Cyclic peptides, cell scaffold materials, cell separation materials and culture media

Abstract

The cyclic peptide comprises a cyclic segment containing an RGD sequence and having 8 to 14 amino acid residues. The amino acid residue X at the most N-terminal side of the cyclic segment a The amino acid residue X located at the C-terminal end of the cyclic segment b There is a thioether bond between the amino acid residues X a and the amino acid residue X b When one of the amino acid residues X is a cysteine ​​residue, the amino acid residue X a and the amino acid residue X b The α carbon of the other amino acid residue in the cysteine ​​residue is separated from the sulfur atom of the cysteine ​​residue by more than 5 atoms.

Description

Technical Field

[0001] The invention relates to a cyclic peptide, a cell scaffold material, a cell separation material and a culture medium. Background Art

[0002] Integrins are cell adhesion molecules, heterodimeric proteins composed of two subunits, the α chain and the β chain. Integrins not only play a role in cell adhesion, but also play an important role in cell extension, cell movement, cell proliferation, tissue formation, cancer metastasis, tissue repair, blood coagulation, etc.

[0003] Japanese Patent Publication No. 2005-507376 discloses a cyclic peptide cyclized via a disulfide bond to integrin. Cyclic peptides having affinity for integrins are also known. For example, Japanese Patent Publication No. 6-509551 describes a cyclic peptide obtained by cyclizing Tyr-Arg-Gly-Asp as a platelet aggregation inhibitor for Gp II. b III a A highly specific platelet aggregation inhibitor. In addition, Bioconju gate Chem, 1995, 6, p. 269-277 describes a technique for cyclizing a peptide and / or bonding it to a carrier protein or a glass cover slip using (bromoacetyl) diaminopropionic acid. Summary of the invention

[0004] Technical issues to be solved by the invention

[0005] The problem to be solved by the embodiments of the present invention is to provide a cyclic peptide having excellent bonding properties with integrins and excellent molecular stability, for example, alkali resistance, and a cell scaffold material, a cell separation material, and a culture medium containing the cyclic peptide.

[0006] Means for solving technical problems

[0007] Means for solving the above-mentioned problems include the following.

[0008] <1> A cyclic peptide comprising a cyclic segment containing an RGD sequence and having 8 to 14 amino acid residues,

[0009] The amino acid residue X located at the most N-terminal side of the above-mentioned cyclic segment a The amino acid residue X located at the C-terminal end of the cyclic segment b There is a thioether bond between them.

[0010] Wherein, when the above amino acid residue X a and the above amino acid residue X b When one of the amino acid residues X is a cysteine ​​residue, the amino acid residue X aand the above amino acid residue X b The α-carbon of another amino acid residue in the cysteine ​​residue is separated from the sulfur atom of the above cysteine ​​residue by 5 or more atoms.

[0011] <2> According to the cyclic peptide described in <1>, it also includes at least one of the first segment between the above-mentioned cyclic segment and the N-terminus of the above-mentioned cyclic peptide and the second segment between the above-mentioned cyclic segment and the C-terminus of the above-mentioned cyclic peptide, and at least one of the above-mentioned first segment and the above-mentioned second segment includes an amino acid residue having an immobilized functional group on the side chain.

[0012] <3> The cyclic peptide according to <2>, wherein the immobilization functional group is an amino group or a thiol group.

[0013] <4> The cyclic peptide according to <2>, wherein the amino acid residue having an immobilized functional group on the side chain is selected from the group consisting of L-lysine residue, D-lysine residue, L-cysteine ​​residue, D-cysteine ​​residue, L-homocysteine ​​residue and D-homocysteine ​​residue.

[0014] <5> The cyclic peptide according to any one of <2> to <4>, wherein the first segment and the second segment, when each is present, have a length of 1 to 20 amino acid residues.

[0015] <6> The cyclic peptide according to any one of <1> to <5>, wherein

[0016] The above amino acid residue X a and the above amino acid residue X b One of the following is an amino acid residue (p) or (q),

[0017] [Chemical formula number 1]

[0018]

[0019] Wherein, * is the bonding position with the adjacent amino acid residue, ** is the bonding position with the sulfur atom of the coordinating amino acid residue of the thioether bond, x1 is an integer greater than 0, and the x1 carbon atom and the carbon atom at the β position may also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 The aryl group is substituted with one or more substituents from the group consisting of,

[0020] **-L is **-(CH2) y1 -C(=O)- or **-(CH2) y1 -C(=O)-NH-, y1 represents an integer from 0 to 10,

[0021] The above amino acid residue Xa and the above amino acid residue X b The other of which is the following residue (t) or (u),

[0022] [Chemical formula number 2]

[0023]

[0024] Wherein, * is the bonding position with the adjacent amino acid residue, *** is the bonding position with the carbon atom of the coordinating amino acid residue of the thioether bond, x2 is an integer greater than 0, and the x2 carbon atoms and the carbon atom at the β position can also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 The aryl group is substituted with one or more substituents from the group consisting of,

[0025] Wherein, when the above amino acid residue X a and the above amino acid residue X b When one of the above amino acid residues is an amino acid residue in which x1 is 0 in (p) or (q), the above amino acid residue X a and the above amino acid residue X b The other one of the amino acids is not an L-cysteine ​​residue or a D-cysteine ​​residue.

[0026] <7> The cyclic peptide according to <6>, wherein the amino acid residue X a It is the amino acid residue of (p) or (q) above.

[0027] <8> The cyclic peptide according to <6>, wherein the amino acid residue X b It is the amino acid residue of (p) or (q) above.

[0028] <9> The cyclic peptide according to any one of <6> to <8>, wherein

[0029] The amino acid residue of (p) or (q) is a residue selected from the following (a) to (h),

[0030] [Chemical formula number 3]

[0031]

[0032] Wherein, * is the bonding position with the adjacent amino acid residue, ** is the bonding position with the sulfur atom of the coordinating amino acid residue of the thioether bond,

[0033] The amino acid residue of (t) or (u) is selected from the group consisting of an L-homocysteine ​​residue, a D-homocysteine ​​residue, an L-penicillamine residue, a D-penicillamine residue, an L-cysteine ​​residue and a D-cysteine ​​residue,

[0034] However, combinations of the residues of (a) or (b) above and L-cysteine ​​residues or D-cysteine ​​residues are not included.

[0035] <10> The cyclic peptide according to any one of <1> to <9>, comprising a plurality of the cyclic segments, wherein the amino acid sequences of the cyclic segments may be the same or different from each other.

[0036] <11> The cyclic peptide according to <10>, wherein the plurality of cyclic segments are linked to each other via a linking portion having a length of 1 to 20 amino acid residues.

[0037] <12> The cyclic peptide according to any one of <1> to <11>, wherein the total number of amino acid residues is 8 to 50.

[0038] <13> The cyclic peptide according to any one of <1> to <9>, which is represented by formula II:

[0039] R N -X v0 -X 6 t0 -X p0 -X a -X m -RGDX n -X b -X q0 -X 7 u0 -X w0 -R c (Formula II)

[0040] In formula II,

[0041] X a X represents amino acid residue a , X b X represents amino acid residue b ,

[0042] X represents any amino acid residue. When there are multiple Xs, the multiple Xs may be the same or different from each other.

[0043] R N Represents the N-terminal group, R C represents the C-terminal group,

[0044] X 6 and X 7 Each independently represents an amino acid residue having a fixed functional group on the side chain. 6 or X 7 In the case of multiple X 6 or X 7 Can be the same or different.

[0045] m and n are integers satisfying 0≤m≤9, 0≤n≤9 and 3≤m+n≤9,

[0046] p0 and q0 are integers satisfying 0≤p0≤15 and 0≤q0≤15 respectively.

[0047] t0 and u0 are integers satisfying 0≤t0≤5 and 0≤u0≤5 respectively.

[0048] v0 and w0 are integers satisfying 0≤v0≤5 and 0≤w0≤5 respectively.

[0049] Moreover, p0, q0, t0, u0, v0 and w0 satisfy 0≤p0+q0+t0+u0+v0+w0≤39.

[0050] <14> The cyclic peptide according to <13>, wherein

[0051] X in Formula II a -X m -RGDX n -X b Yes X a -X t v5 -X 1 -X 2 -RGDX 3 -X 4 -X 5 v6 -X t v7 -X b ,

[0052] X t represents any amino acid residue, in X t If there are multiple X t Can be the same or different.

[0053] X 1 represents I, V, D, E, Y, L, T or homotyrosine,

[0054] X 2 Indicates P, T or S,

[0055] X 3 represents N, S, T, V, A or homoserine,

[0056] X 4 indicates F, Y or P,

[0057] X 5 represents R, D, E, A, T, S or G,

[0058] v5 and v7 each independently represent an integer from 0 to 6,

[0059] v6 means 0 or 1.

[0060] <15> The cyclic peptide according to <14>, which satisfies at least one of the following (i) to (v):

[0061] (i) By X 1 The amino acid residue indicated is I, V, or T;

[0062] (ii) By X 2 The amino acid residue represented by is P;

[0063] (iii) By X 3 The amino acid residue indicated is S or T;

[0064] (iv) By X 4 The amino acid residue represented is F:

[0065] (v) v6 represents 1, represented by X 5 The amino acid residue represented is A.

[0066] <16> The cyclic peptide according to any one of <1> to <15>, wherein the amino acid residue X a and the above amino acid residue X b The amino acid sequence of the clamped region has a sequence homology of more than 70% with the amino acid sequence of IPRGDNFR (sequence number 1), or has a sequence homology of more than 70% with any one of the amino acid sequences of IPRGDSFA (sequence number 170), VPRGDTFA (sequence number 171) and TPRGDTFA (sequence number 172).

[0067] <17> A cell scaffold material comprising a substrate and the cyclic peptide according to any one of <1> to <16>.

[0068] <18> A cell separation material comprising a holding material and the cyclic peptide according to any one of <1> to <16>.

[0069] <19> A culture medium comprising culture components and the cyclic peptide according to any one of <1> to <16>.

[0070] Effects of the Invention

[0071] According to an embodiment of the present invention, there are provided a cyclic peptide having excellent bonding properties with integrins and excellent molecular stability, for example, alkali resistance, and a cell scaffold material, a cell separation material, and a culture medium containing the cyclic peptide. DETAILED DESCRIPTION

[0072] The cyclic peptide, cell scaffold material, cell separation material and culture medium according to the present invention are described below. However, the embodiments of the present invention are not limited to the following embodiments, and can be implemented with appropriate modifications.

[0073] In the present invention, a numerical range expressed using "to" indicates a range including the numerical values ​​before and after "to" as the minimum value and the maximum value, respectively.

[0074] In the numerical ranges recorded in stages in the present invention, the upper limit or lower limit recorded in a certain numerical range can be replaced by the upper limit or lower limit of the numerical range recorded in other stages. In addition, in the numerical ranges recorded in the present invention, the upper limit or lower limit recorded in a certain numerical range can also be replaced by the value shown in the embodiments.

[0075] In the present invention, a combination of two or more preferred aspects is a more preferred aspect.

[0076] In the present invention, when there are plural substances corresponding to each component, the amount of each component means the total amount of the plural substances unless otherwise specified.

[0077] In the present invention, the term "process" includes not only an independent process but also a process that cannot be clearly distinguished from other processes as long as the intended purpose of the process can be achieved.

[0078] The cyclic peptide involved in the present invention comprises a cyclic segment containing an RGD sequence and having 8 to 14 amino acid residues.

[0079] The amino acid residue X located at the most N-terminal side of the above-mentioned cyclic segment a The amino acid residue X located at the C-terminal end of the cyclic segment b There is a thioether bond between them.

[0080] Wherein, when the above amino acid residue X a and the above amino acid residue X b When one of the amino acid residues X is a cysteine ​​residue, the amino acid residue X a and the above amino acid residue X b The α-carbon of another amino acid residue in the cysteine ​​residue is separated from the sulfur atom of the above cysteine ​​residue by 5 or more atoms.

[0081] Integrin-binding cyclic peptides have the ability to bind to integrins, which are cell adhesion molecules. Since integrin-binding cyclic peptides have the ability to bind to integrins on the cell surface, they can be used as scaffold materials for cell culture, cell separation materials for separating cells, and culture media, and are useful molecules. However, cyclic peptides sometimes have higher bonding properties and specificity than linear peptides, but on the other hand, the molecular stability of cyclic peptides tends to be lower than that of linear peptides.

