagen:
- YCNIHQVCHYAQRNDRSYWL,
- (SEQ ID NO:
- 86)
- wherein A is alanine;
- I is isoleucine;
- F is phenylalanine;
- D is aspartic acid;
- M is methionine;
- H is histidine;
- Y is tyrosine;
- K is lysine;
- W is tryptophan;
- C is cysteine, T is threonine, S is serine;
- N is asparagine;
- G is glycine;
- R is arginine;
- V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ
- (xiv) an amino acid sequence E-C-L-W-X-D-X8-G-X-Y-X5-C (SEQ ID NO:
- 179), wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- (xv) a peptide comprising or consisting essentially of twenty-three amino acids of a TIMP protein listed in Table 1;
- or
- (xvi) a peptide comprising or consisting essentially of at least twenty-four amino acids of a TIMP protein listed in Table 1;
- or
- (xvii) a peptide comprising or consisting essentially of 30 amino acids of a TIMP protein listed in Table 1;
- or
- (xviii) a peptide comprising or consisting essentially of an amino acid sequence having at least 85% amino acid sequence identity to ECLWTDMLSNFGYPGYQSKHYACI (SEQ ID NO:
- 155), wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (xiv) a fragment of a TIMP, wherein the peptide comprises a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from TIMP protein listed in Table 1, and wherein the peptide reduces blood vessel formation in a cell, tissue or organ;
- or
- (xv) a fragment of an amino acid sequence selected from the group consisting of SEQ ID Nos. 1-156;
- or
- (xvi) a peptide comprising or consisting essentially of an amino acid sequence having at least 85% identity to an amino acid sequence selected from the group consisting of SEQ ID Nos. 1-156.
322 more elements
13-38. (canceled)
40-42. (canceled)
A peptide conjugate comprising a peptide having an amino acid sequence selected from the group consisting of SEQ ID Nos. 1-156 conjugated to an agent that specifically binds a tumor marker or endothelial cell marker.
44-46. (canceled)
(canceled)
51-53. (canceled)
(canceled)
A method of reducing blood vessel formation in a tissue or organ the method comprising:
- (a) contacting the tissue, or organ with a vector encoding a polypeptide comprising SEQ ID Nos. 1-156;
- and
- (b) expressing the polypeptide in a cell of the tissue or organ, thereby reducing blood vessel formation in the tissue or organ.
59-63. (canceled)
67-81. (canceled)
(canceled)
A method for identifying an amino acid sequence of interest, the method comprising:
- (a) identifying an initial polypeptide or fragment thereof having amino acid sequence identity to a reference sequence having a biological function of interest;
- (b) generating a random sequence comprising the amino acid composition of the initial polypeptide of interest and comparing the random sequence to the reference sequence to determine amino acid sequence identity, wherein said amino acid sequence identity determines a random sequence cut-off value;
- (c) comparing the sequence identity of step a to the random sequence cut-off value of set b, wherein a sequence identity that is significantly greater than the random sequence cut-off value identifies an amino acid sequence of interest.
86-91. (canceled)
Dependencies are inferred from the claim text.