[0082] For example, cyclic peptides tend to have low resistance to alkali, acid, and activation light such as X-rays and gamma rays. Since integrin-binding cyclic peptides have low molecular stability, they decompose during long-term or repeated use, and the desired effect cannot be obtained for a long time. In addition, cyclic peptides do not always have higher bonding than linear peptides, and their bonding to integrins varies depending on their amino acid sequence. Therefore, it is not easy to obtain integrin-binding cyclic peptides that have both excellent molecular stability and excellent integrin bonding.

[0083] However, the cyclic peptide of the specific structure involved in the present invention has both excellent molecular stability and excellent integrin binding properties. The cyclic peptide of the specific structure involved in the present invention comprises a cyclic segment containing an RGD sequence and having 8 to 14 amino acid residues, and an amino acid residue X located at the most N-terminal side of the cyclic segment. a The amino acid residue X located at the C-terminal end of the cyclic segment b There is a thioether bond between them. a and the above amino acid residue X b When one of the amino acid residues X is a cysteine ​​residue, the amino acid residue X a and the above amino acid residue X b The α carbon of another amino acid residue in the cysteine ​​residue is separated from the sulfur atom of the cysteine ​​residue by 5 or more atoms. According to this specific structure, the cyclic peptide of the specific structure involved in the present invention has excellent molecular stability and excellent integrin binding property. Japanese Patent Publication No. 2005-507376, Japanese Patent Publication No. 6-509551 and Bioconjugate Chem, 1995, 6, p. 269-277 do not disclose that by setting the cyclic segment region in a manner that satisfies the above regulations, and setting the amino acid residues related to the thioether bond in the cyclic peptide in a manner that satisfies the above regulations, both excellent molecular stability and excellent integrin binding property are achieved.

[0084] 〈Amino Acids and Amino Acid Residues〉

[0085] In the present invention, amino acids are represented in principle by names, abbreviations, etc. adopted by the Joint Commission on Biochemical Nomenclature (JCBN) of the International Union of Pure and Applied Chemistry and the International Union of Biochemistry and Molecular Biology (INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY and INTERNATIONAL UNION OF BIOCHEMISTRY AND MOLECULAR BIOLOGYIUPAC-IUB Joint Commission on Biochemical Nomenclature. In addition, amino acid residues are represented by the abbreviations of the amino acids from which the amino acid residues are derived.

[0086] Unless otherwise specified, the amino acid sequence of a peptide or protein (also referred to as "primary structure") is represented by arranging one row of amino acid residues from the left end to the right end in a manner from the N-terminus to the C-terminus. In the case of determining the amino acid residues in the amino acid sequence of a peptide or protein including the position, sometimes a number indicating the number of amino acid residues starting from the N-terminal side is marked on the right side of the abbreviation of the amino acid residue to represent it. For example, the second lysine from the N-terminus is sometimes represented as Lys2.

[0087] Furthermore, when the name is used to represent an amino acid, and there are isomers in an enantiomeric relationship, i.e., L-form and D-form, in principle, it can be either the L-form or the D-form, except when the distinction between the L-form and the D-form is clearly indicated. For example, "isoleucine" means "L-isoleucine" or "D-isoleucine", and the same applies to amino acid residues. Similarly, when the abbreviation (3-character abbreviation or 1-character abbreviation) is used to represent an amino acid, and there are isomers in an enantiomeric relationship, i.e., L-form and D-form, in principle, it can be either the L-form or the D-form, except when the distinction between the L-form and the D-form is clearly indicated. For example, "Lys" means "L-lysine" or "D-lysine", and the same applies to amino acid residues. Furthermore, for each amino acid and each amino acid residue, the L-form and the D-form can be selected independently. Among them, with respect to the RGD sequence present in the cyclic segment, all amino acid residues are L-form. Regarding sequences other than the above-mentioned RGD sequence, the amino acid residues present in the cyclic peptide may be all L-form amino acid residues, all D-form amino acid residues, or both L-form amino acid residues and D-form amino acid residues may exist.

[0088] Furthermore, when an amino acid is represented by its name, and there are isomers in a diastereomeric relationship, they are not included in the amino acid identified by its name. Diastereomers are treated as different types of amino acids using the prefix "allo". For example, "threonine" does not include "allothreonine". The same is true for amino acid residues.

[0089] Table 1 shows the names and abbreviations (one-character abbreviation, three-character abbreviation) of amino acids for which one-character abbreviations and three-character abbreviations are officially recognized.

[0090] [Table 1]

[0091] 1 character abbreviation 3-character abbreviation name A Ala Alanine B Asx Aspartic acid or asparagine C Cys Cysteine D Asp Aspartic acid E Glu Glutamate F Phe Phenylalanine G Gly Glycine H His Histidine I Ile Isoleucine K Lys Lysine L Leu Leucine M Met Methionine N Asn Asparagine O Pyl Pyrrolysine P Pro Proline Q Gln Glutamine R Arg Arginine S Ser Serine T Thr Threonine U Sec Selenocysteine V Val Valine W Trp Tryptophan X XA Any amino acid Y Tyr Tyrosine Z Gx Glutamate or glutamine

[0092] The amino acids that can be used in the cyclic peptide according to the present invention are not limited to the amino acids listed in Table 1, and abnormal amino acids can also be used. Examples of abnormal amino acids are listed in Table 2 below, but the abnormal amino acids are not limited thereto.

[0093] [Table 2]

[0094]

[0095] Any amino acid residue contained in the cyclic peptide involved in the present invention may also be chemically modified. Examples of chemical modifications of amino acid residues include N-acetylation, N-formylation, N-acylation, PEGylation, etc. of the amino group present in the amino acid residue, and amidation, PEGylation, etc. of the carboxyl group present in the amino acid residue.

[0096] The cyclic peptide of the present invention comprises a cyclic segment containing an RGD sequence and having 8 to 14 amino acid residues, wherein the amino acid residue X at the most N-terminal side of the cyclic segment a The amino acid residue X located at the C-terminal end of the cyclic segment b The cyclic peptide involved in the present invention may be composed of a cyclic segment only, or may further have an amino acid residue on at least one of the N-terminal side and the C-terminal side of the cyclic segment.

[0097] Furthermore, in the cyclic peptide involved in the present invention, the number of the above-mentioned cyclic segments is not limited to 1, and the above-mentioned cyclic segments may also exist in multiple numbers, that is, more than two. In the case where there are multiple cyclic segments, the number of cyclic segments in the cyclic peptide involved in the present invention may be 2 to 4, or 2 or 3, or 2. The amino acid sequences of multiple cyclic segments may be the same as or different from each other. Furthermore, the cyclic segment may be directly linked to the adjacent cyclic segment, or there may be an amino acid sequence as a linking portion between the cyclic segment and the adjacent cyclic segment. In the case where there is an amino acid sequence as a linking portion, the amino acid sequence as a linking portion is not particularly limited, and the length of each linking portion may be 1 to 20 amino acid residues, or 2 to 10 amino acid residues, or 3 to 5 amino acid residues.

[0098] The cyclic segment contains an RGD sequence. In addition, in the present invention, the term "cyclic segment" is used for a cyclic segment containing the RGD sequence and having 8 to 14 amino acid residues, but a cyclic portion that does not belong to the cyclic segment containing the RGD sequence and having 8 to 14 amino acid residues may be added, such as a cyclic portion that does not contain an RGD sequence, a cyclic portion outside the range of 8 to 14 amino acid residues, etc.

[0099] Since the RGD sequence is a sequence required for bonding with integrins, the above-mentioned cyclic segment constitutes a cyclic peptide in a manner containing the RGD sequence. However, in order for the RGD sequence to fully exert its bonding ability with integrins, amino acid residues need to be present around the RGD sequence, and the cyclic segment is composed of 8 to 14 amino acid residues. The number of RGD sequences present in one cyclic segment may be one, or there may be two, three or four RGD sequences. The position of the RGD sequence in the cyclic segment is preferably aligned with the amino acid residue X. a and amino acid residue X b In other words, it is preferred that the RGD sequence and the amino acid residue X a There is one or more amino acid residues between the RGD sequence and the amino acid residue X b There may be more than one amino acid residue between them. For example, from the viewpoint of improving the bonding property with integrin, amino acid residue X a When counting the amino acid residues toward the C-terminal side as the first amino acid residue, the RGD sequence preferably corresponds to the 3rd to 5th amino acid residues, or to the 4th to 6th amino acid residues.

[0100] As mentioned above, the number of amino acid residues in the cyclic segment is 8 to 14. The number of amino acid residues in the cyclic segment may be 9 to 13, or 10 to 12. If the number of amino acid residues in the cyclic segment is within this range, the intramolecular strain of the cyclic peptide will not become too large, and the higher-order structure such as α-helix is ​​stable, so the cyclic peptide involved in the present invention has excellent integrin binding properties.

[0101] Regarding the RGD sequence in the ring segment, a The amino acid residues represented by X b The amino acid residues other than those represented by are not particularly limited as long as they do not impair the binding property with integrin. a The amino acid residues represented by X b The amino acid residues other than the amino acid residues represented by X may be selected from, for example, isoleucine residues, valine residues, aspartic acid residues, glutamic acid residues, tyrosine residues, leucine residues, threonine residues, homotyrosine residues, proline residues, serine residues, asparagine residues, alanine residues, homoserine residues, phenylalanine residues, arginine residues and glycine residues. In the case where the RGD sequence contained in the cyclic segment is one, the RGD sequence in the cyclic segment, the RGD sequence represented by X a The amino acid residues represented by X b The number of amino acid residues other than the indicated amino acid residues is 3-9, may be 4-8, or may be 5-7.

[0102] For example, the cyclic segment can also be composed of X a -X t v5 -X 11 -X 21 -RGDX 31 -X 41 -X 51 v6 -X t v7 -X b (Formula III) represents a cyclic segment.

[0103] In Formula III, X a X represents the amino acid residue at the most N-terminal side of the cyclic segment a , X b X represents the amino acid residue at the C-terminal end of the cyclic segment b ,

[0104] X t represents any amino acid residue, in X t If there are multiple X tCan be the same or different.

[0105] X 11 , X 21 , X 31 , X 41 and X 51 Each independently represents any amino acid residue,

[0106] v5 and v7 each independently represent an integer from 0 to 6,

[0107] v6 means 0 or 1,

[0108] Among them, at least one of the following (a) to (e) is satisfied.

[0109] (a)X 11 Indicates I, V, D, E, Y, L, T, or homotyrosine.

[0110] (b)X 21 Indicates P, T, or S.

[0111] (c)X 31 Indicates N, S, T, V, A or homoserine.

[0112] (d)X 41 Indicates F, Y, or P.

[0113] (e) v6 is 1, X 51 Indicates R, D, E, A, T, S, or G.

[0114] Regarding X in formula (III) a and X b Preferred examples are described later. v5 and v7 may be independently 0 to 4, 0 to 2, 0 or 1, or 0. Furthermore, X t They may each independently be an amino acid residue selected from the group consisting of A, F, G, I, L, M, P, V, and W, may be an amino acid residue selected from the group consisting of A, G, I, L, P, and V, or may be A.

[0115] More specifically, for example, the cyclic segment may also be composed of X a -X t v5 -X 1 -X 2 -RGDX 3 -X 4 -X 5 v6 -X t v7 -X b (Formula IV) represents a cyclic segment.

[0116] In Formula IV, X a X represents the amino acid residue at the most N-terminal side of the cyclic segment a , X b X represents the amino acid residue at the C-terminal end of the cyclic segment b ,

[0117] X t represents any amino acid residue, in X t If there are multiple X t Can be the same or different.

[0118] X 1 represents I, V, D, E, Y, L, T or homotyrosine,

[0119] X 2 Indicates P, T or S,

[0120] X 3 represents N, S, T, V, A or homoserine,

[0121] X 4 indicates F, Y or P,

[0122] X 5 represents R, D, E, A, T, S or G,

[0123] v5 and v7 each independently represent an integer from 0 to 6,

[0124] v6 means 0 or 1.

[0125] About X a and X b Preferred examples are described later. v5 and v7 may be independently 0 to 4, 0 to 2, 0 or 1, or 0. Furthermore, X t They may each independently be an amino acid residue selected from the group consisting of A, F, G, I, L, M, P, V, and W, may be an amino acid residue selected from the group consisting of A, G, I, L, P, and V, or may be A.

[0126] By X 1 The amino acid residue represented by X can also be I, V or T. 2 The amino acid residue represented by may also be P. 3 The amino acid residue represented by X can also be S or T. 4 The amino acid residue represented by may also be F. When v6 represents 1, X 5 The amino acid residue represented by may also be A. 1 ~X 5The exemplary provisions of these amino acid residue candidates may satisfy at least one, may combine two or more, or may combine all.

[0127] In the cyclic segment, the amino acid residue X a and amino acid residue X b The amino acid sequence of the sandwiched region may be the same as IPRGDNFR (SEQ ID NO. 1), or may be an amino acid sequence in which amino acid residues are added, deleted or substituted to the amino acid sequence of SEQ ID NO. 1. However, the RGD region in SEQ ID NO. 1 must not be changed. When amino acid residues are added to the interior of the amino acid sequence of SEQ ID NO. 1, the total number of added amino acid residues is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 or 2. When amino acid residues are added to the exterior of the amino acid sequence of SEQ ID NO. 1, i.e., amino acid residues X a Between the I residue at the N-terminus of SEQ ID NO: 1 and the amino acid residue X b When an amino acid residue is added to at least one of the R residues at the C-terminus of SEQ ID NO: 1, the total number of the added amino acids is preferably 1 to 10, more preferably 1 to 5, and even more preferably 1 to 3. When an amino acid residue within the amino acid sequence of SEQ ID NO: 1 is deleted, the total number of the deleted amino acid residues is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. When an amino acid residue within the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid residue, the total number of the substituted amino acid residues is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 or 2.

[0128] In the cyclic segment, the amino acid residue X a and amino acid residue X b When the amino acid sequence of the clamped region is compared with the amino acid sequence of SEQ ID NO: 1, it may contain two or more of the addition, deletion and substitution of amino acid residues. The total number of the added, deleted or substituted amino acid residues is preferably 1 to 15, more preferably 1 to 10, further preferably 1 to 5, and further preferably 1 to 3. Furthermore, in the case of the addition or deletion of amino acid residues, it is preferred that the addition or deletion is at the end of the amino acid sequence of SEQ ID NO: 1. For the two cross-linked amino acid residues (i.e., amino acid residues X) in the cyclic segment in the amino acid sequences of SEQ ID NO: 2 to 166 described later, a and X b )The sequence of the regions clamped by is also the same.

[0129] For example, the deletion of the amino acid residue preferably occurs in the C-terminal R residue in the amino acid sequence of SEQ ID NO:1.

[0130] In the cyclic segment, the amino acid residue X a and amino acid residue X bThe amino acid sequence of the sandwiched region preferably has a sequence homology of 70% or more with the amino acid sequence of IPRGDNFR (SEQ ID NO: 1). a and amino acid residue X b The amino acid sequence of the clamped region preferably has a sequence homology of 70% or more with the amino acid sequence of IPRGDNFR (SEQ ID NO. 1), more preferably has a sequence homology of 80% or more, and further preferably has a sequence homology of 85% or more. In addition, the range of amino acid sequences having a sequence homology of 70% or more with the amino acid sequence of IPRGDNFR (SEQ ID NO. 1) also includes the amino acid sequence of IPRGDNFR (SEQ ID NO. 1) itself.

[0131] In the present invention, the sequence homology between two amino acid sequences is determined as follows.

[0132] (i) Alignment of two amino acid sequences is performed.

[0133] For example, alignment between two sequences can be performed using an alignment algorithm and / or program such as FASTA, BLAST, etc. that can be used in the initial setting.

[0134] (ii) Calculate sequence homology.

[0135] Based on the obtained alignment, sequence homology was calculated by the following formula.

[0136] Sequence homology [%] = (number of identical positions / total number of positions) × 100 [%]

[0137] The total number of positions is the length of the alignment, and the number of identical positions is the number of positions where the identity of the amino acid is identical.

[0138] (iii) Example of calculation of sequence homology

[0139] For example, consider the following amino acid sequence.

[0140] Sequence A AYHRGELVWE

[0141] Sequence B SAWHGELVW

[0142] When aligned under the above conditions, the sequence becomes as follows: For the sake of easy visualization, the symbol "|" is used to indicate the site where the types of amino acids (residues) are identical between sequences A and B. Also, "-" indicates a site where there is no corresponding amino acid.

[0143]

[0144] In this example, the total number of positions is 11 and the number of identical positions is 7, so the sequence homology calculated according to the above formula is 7 / 11×100=63.6%.

[0145] In the above, the number of amino acid residues added, deleted or substituted to the amino acid sequence of SEQ ID NO: 1 and the sequence homology to the amino acid sequence of SEQ ID NO: 1 are described, but the provisions on the number of amino acid residues added, deleted or substituted to the above amino acid sequence and the provisions on sequence homology can also be similarly applied to the two cross-linked amino acid residues (i.e., amino acid residues X) in the cyclic segment in the amino acid sequences of SEQ ID NOs: 2 to 166 (i.e., the amino acid sequences of cyclic peptides 1 to 165). a and X b ) is used as the reference sequence. For example, the amino acid sequence of IPRGDNF (SEQ ID NO: 169) which is the region between the homocysteine ​​residue and the 2-amino-4-acetylamino-butyric acid residue in cyclic peptide 10 can also be similarly applied to the regulations on the number of amino acid residues added, deleted or substituted and the regulations on sequence homology for the above amino acid sequence.

[0146] For example, in the cyclic segment, the amino acid residue X a and amino acid residue X b The amino acid sequence of the sandwiched region may be the same as any one of IPRGDSFA (SEQ ID NO. 170), VPRGDTFA (SEQ ID NO. 171) and TPRGDTFA (SEQ ID NO. 172), or may be an amino acid sequence in which amino acid residues are added, deleted or substituted to any one of the amino acid sequences of SEQ ID NOs. 170 to 172. The RGD region in SEQ ID NOs. 170 to 172 may not be changed. When amino acid residues are added to the interior of any one of the amino acid sequences of SEQ ID NOs. 170 to 172, the total number of added amino acid residues is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 or 2. When amino acid residues X are added to the exterior of any one of the amino acid sequences of SEQ ID NOs. 170 to 172, that is, amino acid residues X a Between the N-terminal residues of any of SEQ ID NOs: 170 to 172 and the amino acid residue X b When an amino acid residue is added to at least one of the C-terminal residues of any one of SEQ ID NOs: 170 to 172, the total number of the added amino acids is preferably 1 to 10, more preferably 1 to 5, and even more preferably 1 to 3. When an amino acid residue within the amino acid sequence of any one of SEQ ID NOs: 170 to 172 is deleted, the total number of the deleted amino acid residues is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. When an amino acid residue within the amino acid sequence of any one of SEQ ID NOs: 170 to 172 is substituted with another amino acid residue, the total number of the substituted amino acid residues is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 or 2.

[0147] In the cyclic segment, the amino acid residue X a and amino acid residue X b The amino acid sequence of the clamped region may contain two or more of the addition, deletion and substitution of amino acid residues when compared with any one of the amino acid sequences in SEQ ID NOs: 170 to 172. The total number of the added, deleted or substituted amino acid residues is preferably 1 to 15, more preferably 1 to 10, further preferably 1 to 5, and further preferably 1 to 3. Furthermore, in the case of the addition or deletion of amino acid residues, it is preferred that the addition or deletion is present at the end of any one of the amino acid sequences in SEQ ID NOs: 170 to 172.

[0148] For example, the deletion of the amino acid residue preferably occurs at the C-terminal residue in any one of the amino acid sequences of SEQ ID NOs: 170 to 172.

[0149] In the cyclic segment, the amino acid residue X a and amino acid residue X b The amino acid sequence of the sandwiched region preferably has a sequence homology of 70% or more with any one of IPRGDSFA (SEQ ID NO: 170), VPRGDTFA (SEQ ID NO: 171) and TPRGDTFA (SEQ ID NO: 172). a and amino acid residue X b The amino acid sequence of the sandwiched region preferably has a sequence identity of 70% or more, more preferably 80% or more, and even more preferably 85% or more with any one of the amino acid sequences in SEQ ID NOs: 170 to 172. In addition, the range of the amino acid sequence having a sequence identity of 70% or more with any one of the amino acid sequences in SEQ ID NOs: 170 to 172 also includes any one of the amino acid sequences in SEQ ID NOs: 170 to 172 itself.

[0150] The total length (total number of amino acid residues) of the cyclic peptide of the present invention including the cyclic segment may be 8 to 50 amino acid residues, 9 to 30 amino acid residues, 10 to 20 amino acid residues, or 11 to 15 amino acid residues. The shorter the total length, the easier it is to synthesize the peptide.

[0151] The region between the N-terminus of the cyclic peptide involved in the present invention and the N-terminus of the cyclic segment (when the cyclic peptide contains multiple cyclic segments, the N-terminus of the cyclic segment on the most N-terminal side) is sometimes referred to as the cyclic peptide N-terminal region or the first segment in the present invention, and the region between the C-terminus of the cyclic peptide involved in the present invention and the C-terminus of the cyclic segment (when the cyclic peptide contains multiple cyclic segments, the C-terminus of the cyclic segment on the most C-terminal side) is sometimes referred to as the cyclic peptide C-terminal region or the second segment in the present invention.

[0152] The presence of the N-terminal region of the cyclic peptide is arbitrary and may not exist. In the absence of the N-terminal region of the cyclic peptide, the N-terminus of the cyclic segment also corresponds to the N-terminus of the cyclic peptide. Similarly, the presence of the C-terminal region of the cyclic peptide is arbitrary and may not exist. In the absence of the C-terminal region of the cyclic peptide, the C-terminus of the cyclic segment also corresponds to the C-terminus of the cyclic peptide.

[0153] The amino group at the N-terminus of the cyclic peptide may be subjected to N-acetylation, N-formylation, N-acylation, PEGylation, etc., and the carboxyl group at the C-terminus of the cyclic peptide may be subjected to C-terminus modification such as amidation, PEGylation, etc.

[0154] The cyclic peptide involved in the present invention may also be a cyclic peptide represented by the following formula II.

[0155] R N -X v0 -X 6 t0 -X p0 -X a -X m -RGDX n -X b -X q0 -X 7 u0 -X w0 -R c (Formula II)

[0156] In formula II,

[0157] X a represents the amino acid residue at the most N-terminal side of the cyclic segment, X b represents the amino acid residue at the C-terminal end of the cyclic segment. a With amino acid residue X b There is a thioether bond between them.

[0158] X represents any amino acid residue. When there are multiple Xs, the multiple Xs may be the same or different from each other.

[0159] R N Represents the N-terminal group, R C represents the C-terminal group,

[0160] X 6 and X 7 Each independently represents an amino acid residue having a fixed functional group on the side chain. 6 or X 7 In the case of multiple X 6 or X 7 Can be the same or different.

[0161] m and n are integers satisfying 0≤m≤9, 0≤n≤9 and 3≤m+n≤9,

[0162] p0 and q0 are integers satisfying 0≤p0≤15 and 0≤q0≤15 respectively.

[0163] t0 and u0 are integers satisfying 0≤t0≤5 and 0≤u0≤5 respectively.

[0164] v0 and w0 are integers satisfying 0≤v0≤5 and 0≤w0≤5 respectively.

[0165] Moreover, p0, q0, t0, u0, v0 and w0 satisfy 0≤p0+q0+t0+u0+v0+w0≤39.

[0166] In Formula II and Formula V described below, the subscript characters are integers indicating the number of amino acid residues represented by the previously described symbols. p0 The p0 in the mark of indicates that there are p0 amino acid residues represented by X arranged in an array. When the subscript character represents an integer greater than 2, there are multiple amino acid residues represented by the symbols described above, but as long as the definition is satisfied, the multiple amino acid residues may be the same as or different from each other.

[0167] In the cyclic peptide represented by Formula II, X a -X m -RGDX n -X b Corresponding to the cyclic segment. a and X b Preferred examples are described later.

[0168] 《X 6 t0 and X 7 u0 》

[0169] In Formula II, X 6 and X 7 Each independently represents an amino acid residue having an immobilized functional group on its side chain.

[0170] In X 6 or X 7 In the case of multiple X 6 or X 7 They can be the same as each other or different.

[0171] (Immobilized functional group)

[0172] The above-mentioned "immobilization functional group" refers to a functional group that can react with a functional group on a substrate or a holding material described later to form a covalent bond.

[0173] Examples of the immobilized functional group include an amino group, a carboxyl group, a hydroxyl group, a thiol group, an aldehyde group (formyl group), a carbamoyl group, an azide group, and an alkynyl group.

[0174] Examples of the combination of the immobilized functional group possessed by the cyclic peptide involved in the present invention and the functional group on the substrate or the retaining material include a combination of an amino group and a carboxyl group, a combination of an amino group and an aldehyde group, a combination of an amino group and an epoxy group, a combination of a hydroxyl group and an epoxy group, a combination of a carboxyl group and a hydroxyl group, a combination of a thiol group and an epoxy group, a combination of an azide group and an alkyne group, and the like.

[0175] The cyclic peptide involved in the present invention is fixed on the substrate or the retaining material by reacting the immobilization functional group of the cyclic peptide involved in the present invention with the functional group on the substrate or the retaining material to form a covalent bond. In addition, as long as at least a part of the immobilization functional groups of the cyclic peptide involved in the present invention reacts with the functional group on the substrate or the retaining material to form a covalent bond, all the immobilization functional groups may not react with the functional groups on the substrate or the retaining material.

[0176] In the amino acid having an immobilization functional group on the side chain, the immobilization functional group is preferably at least one selected from the group consisting of an amino group, a thiol group, and an aldehyde group, and more preferably at least one selected from the group consisting of an amino group and a thiol group.

[0177] (Amino acids with fixed functional groups on side chains)

[0178] The amino acid having an immobilized functional group on the side chain is preferably at least one amino acid selected from the group consisting of L-lysine, D-lysine, L-cysteine, D-cysteine, L-homocysteine ​​and D-homocysteine.

[0179] When an amino group is used as an immobilization functional group, the amino group can be bonded to a carboxyl group on a substrate or a holding material via an amide bond, and the cyclic peptide involved in the present invention can be easily immobilized on the substrate or the holding material.

[0180] Furthermore, when a thiol group is used as the immobilization functional group, the thiol group can be bonded to an epoxy group on a substrate or a holding material via a covalent bond, and the cyclic peptide involved in the present invention can be easily immobilized on the substrate or the holding material.

[0181] As the amino acid residue having an amino group on the side chain, L-lysine residue, D-lysine residue etc. can be enumerated, and as the amino acid residue having a thiol group on the side chain, L-cysteine ​​residue, D-cysteine ​​residue etc. can be enumerated. These amino acid residues can be introduced relatively cheaply, and therefore the manufacturing cost of the cyclic peptide involved in the present invention can be suppressed. Therefore, from an economic point of view, it is preferred to use the above-mentioned amino acid residues.

[0182] In Formula II, t0 and u0 are integers satisfying 0≤t0≤5 and 0≤u0≤5, respectively.

[0183] t0 preferably satisfies 0≤t0≤3, and more preferably satisfies 0≤t0≤2.

[0184] u0 preferably satisfies 0≤u0≤3, and more preferably satisfies 0≤u0≤2.

[0185] 《X p0 , X q0 , X v0 and X w0 》

[0186] X p0 , X q0 , X v0 and X w0 X in represents an arbitrary amino acid residue. When there are plural Xs, the plural Xs may be the same as or different from each other.

[0187] X is not particularly limited as long as it is an amino acid residue, but is preferably an amino acid residue derived from an amino acid selected from the group consisting of the amino acids shown in Table 1 (excluding B, Z and X) and the amino acids shown in Table 2, and more preferably an amino acid residue derived from the group consisting of the amino acids shown in Table 1 (excluding B, Z and X). Furthermore, when present, it may be an amino acid residue derived from an enantiomer or diastereomer of these amino acids.

[0188] The above-mentioned p0 and the above-mentioned q0 are integers satisfying 0≤p0≤15 and 0≤q0≤15, respectively.

[0189] p0 preferably satisfies 0≤p0≤10, more preferably satisfies 0≤p0≤5, further preferably satisfies 0≤p0≤3, and further preferably satisfies 0≤p0≤2.

[0190] q0 preferably satisfies 0≤q0≤10, more preferably satisfies 0≤q0≤5, further preferably satisfies 0≤q0≤3, and further preferably satisfies 0≤q0≤2.

[0191] The above-mentioned v0 and the above-mentioned w0 are integers satisfying 0≤v0≤5 and 0≤w0≤5, respectively.

[0192] v0 preferably satisfies 0≤v0≤3, and more preferably satisfies 0≤v0≤2.

[0193] w0 preferably satisfies 0≤w0≤3, and more preferably satisfies 0≤w0≤2.

[0194] 《X m and X n 》

[0195] Xm and X n Each X in the above may be any amino acid residue, for example, an isoleucine residue, a valine residue, an aspartic acid residue, a glutamic acid residue, a tyrosine residue, a leucine residue, a threonine residue, a homotyrosine residue, a proline residue, a serine residue, an asparagine residue, an alanine residue, a homoserine residue, a phenylalanine residue, an arginine residue or a glycine residue.

[0196] The above m and the above n are integers that simultaneously satisfy 0≤m≤9, 0≤n≤9, and 3≤m+n≤9.

[0197] m preferably satisfies 0≤m≤5, more preferably satisfies 0≤m≤3, and further preferably satisfies 0≤m≤2.

[0198] n preferably satisfies 1≤n≤5, and more preferably satisfies 2≤n≤4. n may be an integer satisfying 2≤n≤3.

[0199] 《R N and R C 》

[0200] R N Indicates the N-terminal group.

[0201] Examples of the N-terminal group include an amino group, and the amino group as the N-terminal group may be subjected to N-terminal modification such as N-acetylation, N-formylation, N-acylation, or PEGylation.

[0202] R C represents the C-terminal group.

[0203] Examples of the C-terminal group include a carboxyl group, and the carboxyl group as the C-terminal group may be subjected to C-terminal modification such as amidation or PEGylation.

[0204] In Formula II, R N Recorded in X v0 For example, if V0, t0, and p0 are all 0, then R N Corresponding to X a The amino group or modified amino group of the amino acid residue represented by c Recorded in X w0 For example, if q0, u0, and w0 are all 0, then R c Corresponding to X b The carboxyl group or modified carboxyl group of the amino acid residue represented by .

[0205] X in the above formula II a -X m -RGDX n -X bThe part can also be composed of the above formula III (X a -X t v5 -X 11 -X 21 -RGDX 31 -X 41 -X 51 v6 -X t v7 -X b ) or the above formula IV (X a -X t v5 -X 1 -X 2 -RGDX 3 -X 4 -X 5 v6 -X t v7 -X b ) represented by the part. By using the cyclic segment as the part represented by formula III or formula IV, a more reliable integrin binding property can be obtained. In this case, the cyclic peptide can also be composed of X J1 g1 -(Cyclic segment)-X J2 g2 The structure of the cyclic peptide is represented by J1 Each independently represents an arbitrary amino acid residue, X J2 Also, they each independently represent an arbitrary amino acid residue, g1 represents an integer of 0 to 8, and g2 represents an integer of 0 to 8. J1 Preferably, each independently represents K, A, G, D, E or β-alanine. J2 Preferably, each independently represents K, A, G, D, E or β-alanine. J1 and X J2 At least one of them may contain (K) g3 (g3 consecutive K residues), wherein g3 represents an integer of 2 to 6, preferably 3 or 4. g1 and g2 each independently represent an integer of 0 to 6, more preferably an integer of 0 to 4, an integer of 0 to 2, 0 or 1, or 0. X J1 g1 For example, it can be KKKA, X J2 g2 For example, it could be A.

[0206] When containing two or more cyclic segment parts, the cyclic peptide involved in the present invention may be a cyclic peptide represented by the following formula V.

[0207] R N-X v0 -X 6 t0 -X p0 -X a -X m -RGDX n -X b -(X e0 -X a -X m -RGDX n -X b ) d0 -X q0 -X 7 u0 -X w0 -R c (Formula V)

[0208] In Formula V, R N ,X,V0,X 6 ,t0,p0,X a , m, n, X b ,q0,X 7 , u0, w0 and R c The meanings are the same as those of R in formula (II). N ,X,V0,X 6 ,t0,p0,X a , m, n, X b ,q0,X 7 , u0, w0 and R c The preferred embodiments and ranges thereof are the same as those in Formula II.

[0209] e0 represents an integer greater than or equal to 0. e0 may represent an integer from 0 to 20, or an integer from 1 to 10, and more preferably an integer from 2 to 5. d0 represents an integer greater than or equal to 1. d0 may represent an integer from 1 to 3, or 1 or 2, or 1. X a , X m , X n and X b Appearing multiple times, X that appears multiple times a Can be the same or different. X that appears multiple times b Can be the same or different. X that appears multiple times m Can be the same or different. X that appears multiple times n They can be the same or different. m The same means that the m permutations of X are exactly the same as the m permutations of X. m Different from each other means that the m permutations of X are different from the m permutations of X for at least one X. nSame.

[0210] The number of cyclic segments is not particularly limited, but the greater the number of cyclic segments, the more the integrin binding property tends to be improved, and the smaller the number of cyclic segments, the more the total number of amino acid residues can be reduced, thus tending to suppress antigenicity. From the viewpoint of the synthesis cost of the cyclic peptide, the fewer the number of amino acid residues, the less the number of cyclic segments.

[0211] The amino acid residue Xa and the amino acid residue Xb are amino acid residues that form a thioether bond between Xa and Xb. The thioether bond is formed by R 1 -SR 2 Represents a divalent linked structure, where R 1 and R 2 It is an organic group, usually a carbon atom. By cross-linking the amino acid residue Xa and the amino acid residue Xb with a thioether bond, a higher bonding stability can be obtained compared to when cross-linking by a disulfide bond. In the present invention, the scheme for forming a thioether bond is not particularly limited. For example, by reacting a thiol group with an organic group having a halogen, a thioether bond formed by bonding the sulfur atom of the thiol group to the organic group can be formed while accompanying the generation of hydrogen halide. As an organic group having a halogen, for example, a haloacetyl group can be cited. The halogen atom of the haloacetyl group can also be any one of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Among them, from the viewpoint of reactivity, easy formation of a thioether bond and safety, preferably a bromine atom or a chlorine atom, more preferably a chlorine atom.

[0212] When the amino acid residue Xa is an amino acid residue derived from an α-amino acid, the thioether bond is preferably present on the side chain of the amino acid residue derived from the α-amino acid, rather than on the amino group or modified amino group bonded to the α-carbon of the α-amino acid. Similarly, in the amino acid residue Xb, when the amino acid residue Xb is an amino acid residue derived from an α-amino acid, the thioether bond is preferably present on the side chain of the amino acid residue derived from the α-amino acid, rather than on the carboxyl group or modified carboxyl group bonded to the α-carbon of the α-amino acid.

[0213] In order to form a thioether bond on the side chain of the amino acid residue as described above, it is preferred that one of the amino acid residue Xa and the amino acid residue Xb before the thioether bond formation is an amino acid residue having a thiol group on the side chain, and the other is an amino acid residue having an organic group having a halogen on the side chain. Examples of the amino acid residue having a thiol group on the side chain include amino acid residues represented by the following structural formula (t-2) or (u-2).

[0214] [Chemical formula number 4]

[0215]

[0216] In the structural formulas (t-2) and (u-2), * is the bonding position to the adjacent amino acid residue, x2 is an integer greater than 0, and the x2 carbon atoms and the carbon atom at the β position may also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 x2 may be an integer from 0 to 10, an integer from 0 to 6, or an integer from 1 to 4. 10 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 14 The aryl group includes phenyl, naphthyl, anthracenyl, phenanthryl and the like.

[0217] More specific examples of the amino acid residue having a thiol group in the side chain include a cysteine ​​residue, a penicillamine residue, a homocysteine ​​residue (a residue derived from 2-amino-4-mercaptobutyric acid), a residue derived from 2-amino-5-mercaptopentanoic acid, and the like.

[0218] Examples of the amino acid residue having an organic group having a halogen in a side chain include amino acid residues represented by the following structural formula (p-2) or (q-2).

[0219] [Chemical formula number 5]

[0220]

[0221] In the structural formulas (p-2) and (q-2), * is the bonding position with the adjacent amino acid residue, halogen is any halogen atom, such as F, Cl, Br, I, etc., x1 is an integer greater than 0, and the x1 carbon atom and the carbon atom at the β position can also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 The aryl group is substituted with one or more substituents from the group consisting of,

[0222] Halogen-L is a halogen atom -(CH2) y1 -C(=O)- or halogen atom -(CH2) y1 -C(=O)-NH-, y1 represents an integer of 0 to 10. x1 may be an integer of 0 to 10, an integer of 1 to 6, or an integer of 2 to 4. y1 may be an integer of 0 to 10, an integer of 1 to 6, or an integer of 1 to 3. 10 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 14 The aryl group includes phenyl, naphthyl, anthracenyl, phenanthryl and the like.

[0223] As more specific examples of amino acid residues having an organic group having a halogen atom on the side chain, amino acid residues derived from 2-amino-3-[(2-haloacetyl)amino]propionic acid, 2-amino-4-[(2-haloacetyl)amino]butyric acid, N-δ-haloacetyl ornithine, N-ε-haloacetyl lysine and N-ζ-haloacetyl homolysine, etc., can be cited, but are not limited thereto. As the halogen atom in these amino acid residues, fluorine atom, chlorine atom, bromine atom, iodine atom, etc. can be cited, among which chlorine atom and bromine atom are preferred, and chlorine atom is more preferred.

[0224] In an exemplary embodiment, the amino acid residue X after the thioether bond is formed a and amino acid residue X b In the above, the amino acid residue on the sulfur atom side that does not contribute to the thioether bond is an amino acid residue represented by the following (p) or (q).

[0225] [Chemical formula number 6]

[0226]

[0227] In formula (p) and formula (q), * is the bonding position with the adjacent amino acid residue, ** is the bonding position with the sulfur atom of the coordinating amino acid residue of the thioether bond, x1 is an integer greater than 0, and the x1 carbon atom and the carbon atom at the β position may also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 The aryl group is substituted with one or more substituents from the group consisting of,

[0228] **-L is **-(CH2) y1 -C(=O)- or **-(CH2) y1 -C(=O)-NH-, y1 represents an integer of 0 to 10. x1 may be an integer of 0 to 10, an integer of 1 to 6, or an integer of 2 to 4. y1 may be an integer of 0 to 10, an integer of 1 to 6, or an integer of 1 to 3.

[0229] As C1-C 10 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 14 The aryl group includes phenyl, naphthyl, anthracenyl, phenanthryl and the like.

[0230] More specific examples of the amino acid residue that does not donate a sulfur atom to the thioether bond include an amino acid residue in which one of the hydrogen atoms of the CH3 portion of the acetyl group of an amino acid residue derived from 2-amino-3-[acetylamino]propionic acid, 2-amino-4-[acetylamino]butyric acid, N-δ-acetylornithine, N-ε-acetylysine, or N-ζ-acetylhomolysine is substituted with a bond to a coordinating amino acid residue of the thioether bond.

[0231] In an exemplary embodiment, the amino acid residue X after the thioether bond is formed a and amino acid residue X b In the formula (a), the amino acid residue that contributes to the sulfur atom of the thioether bond is an amino acid residue represented by the following (t) or (u).

[0232] [Chemical formula number 7]

[0233]

[0234] Wherein, in formula (t) and formula (u), * is the bonding position with the adjacent amino acid residue, *** is the bonding position with the carbon atom of the coordinating amino acid residue of the thioether bond, x2 is an integer greater than 0, and the x2 carbon atoms and the carbon atom at the β position may also be selected from -NH2, -SH, -COOH, C1-C 10 Alkyl and C6-C 14 The aryl group is substituted with one or more substituents from the group consisting of,

[0235] Wherein, when the above amino acid residue X a and the above amino acid residue X b When one of the above amino acid residues is an amino acid residue in which x1 is 0 in (p) or (q), the above amino acid residue X a and the above amino acid residue X b The other of x2 is not an L-cysteine ​​residue or a D-cysteine ​​residue. x2 may be an integer of 0-10, an integer of 0-6, or an integer of 1-4.

[0236] As C1-C 10 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 14 The aryl group includes phenyl, naphthyl, anthracenyl, phenanthryl and the like.

[0237] More specific examples of the amino acid residue donating a sulfur atom to the thioether bond include a cysteine ​​residue, a penicillamine residue, a homocysteine ​​residue (a residue derived from 2-amino-4-mercaptobutyric acid), or an amino acid residue in which the hydrogen atom of the thiol group in a residue derived from 2-amino-5-mercaptopentanoic acid is substituted by a bond with a coordinating amino acid residue to the thioether bond.

[0238] Preferably, the amino acid residue X a and amino acid residue X b One of them is an amino acid residue (p) or (q), and the amino acid residue X a and amino acid residue X b The other is a residue of (t) or (u), wherein when the amino acid residue X a and amino acid residue X b When one of the two is an amino acid residue in (p) or (q) where x1 is 0, the amino acid residue X a and amino acid residue X b The other one of the amino acids is not an L-cysteine ​​residue or a D-cysteine ​​residue.

[0239] The amino acid residue that does not donate a sulfur atom to the thioether bond, such as the amino acid residue (p) or (q), may be present at the N-terminus of the cyclic segment, that is, the amino acid residue Xa, or may be present at the C-terminus of the cyclic segment, that is, the amino acid residue Xb. Correspondingly, the amino acid residue that donates a sulfur atom to the thioether bond, such as the amino acid residue (t) or (u), may be present at the C-terminus of the cyclic segment, that is, the amino acid residue Xb, or may be present at the N-terminus of the cyclic segment, that is, the amino acid residue Xa.

[0240] The amino acid residue of (p) or (q) may be a residue selected from the following (a) to (h).

[0241] [Chemical formula number 8]

[0242]

[0243] In the formula, * is the bonding position to the adjacent amino acid residue, and ** is the bonding position to the sulfur atom of the coordinating amino acid residue of the thioether bond.

[0244] The amino acid residue of (t) or (u) may be selected from the group consisting of L-homocysteine ​​residue, D-homocysteine ​​residue, L-penicillamine residue, D-penicillamine residue, L-cysteine ​​residue and D-cysteine ​​residue.

[0245] In the present invention, it was found that even when an integrin-binding cyclic peptide is prepared by cross-linking amino acid residues with a thioether bond that can provide a higher bonding stability than a disulfide bond, the molecular stability of the cyclic peptide varies depending on the structure around the thioether bond. In the present invention, it was found that when the amino acid residue X a and amino acid residue X b When one of the amino acid residues is a cysteine ​​residue, by designing the amino acid residue X a and amino acid residue X bThe α carbon of another amino acid residue in the peptide is separated from the sulfur atom of the cysteine ​​residue by 5 or more atoms, which can obtain better molecular stability. The reason for obtaining better molecular stability is not clear, but it is speculated that by extending the carbon chain length from the cross-linking part to the cyclic peptide main chain, the electronic configuration of the thioether bond is stabilized, resulting in higher bonding stability.

[0246] Thus, for example, from amino acid residue X a and amino acid residue X b Among the possible combinations, the combination of the amino acid residue of (a) or (b) and the L-cysteine ​​residue or the D-cysteine ​​residue is removed.

[0247] The state where the amino acid residue in (a) above is bonded to the L-cysteine ​​residue is as follows.

[0248] [Chemical formula number 9]

[0249]

[0250] Wherein, * is the bonding position with the adjacent amino acid residue. When the amino acid residue of (a) is bonded to an L-cysteine ​​residue, the α carbon and the sulfur atom of the cysteine ​​residue are separated by 4 atoms, namely, 1 nitrogen atom and 3 carbon atoms. Thus, the number of atoms separating the α carbon of the coordinating amino acid residue of the thioether bond from the sulfur atom of the cysteine ​​residue refers to the number of atoms on the chain connecting the α atom and the sulfur atom, and atoms not participating in the above chain, such as hydrogen atoms bonded to atoms on the chain, are not counted.

[0251] Amino acid residue X a and amino acid residue X b In the embodiment, the amino acid residue that provides the sulfur atom of the thioether bond may be an amino acid residue having 1 to 10 carbon atoms in the side chain having the sulfur atom (including the total number of carbon atoms in the branched portion when there is a branch). a and amino acid residue X b In the amino acid residue on one side of the sulfur atom donating the thioether bond, it is preferred that the number of carbon atoms on the side chain having the sulfur atom (including the total number of carbon atoms in the branch portion when there is a branch) is 2 to 10. The number of carbon atoms on the side chain of the amino acid residue of the sulfur atom donating the thioether bond may be 2 to 6, or 2 to 3. From this viewpoint, the amino acid residue of the sulfur atom donating the thioether bond may be, for example, penicillamine (the number of carbon atoms on the side chain is 3), homocysteine ​​(the number of carbon atoms on the side chain is 2), etc. In addition, the number of carbon atoms on the side chain of the cysteine ​​residue is 1. The counting of the number of carbon atoms on the side chain in the case of penicillamine is as follows. In addition, in the following structural formula, * represents the bonding position to the adjacent amino acid residue.

[0252] [Chemical formula number 10]

[0253]

[0254] Amino acid residue X a and amino acid residue X b In the embodiment, the amino acid residue that provides the sulfur atom of the thioether bond may be an amino acid residue in which the sulfur atom on the main chain and the side chain is separated by 1 to 10 carbon atoms. a and amino acid residue X b In the amino acid residue on one side of the sulfur atom supplying the thioether bond, it is preferably an amino acid residue in which the sulfur atoms on the main chain and the side chain are separated by 2 to 10 carbon atoms. That is, in the case of an amino acid residue derived from an α amino acid, it is preferred that the α carbon and the sulfur atom are separated by 2 to 10 carbon atoms. The sulfur atoms on the main chain and the side chain may be separated by 2 to 6 carbon atoms, or may be separated by 2 to 4 carbon atoms. Among them, "it may also be an amino acid residue in which the sulfur atoms on the main chain and the side chain are separated by X carbon atoms" refers to an amino acid residue in which the carbon atom on the main chain of the cyclic peptide as the starting point of the side chain and the sulfur atom on the side chain are connected by a chain consisting of X carbon atoms, and the number of carbon atoms in the branch part branching from the chain is not counted. In addition, in the case where there are multiple paths connecting the carbon atom on the main chain of the cyclic peptide as the starting point of the side chain and the chain of the sulfur atom on the side chain, the number of carbon atoms in the shortest chain is counted.

[0255] For example, the α carbon and sulfur atom of the penicillamine residue are separated by one carbon atom. This is because, in the penicillamine residue, as shown in the following structural formula, the α carbon and sulfur atom are linked by -C(CH3)2-, but the carbon atoms of the two methyl groups not included in the chain connecting the α carbon and sulfur atom are not counted. Similarly, in the cysteine ​​residue, the α carbon and sulfur atom are separated by one carbon atom. In the homocysteine ​​residue, the α carbon and sulfur atom are separated by two carbon atoms.

[0256] In addition, cysteine ​​and penicillamine have a stronger tendency to racemize than other sulfur-containing amino acids such as homocysteine. Therefore, when an amino acid that satisfies the above-mentioned requirements for the number of carbon atoms, such as a homocysteine ​​residue, is used, it is advantageous in terms of controlling the stereostructure compared to when cysteine, penicillamine, etc. is used, and the proportion of stereoisomers with low or no integrin binding properties can be reduced, so there is a tendency to be able to increase the integrin binding property per unit amount.

[0257] In the following structural formulae, * indicates a bonding position to an adjacent amino acid residue.

[0258] [Chemical formula number 11]

[0259]

[0260] Even when the amino acid residue donating the sulfur atom of the thioether bond is not a cysteine ​​residue, the amino acid residue X is preferably a and amino acid residue X b The α-carbon of the amino acid residue that does not donate the sulfur atom for the thioether bond and the sulfur atom of the amino acid residue that donates the sulfur atom for the thioether bond are separated by 5 or more atoms. For example, regardless of whether the amino acid residue that donates the sulfur atom for the thioether bond is a cysteine ​​residue, the α-carbon of the amino acid residue that does not donate the sulfur atom for the thioether bond and the sulfur atom of the amino acid residue that donates the sulfur atom for the thioether bond may be separated by 5 to 9 atoms or 5 to 7 atoms.

[0261] In the case of forming a thioether bond by reacting the thiol group with the organic group with the halogen between the amino acid residue having a thiol group on the side chain and the amino acid residue having an organic group with a halogen on the side chain, the thioether bond can be formed by reacting the linear peptide before cyclization in a neutral or alkaline buffer. For example, an aqueous solution containing the linear peptide is slowly added dropwise to a Tris-HCl (pH 8.5) buffer and allowed to stand. Since the reactivity of the thioether bond formation reaction is high, the reaction is rapidly carried out at room temperature even without special heating. In the cyclization reaction, depending on the reaction conditions, in addition to the cyclic peptide, a plurality of non-cyclic peptides are sometimes formed, in which oligomers are linked by intermolecular bonding. Therefore, in order to obtain only the cyclic peptide, it is preferred to purify the peptide after the cyclization reaction by reversed-phase high performance liquid chromatography or the like.

[0262] The cyclic peptide involved in the present invention may include at least one of the N-terminal region (the first segment) of the cyclic peptide and the C-terminal region (the second segment) of the cyclic peptide, and at least one of the first segment and the second segment may also have a structure containing an amino acid residue having an immobilized functional group on the side chain. The immobilized functional group may also be an amino group or a thiol group. The amino acid residue having an immobilized functional group on the side chain may also be selected from the group consisting of L-lysine residues, D-lysine residues, L-cysteine ​​residues, D-cysteine ​​residues, L-homocysteine ​​residues and D-homocysteine ​​residues. The details of the amino acid residue having an immobilized functional group on the side chain can refer to X in the above formula II. 6 or X 7 Description of the amino acid residues represented.

[0263] In the present invention, at least one of the N-terminal region of the cyclic peptide and the C-terminal region of the cyclic peptide may also contain a lysine residue as an amino acid residue having an immobilized functional group on the side chain. More specifically, at least one of the N-terminal region of the cyclic peptide and the C-terminal region of the cyclic peptide may contain one lysine residue as an amino acid residue having an immobilized functional group on the side chain, or may contain two or more lysine residues in succession, may contain 2 to 10 in succession, or may contain 2 to 5 in succession.

[0264] The amino acid residue having the above-mentioned immobilized functional group is preferably present in at least one of the N-terminus of the first segment and the C-terminus of the second segment of the cyclic peptide involved in the present invention. For example, the amino acid residue having the immobilized functional group may also be present continuously in at least one of the N-terminus of the first segment and the C-terminus of the second segment of the cyclic peptide involved in the present invention, and the number of continuous amino acid residues having the immobilized functional group may be, for example, 2 to 10 residues, or 2 to 5 residues. More specifically, the lysine residue may also be present continuously in at least one of the N-terminus of the first segment and the C-terminus of the second segment of the cyclic peptide involved in the present invention, and the number of continuous lysine residues may be, for example, 2 to 10 residues, or 2 to 5 residues. In this case, the first segment or the second segment may be composed only of continuous lysine residues, or may contain other amino acid residues at will. For example, in the first segment or the second segment, there may be no other amino acid residues in the region between the continuous lysine residues and the cyclic segment, or the region between the continuous lysine residues and the cyclic segment may be composed of 1 to 20, 1 to 10, 1 to 5, or 1 to 3 amino acid residues selected from alanine residues, β-alanine residues, glutamic acid residues, aspartic acid residues, and glycine residues. Alternatively, a lysine residue may be further sandwiched between the amino acid residue selected from the alanine residues, β-alanine residues, glutamic acid residues, aspartic acid residues, and glycine residues and the cyclic segment.

[0265] The first segment may be composed of 1 to 20, 1 to 10, 1 to 5, or 1 to 3 arbitrary amino acid residues. The first segment may contain or not contain lysine residues. In the case of not containing lysine residues, it may also be composed of at least one amino acid residue selected from 1 to 20, 1 to 10, 1 to 5, or 1 to 3 alanine residues, β-alanine residues, glutamic acid residues, aspartic acid residues and glycine residues. Similarly, the second segment may be composed of 1 to 20, 1 to 10, 1 to 5, or 1 to 3 arbitrary amino acid residues. The second segment may contain or not contain lysine residues. In the case of not containing lysine residues, it may also be composed of at least one amino acid residue selected from 1 to 20, 1 to 10, 1 to 5, or 1 to 3 alanine residues, β-alanine residues, glutamic acid residues, aspartic acid residues and glycine residues.

[0266] Regarding the cyclic peptide involved in the present invention, the dissociation constant (dissociation constant for bonding to integrin) measured by the method described in "(2) Immobilization of cyclic peptide" and "(3) Evaluation of integrin binding" in the Examples is preferably 200 nM or less, more preferably 100 nM or less, and further preferably 50 nM or less. The closer the dissociation constant is to 0 nM, the more preferred it is. From a practical point of view, as a lower limit value that can be combined with the above upper limit value, for example, 0.1 nM or 0.5 nM can be cited. Furthermore, regarding the cyclic peptide involved in the present invention, the residual rate measured by the method described in "(4) Evaluation of molecular stability" in the Examples is preferably 30% or more, more preferably 50% or more, and further preferably 70% or more. The closer the residual rate is to 100%, the more preferred it is, and therefore, as an upper limit value that can be combined with the above lower limit value, 100% can be cited.

[0267] The integrin in the present invention is not particularly limited as long as it is an integrin that recognizes the RGD sequence. In the examples, integrin αvβ5 was used to evaluate the integrin binding property, but the integrin is not limited thereto, and the cyclic peptide involved in the present invention can also bind to integrins that recognize the RGD sequence such as integrin αVβ3.

[0268] Furthermore, in the present invention, the molecular stability of the cyclic peptide is measured using alkali resistance as an index, but the molecular stability of the cyclic peptide is also exerted in the same manner in terms of resistance to stimulations other than alkali, such as X-ray resistance, gamma-ray resistance, ultraviolet resistance, heat resistance, and chemical resistance. This is because molecular stability basically means that the molecule is more stable in terms of free energy. For example, due to excellent alkali resistance, when the cyclic peptide involved in the present invention is used as an affinity ligand for affinity chromatography in cell purification, even if it is repeatedly washed with alkali, the integrin binding property is maintained, and the cell separation cost can be reduced.

[0269] Examples of cyclic peptides involved in the present invention are described in the following Tables 3 to 7. Cyclic peptides 1 to 165 described in Tables 3 to 7 are all amino acid residues that do not have L-amino acid residues or optical isomers such as glycine. In the table, Hcy represents a homocysteine ​​residue, and Pen represents a penicillamine residue. Dab (acetyl) represents a 2-amino-4-acetylamino-butyric acid residue, Dap (acetyl) represents a 2-amino-3-acetylamino-propionic acid residue, Orn (acetyl) represents an N-δ-acetyl-ornithine residue, and Lys (acetyl) represents an N-ε-acetyl-lysine residue. One of the hydrogen atoms on the methyl group in the acetyl group in the amino acid residues containing these acetyl groups is replaced by a bond with a sulfur atom in the amino acid residue that is the bonding object of the thioether bond, forming an intramolecular crosslink based on the thioether bond. In addition, in the column of the amino acid residue in the crosslinking portion, the acetyl group is omitted. Although not listed in the table, cyclic peptides 49 to 53 have C-terminal amidated structures formed by amide bonding of C-terminal carboxylic acid and NH2. In addition, βA in cyclic peptide 51 represents a β-alanine residue, HmY in cyclic peptide 68 represents a homotyrosine residue, and HmS in cyclic peptide 73 represents a homoserine residue. In Tables 3 to 7, the amino acid residues listed in parentheses represent amino acid residues related to intramolecular cross-linking based on thioether bonds.

[0270] [Table 3]

[0271]

[0272] [Table 4]

[0273]

[0274] [Table 5]

[0275]

[0276] [Table 6]

[0277]

[0278] [Table 7]

[0279]

[0280] Among these cyclic peptides, cyclic peptides 1 to 137 and cyclic peptides 144 to 165 are preferred from the viewpoint of molecular stability. Furthermore, from the viewpoint of the balance between molecular stability and integrin binding, cyclic peptides 1 to 127 and cyclic peptides 144 to 165 are more preferred. Cyclic peptides 1, 92, 108 and 160 are further preferred, and cyclic peptides 92, 108 and 160 are still more preferred. When the above-mentioned provisions on added, deleted or substituted amino acid residues or the above-mentioned provisions on sequence homology are applied, it is also preferred that the region between the amino acids in the cross-linked portion of the cyclic segment in the above-mentioned preferred cyclic peptides be applied to the reference sequence.

[0281] In addition, the sequence changes can also be applied by considering the cyclic peptide as a whole as a reference sequence. Therefore, an amino acid sequence in which amino acid residues are added, deleted or substituted to any of the amino acid sequences in sequence numbers 2 to 166 as long as the necessary conditions of the cyclic peptide involved in the present invention are met can also be used. Among them, the RGD region in the cyclic segment must not be changed. In the case of addition, deletion or substitution of amino acid residues to any of the amino acid sequences in sequence numbers 2 to 166, the total number of added, deleted or substituted amino acid residues is preferably 1 to 15, more preferably 1 to 10, further preferably 1 to 5, further preferably 1 to 3, and further preferably 1 or 2.

[0282] The cyclic peptide involved in the present invention preferably has a sequence identity of 70% or more with any one of the amino acid sequences of SEQ ID NOs: 2 to 166, more preferably has a sequence identity of 80% or more, and even more preferably has a sequence identity of 90% or more. In addition, for example, the range of amino acid sequences having a sequence identity of 70% or more with the amino acid sequence of SEQ ID NO: 2 also includes the amino acid sequence of SEQ ID NO: 2 itself.

[0283] The present invention also provides a substrate and a cell scaffold material (hereinafter, also referred to as the cell scaffold material involved in the present invention) comprising the cyclic peptide involved in the present invention. Since cells are supported by extracellular matrix in vivo, cells can be cultured better by using a cell scaffold material that reproduces the same state. As the above-mentioned substrate for cell culture, a matrix composed of polysaccharides such as polylactic acid, polyglycolic acid, polycaprolactone, gelatin, fibronectin, collagen or its thermally denatured body, or hyaluronic acid, chitin, alginic acid, etc. can be cited. For example, by reacting the immobilization functional group in the cyclic peptide involved in the present invention with the functional group in the substrate, the cyclic peptide involved in the present invention can be bonded to the substrate. For example, in the case where the cyclic peptide involved in the present invention has an amino group of a lysine residue as an immobilization functional group, by reacting the amino group with the carboxyl group on the substrate to form an amide bond, the cyclic peptide can be fixed on the substrate. By using this method, a cell scaffold material formed by the surface bonding of the cyclic peptide involved in the present invention and the substrate can be obtained. The amount of the cyclic peptide involved in the present invention is not particularly limited, and may be 0.01% by mass to 100% by mass, or 0.1% by mass to 50% by mass, relative to the substrate.

[0284] The cell scaffold material involved in the present invention can be imparted to any culture tool such as a culture dish, a flask, a plate (for example, a polystyrene well plate), a culture bag, a hollow fiber membrane, a bead, etc. Since the cell scaffold material involved in the present invention contains the cyclic peptide involved in the present invention, it has good bonding with integrin, and the cell can adhere well to the cell scaffold material. Among them, as the cell to be cultured, as long as it is a cell of a biological organism that expresses integrin, it is not particularly limited, and can be any animal cell, any vertebrate cell, any mammalian cell, or a human cell or a mammalian cell other than a human. As examples of cells, embryonic stem (ES) cells, artificial pluripotent stem (iPS) cells, perinatal stem cells, stem cells derived from amniotic fluid (AFSC), mesenchymal stem cells (MSC) of any origin, precursor cells or adult cells with a determined differentiation direction of any tissue type, mature cells, normal cells, diseased cells, tumor cells, etc. can be cited. More specific examples include liver cells, parenchymal cells, astrocytes, endothelial cells, hepatocytes, bile duct cells, biliary tree cells, pancreatic cells, etc. Examples of these cells are the same as those of the cell separation material and culture medium described below.

[0285] The present invention also provides a holding material and a cell separation material comprising the cyclic peptide of the present invention (hereinafter, also referred to as the cell separation material of the present invention). Since the cell separation material of the present invention comprises the cyclic peptide of the present invention, it can bind to the integrin on the cell surface and capture the cell. Therefore, by using the cell separation material of the present invention as, for example, affinity chromatography, cells can be effectively separated from a cell suspension.

[0286] For example, the cyclic peptide involved in the present invention can be bonded to the holding material by reacting the immobilization functional group in the cyclic peptide involved in the present invention with the functional group in the holding material. For example, when the cyclic peptide involved in the present invention has an amino group of a lysine residue as the immobilization functional group, the cyclic peptide can be fixed to the holding material by reacting the amino group with the carboxyl group on the holding material to form an amide bond.

[0287] The retaining material can be composed of, for example, a material selected from polysaccharides such as agarose, dextran, starch, cellulose, pullulan, chitin, chitosan, cellulose triacetate and cellulose diacetate and their derivatives, and ethylene polymers such as polyacrylamide, polymethacrylamide, polyacrylate, polymethacrylate, polyalkyl vinyl ether and polyvinyl alcohol. These materials can also form a cross-linked structure. The cross-linked structure has a tendency to improve mechanical strength. The retaining material is preferably composed of one or more of the above materials.

[0288] Furthermore, the holding material is preferably porous, more preferably a porous film or porous particles, and even more preferably porous particles.

[0289] It is also possible to fix the cell separation material of the cyclic peptide involved in the present invention on a water-insoluble retaining material for affinity chromatography. As a water-insoluble retaining material, for example, polysaccharides such as crystalline cellulose, cross-linked cellulose, cross-linked agarose, cross-linked dextran and cross-linked pullulan, organic retaining materials such as acrylate polymers and styrene polymers, inorganic retaining materials such as glass beads and silica gel, and organic-organic, organic-inorganic composite retaining materials obtained by their combination, etc. As a water-insoluble retaining material, from the viewpoint of alkali resistance, polysaccharides or acrylate polymers are more preferably used, and polysaccharides such as agarose or cellulose are further preferably used. Examples of commercially available products that can be used as water-insoluble holding materials include Cellufine GCL2000 (manufactured by JNC Corporation) (CELLUFINE is a registered trademark) and Cellufine MAX (manufactured by JNC Corporation) as porous cellulose gels, Sephacryl S-1000SF (manufactured by GE Healthcare) (SEPHACRYL is a registered trademark) in which allyl dextran and methylenebisacrylamide are cross-linked by covalent bonds, TOYOPEARL (manufactured by Tosoh Corporation) (TOYOPEARL is a registered trademark), TOYOPEARL AF-Carboxy-650 (manufactured by Tosoh Corporation), and TOYOPEARL GigaCap CM-650 (manufactured by Tosoh Corporation) as acrylate-based holding materials, Sepharose CL4B (manufactured by GE Healthcare) (SEPHAROSE is a registered trademark) as an agarose-based cross-linked holding material, and Eupergit C250L (Sigma-Aldrich) as polymethacrylamide activated with an epoxy group. Co.LLC) (EUPERGIT is a registered trademark), etc. Among them, the water-insoluble retaining material in the present invention is not limited to these retaining materials or activated retaining materials. Moreover, the water-insoluble retaining material used in the present invention preferably has a large surface area, and is preferably porous with a plurality of pores of appropriate sizes, from the perspective of the purpose and method of use of the adsorption material. There is no particular limitation on the form of the retaining material, and it can be any shape such as beads, fibers, membranes, and hollow fibers, and any form can be selected.

[0290] As a method for fixing the cyclic peptide involved in the present invention on a water-insoluble retaining material, as described above, an immobilization method using the amino group of a lysine residue can be cited, but it is not limited to this. Generally, the method used when fixing a protein or polypeptide on a retaining material can be adopted. For example, the retaining material can be activated by reacting with cyanogen bromide, epichlorohydrin, diglycidyl ether, toluenesulfonyl chloride, trifluoroethanesulfonyl chloride and hydrazine, or a reactive functional group can be introduced into the surface of the retaining material, and the cyclic peptide involved in the present invention is reacted and fixed, and a condensing agent such as carbodiimide or a reagent having multiple functional groups in the molecule such as glyceraldehyde is added to the system where the retaining material and the cyclic peptide involved in the present invention are present to perform condensation and cross-linking immobilization.

[0291] When the cyclic peptide involved in the present invention is fixed on the holding material, it is preferred to dissolve (disperse) the cyclic peptide involved in the present invention in an aqueous solvent (aqueous dispersion medium) or an organic solvent (organic dispersion medium). The aqueous solvent (aqueous dispersion medium) is not particularly limited, and examples thereof include HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; hydroxyethylpiperazineethanesulfonic acid) buffer, acetic acid buffer, phosphate buffer, citrate buffer, tris-hydrochloric acid buffer, and the like. The organic solvent (organic dispersion medium) is not particularly limited, but is preferably a polar organic solvent, particularly preferably DMSO (dimethyl sulfoxide), DMF (N,N-dimethylformamide) or an alcohol, for example, methanol, ethanol, IPA (isopropylalcohol), TFE (2,2,2-trifluoroethanol) and HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) and the like.

[0292] The pH conditions when the cyclic peptide according to the present invention is immobilized are not particularly limited, and may be any of acidic, neutral, and alkaline, and can be appropriately set, for example, depending on the solvent (dispersion medium) used.

[0293] For example, in the case of making the solution alkaline, a base such as DBU (diazabicycloundecene) or TEA (triethylamine) may be added to DMSO (dimethyl sulfoxide) or alcohol.

[0294] The density of the cyclic peptide involved in the present invention when the above-mentioned cell separation material is used as a filler for affinity chromatography is not particularly limited, but is preferably 0.1 to 1000 mmol / filler 1 L, more preferably 0.1 to 100 mmol / filler 1 L, and further preferably 0.5 to 20 mmol / filler 1 L. Within this range, the balance between the amount of the cyclic peptide involved in the present invention and the cell separation performance is good, and cells can be separated efficiently at a lower cost.

[0295] The cells separated by the cell separation material of the present invention are not particularly limited as long as they are biological cells expressing integrins, and may be any animal cells, any vertebrate cells, any mammalian cells, human cells, or non-human mammalian cells.

[0296] The present invention also provides a culture component and a culture medium containing the cyclic peptide involved in the present invention (hereinafter, also referred to as the culture medium involved in the present invention). By containing the cyclic peptide involved in the present invention in the culture medium, the integrin of the cells cultured in the culture medium and the cyclic peptide are bonded, and by transmitting the signal from the integrin, the effect of increasing the cell survival rate through apoptosis inhibition can be obtained. The culture component refers to the culture medium component used to culture cells. Among them, the cells to be cultured are not particularly limited as long as they are cells of organisms that express integrins, and can be any animal cells, any vertebrate cells, any mammalian cells, human cells, or mammalian cells other than humans. The culture medium used as the culture component can be selected appropriately according to the type of cells to be cultured, and examples thereof include DMEM (Dulbecco's modified Eagle's medium), MEM (Eagle's minimum essential medium), F12, Ham, RPMI1640, MCDB (MCDB102, 104, 107, 131, 153, 199, etc.), L15, SkBM (registered trademark), RITC80-7, MesenPro (Life Technologies Corporation), etc.

[0297] As culture components, culture media such as the above-mentioned culture media can be used directly with standard compositions (e.g., in a commercially available state), or their compositions can be appropriately changed according to cell types or cell conditions. Therefore, culture components are not limited to components of known compositions, and can also be components of adding, removing, increasing or decreasing one or more components.

[0298] The amino acids contained in the culture components are not particularly limited, and examples thereof include L-arginine, L-cystine, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.

[0299] The vitamins contained in the culture components are not particularly limited, and examples thereof include calcium D-pantothenate, choline chloride, folic acid, i-inositol, nicotinamide, riboflavin, thiamine, pyridoxine, biotin, lipoic acid, vitamin B12, adenine, and thymidine.

[0300] The electrolyte contained in the culture component is not particularly limited, and examples thereof include CaCl2, KCl, MgSO4, NaCl, NaH2PO4, NaHCO3, Fe(NO3)3, FeSO4, CuSO4, MnSO4, Na2SiO3, (NH4)6Mo7O 24 , NaVO3, NiCl2, ZnSO4, etc.

[0301] The culture components may contain, in addition to these components, sugars such as D-glucose, sodium pyruvate, pH indicators such as phenol red, putrescine, antibiotics, and the like.

[0302] The culture components may or may not contain serum. The content of serum in the culture medium of the present invention is preferably 0% by volume or more and 30% by volume or less, more preferably 0% by volume or more and 10% by volume or less, further preferably 0% by volume or more and 5% by volume or less, and particularly preferably 0% by volume or more and 2% by volume or less.

[0303] The content of the cyclic peptide in the medium of the present invention is not particularly limited, and is, for example, 0.01 ng / mL to 10 mg / mL, or 0.1 ng / mL to 1 mg / mL. In the medium of the present invention, unlike cell scaffold materials and cell separation materials, it is not necessary to immobilize the cyclic peptide.

[0304] As described above, according to the present invention, it is possible to provide a cyclic peptide having excellent bonding properties with integrins and excellent molecular stability, for example, alkali resistance, and a cell scaffold material, a cell separation material, and a culture medium containing the cyclic peptide.

[0305] Example

[0306] The embodiments of the present invention are described in more detail with reference to the following examples, but the embodiments are not limited thereto.

[0307] (1) Synthesis of cyclic peptides

[0308] Cyclic peptides 1 to 146 described in Tables 3 to 7 and cyclic peptides 147 and 148 described in Table 8 below were synthesized using a fully automatic peptide synthesizer (PSSM-8, manufactured by Shimadzu Corporation). In addition, when optical isomers exist for the amino acid residues contained in the cyclic peptides prepared in the examples, the amino acid residues are all L-isomers. That is, for example, the D mark in the peptides prepared in the examples represents an L-aspartic acid residue. In Table 8, the amino acid residues recorded in brackets represent amino acid residues related to intramolecular crosslinking based on thioether bonds.

[0309] [Table 8]

[0310]

[0311] (2) Immobilization of cyclic peptides

[0312] A commercially available CM5 (carboxymethyl dextran-introduced type, manufactured by GE Healthcare) sensor chip was installed in a surface plasmon resonance device, i.e., Biacore 3000 manufactured by GE Healthcare, and SPR (surface plasmon resonance) was stabilized at a flow rate of 10 μL / min using a HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer (20 mM HEPES-HCl, 150 mM NaCl, pH 7.4), and 70 μL of a mixed aqueous solution of 0.2 M EDC (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide) and 0.04 M NHS (N-Hydroxysuccinimide) was added. The unit M of concentration represents mol / L, and the same shall apply hereinafter. Then, 20 μL of the sample solution of each of the above cyclic peptides diluted to 0.2 g / L with HEPES buffer was supplied to the sensor chip, and then, a blocking treatment was performed with an ethanolamine solution, and the solution was washed with a sodium hydroxide aqueous solution for fixation. Among them, only for cyclic peptides 125, 126 and 127 having 0 lysine residues as an amino group serving as an immobilized functional group, the amount of sample solution supplied to the sensor chip was set to 500 μL instead of 20 μL. Moreover, the sample was not fixed in other flow paths of the sensor chip, and after adding 70 μL of a mixed aqueous solution of 0.2 M EDC and 0.04 M NHS, a blocking treatment and a washing treatment were performed. The obtained immobilized sensor chip is hereinafter referred to as "immobilized sensor chip A".

[0313] (3) Evaluation of integrin binding properties

[0314] In each channel of the immobilized sensor chip A prepared in (2) above, human integrin αvβ5 diluted to 30 nM using hydroxyethylpiperazine ethanesulfonic acid (HEPES) buffer to which magnesium chloride was added to reach 5 mM was added at 25° C. for 10 minutes, and then the hydroxyethylpiperazine ethanesulfonic acid buffer (containing 5 mM magnesium chloride) was flowed as a running buffer for 30 minutes, and measurement was performed using Biacore 3000. Then, a regeneration treatment to remove human integrin αvβ5 was performed by flowing a 0.5 M EDTA aqueous solution in each channel for 10 minutes. Furthermore, a measurement treatment consisting of adding integrin for 10 minutes, flowing the running buffer for 30 minutes, measuring by Biacore 3000, and regeneration treatment with a 0.5 M EDTA aqueous solution was similarly performed for 100 nM human integrin αvβ5, 300 nM human integrin αvβ5, and 1000 nM human integrin αvβ5 was performed. The dissociation constant between the cyclic peptide and human integrin αvβ5 was calculated from the difference between the measured value based on Biacore3000 in the flow channel to which the cyclic peptide was immobilized and the measured value based on Biacore3000 in the flow channel to which the cyclic peptide was not immobilized when human integrin αvβ5 at various concentrations was allowed to flow, and the integrin binding property was evaluated according to the following evaluation criteria. Evaluation criteria A, B or C are preferred.

[0315] (Evaluation criteria for dissociation constant)

[0316] A... The dissociation constant is 50 nM or less.

[0317] B... The dissociation constant is more than 50 nM and less than 100 nM.

[0318] C... The dissociation constant is more than 100 nM and less than 200 nM.

[0319] D...dissociation constant exceeds 200nM.

[0320] The evaluation results are shown in the corresponding columns of Tables 9 to 13.

[0321] By using a cyclic peptide showing integrin-binding properties of grades A to C, specific binding of the cyclic peptide to integrin can be achieved, thereby enabling more effective cell control.

[0322] (4) Evaluation of molecular stability

[0323] The molecular stability of the cyclic peptide was evaluated by analyzing the alkali-treated aqueous cyclic peptide solution using LC / MS (Liquid Chromatography Mass Spectroscopy).

[0324] The alkali treatment is carried out by the following method. A 500 μM cyclopeptide aqueous solution is prepared, an equivalent 1M sodium hydroxide aqueous solution is added to the aqueous solution, and the solution is incubated at 15° C. for 3 hours to obtain an alkali-treated cyclopeptide aqueous solution. The total area of ​​all peaks in the LC / MS of the cyclopeptide before alkali treatment is set to 100%, and the cyclopeptide residual rate is calculated by finding the ratio of the total area of ​​all peaks in the LC / MS of the alkali-treated cyclopeptide aqueous solution, and the molecular stability is evaluated according to the following evaluation criteria. Preferably, the evaluation criteria A, B or C.

[0325] (Evaluation criteria for residual rate of cyclic peptide)

[0326] A……The residual rate of cyclic peptide is more than 70%

[0327] B……The residual rate of cyclic peptide is 50% or more and less than 70%

[0328] C……The residual rate of cyclic peptide is 30% or more and less than 50%

[0329] D……The residual rate of cyclic peptide is less than 30%

[0330] In addition, the LC / MS used for the evaluation of molecular stability was set to the following conditions.

[0331] LC equipment: Prominence series (pump, column oven, autosampler, detector) (manufactured by Shimadzu Corporation)

[0332] MS detector: LC / MS2010EV (manufactured by Shimadzu Corporation)

[0333] Column: Cadenza CD-C18, inner diameter 2.0 mm×length 250 mm, particle size 3 μm (manufactured by Intact Corporation)

[0334] ·Eluent A: A solution containing 10 mM ammonium formate as a solubilizer and 100% water as a solvent (pH 3)

[0335] ·Eluent B: Contains 10 mM ammonium formate as a solvent, and the solvent is acetonitrile / water = 90 / 10 solution (pH 3)

[0336] Flow rate: 0.2mL / min

[0337] Injection volume: 4μL

[0338] Gradient: 0-30%: eluent B (0-30 minutes), 100%: eluent B (30-40 minutes), 0%: eluent B (40-60 minutes)

[0339] Column temperature: 45°C

[0340] Ionization method: ESI (Electrospray Ionization) positive, ESI negative

[0341] The evaluation results are shown in the corresponding columns of Tables 9 to 13.

[0342] By using a cyclic peptide showing molecular stability of grades A to C, the cyclic peptide can specifically bind to cells even when used for a long period of time or repeatedly, and cells can be controlled even when used in a long period of time or repeatedly, which can further reduce costs.

[0343] The evaluation results of the integrin binding properties and molecular stability of cyclic peptides 1 to 167 are summarized in the following Tables 9 to 13. In addition, similarly to Tables 3 to 7, the description of acetyl groups is omitted in the column of amino acid residues in the cross-linking region.

[0344] [Table 9]

[0345]

[0346] [Table 10]

[0347]

[0348] [Table 11]

[0349]

[0350] [Table 12]

[0351]

[0352] [Table 13]

[0353]

[0354] As can be seen from the results of Tables 9 to 13, the cyclic peptides 1 to 165 of the present invention have practically sufficient integrin binding properties and practically sufficient molecular stability. The values ​​of the residual rates of the cyclic peptides 1 to 165 of the present invention in the evaluation of molecular stability are all higher than 35%. On the other hand, in cyclic peptides 166 and 167, in which the sulfur atom of the cysteine ​​residue is separated from the α-carbon of other amino acid residues by 4 or less atoms, practically sufficient molecular stability is not obtained. In particular, the values ​​of the residual rates of cyclic peptides 166 and 167 in the evaluation of molecular stability are all less than 25%.

[0355] Furthermore, cyclic peptides 1 to 137 and cyclic peptides 144 to 165, in which the amino acid residue having 2 to 10 carbon atoms on the side chain having a sulfur atom (including the total number of carbon atoms in the branch portion when there is a branch) is one amino acid residue cross-linked within the molecule, have improved molecular stability than cyclic peptides 138 to 143, in which the cysteine ​​residue having 1 carbon atom on the side chain having a sulfur atom is one amino acid residue cross-linked within the molecule. Furthermore, for example, as can be seen from the comparison between cyclic peptide 116 and cyclic peptide 131, cyclic peptides in which the amino acid residue separated by 2 to 10 carbon atoms between the carbon atom of the main chain and the sulfur atom on the side chain is one amino acid residue cross-linked within the molecule tend to show improved integrin binding properties compared to the case in which the amino acid residue such as the penicillamine residue separated by 1 carbon atom between the carbon atom of the main chain and the sulfur atom on the side chain is one amino acid residue cross-linked within the molecule.

[0356] Next, the obtained peptides were used to prepare cell scaffold materials and iPS cell culture experiments were performed.

[0357] (Surface treatment of polystyrene board)

[0358] A surface treatment of a polystyrene 6-well plate (manufactured by Corning Incorporated) was performed using a plasma treatment apparatus (SCB-106 manufactured by SAKIGAKE-Semiconductor Co., Ltd.) in an ammonia gas under the conditions of a gas pressure of 10 Pa, an output of 700 W, and a treatment time of 5 minutes.

[0359] (Production of CMD coating holes)

[0360] 9.5 g of distilled water was added to 0.5 g of sodium carboxymethyl dextran (produced by Meito Sangyo Co., Ltd., trade name: "CMD", molecular weight: 1 million, hereinafter referred to as "CMD"), and CMD was fully dissolved by stirring to prepare a 5 wt% CMD solution.

[0361] Next, 1 mL of distilled water was added to 383.4 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (manufactured by NACALAI TESQUE, INC., hereinafter referred to as "EDC") to prepare an EDC solution. Next, 1 mL of distilled water was added to 57.5 mg of N-hydroxysuccinimide (manufactured by FUJIFILM Wako Pure Chemical Corporation, hereinafter referred to as "NHS") to prepare an NHS solution.

[0362] Next, 0.05 mL of the EDC solution and 0.05 mL of the NHS solution were added to 10 g of the CMD solution prepared above and stirred, and 1 mL of the obtained CMD-containing coating liquid was immediately dripped into one hole of the polystyrene plate surface-treated above. After the polystyrene plate was left to stand at room temperature for 1 hour, the hole was fully washed with distilled water to remove the CMD-containing coating liquid, thereby obtaining a CMD-coated hole.

[0363] (Fabrication of Ligand-Coated Holes)

[0364] 1 mL of HBS-N buffer (manufactured by GE Yokogawa Medical Systems Ltd.) was added to 0.2 mg of cyclic peptide 92 to prepare a cyclic peptide solution. Next, 1 mL of distilled water was added to 76.7 mg of EDC to prepare an EDC solution. Next, 1 mL of distilled water was added to 11.5 mg of NHS to prepare an NHS solution. Next, 1 mL of distilled water was added to 1 mL of ethanolamine (manufactured by BIO RAD, trade name "ProteOn Ethanolamine HCL") to prepare an ethanolamine solution.

[0365] Next, add 0.5 mL of the above-mentioned NHS solution to 0.5 mL of the EDC solution prepared above and stir, and immediately drop 1 mL of the resulting mixed solution into the above-mentioned CMD-coated holes. After the polystyrene plate was allowed to stand for 7 minutes, the holes were thoroughly rinsed with distilled water, and the mixed solution was removed from the holes. Furthermore, 1 mL of the above-mentioned cyclopeptide solution was dropped into the holes, and after standing for 25 minutes, the holes were thoroughly rinsed with distilled water, and the cyclopeptide solution was removed. Furthermore, 1 mL of the ethanolamine solution was dropped into the holes, and after standing for 7 minutes, the holes were thoroughly rinsed with distilled water, and the ethanolamine solution was removed, thereby obtaining holes (hereinafter referred to as "ligand-coated holes") having a cell scaffold material having cyclopeptide 92 fixed on CMD as a substrate.

[0366] (γ-ray sterilization)

[0367] The ligand-coated holes prepared above were sealed in a sterilization bag and sterilized with gamma rays at a dose of 25 kGy using the irradiation facility No. 1 of RADIA INDUSTRY CO., LTD. Thus, a cell scaffold material irradiated with gamma rays (hereinafter referred to as "irradiated cell scaffold material A") was obtained.

[0368] (Evaluation of iPS cell culture performance of peptides)

[0369] iPS cells used the 01434 clone established by Fujifilm Cellular Dynamics, Inc. . iPS cells were seeded on a culture polystyrene plate with an irradiated cell scaffold material A on the surface at a split rate of 1:6, and cultured in a feeder-free ES and iPS cell culture medium (manufactured by Stem Cell Technologies, product name: mTeSR1) for 3 days, and then the iPS cells were detached and recovered by treatment with a cell dissociation reagent (manufactured by Thermo Fisher, product name TrypLE Select). From the obtained cell suspension, the number of cells was measured using an automatic life and death cell analyzer (manufactured by BECKMAN COULTER, product name: Vi-Cell XR) to determine whether the cells proliferated. The obtained results were evaluated according to the following criteria. The evaluation results are shown in Table 14. In addition, in Table 14, Hcy represents a homocysteine ​​residue, Dab (acetyl) represents a 2-amino-4-acetylamino-butyric acid residue, and Dap (acetyl) represents a 2-amino-3-acetylamino-propionic acid residue.

[0370] Evaluation criteria for iPS cell culture performance

[0371] A: The proliferation of iPS cells was confirmed.

[0372] B: No proliferation of iPS cells was observed.

[0373] [Table 14]

[0374]

[0375] From the results shown in Table 14, it can be seen that iPS cells proliferated when using a cell scaffold material containing cyclic peptide 92, which is equivalent to the cyclic peptide involved in the present invention, whereas iPS cells did not proliferate when using a cell scaffold material containing a cyclic peptide 167 (Comparative Example). This indicates that the cell scaffold material containing the cyclic peptide involved in the present invention has high stability to gamma rays, etc., compared to the cell scaffold material containing the cyclic peptide of the comparative example, and has good cell proliferation ability even when sterilized with gamma rays, etc.

[0376] The entire contents of the disclosure of Japanese Patent Application No. 2019-108962 filed on June 11, 2019 are incorporated into this specification by reference.

[0377] All documents, patent applications, and technical standards described in this specification are incorporated herein by reference to the same extent as if each individual document, patent application, or technical standard was specifically and individually indicated to be incorporated by reference. Sequence Listing <110> Fujifilm Corporation <120> Cyclic peptides, cell scaffold materials, cell separation materials and culture media <130> 19F00785W1 <140> PCT / JP2020 / 022558 <141> 2020-06-08 <150> JP2019-108962 <151> 2019-06-11 <160> 172 <170> PatentIn version 3.5 <210> 1 <211> 8 <212> PRT <213> Artificial <220> <223> Regions in the ring segments <400> 1 Ile Pro Arg Gly Asp Asn Phe Arg 1 5 <210> 2 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 1 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 2 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 15 <210> 3 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 2 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 3 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 15 <210> 4 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 3 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 4 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> 5 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 4 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 5 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa Gly 1 5 10 <210> 6 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 5 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 6 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa Asp 1 5 10 <210> 7 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 6 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(13) <223> Thioether bond between residues 5 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 7 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Asn Phe Xaa Ala 1 5 10 <210> 8 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 7 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 8 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa 1 5 10 <210> 9 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 8 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(13) <223> Thioether bond between residues 5 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 9 Lys Lys Lys Gly Xaa Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> 10 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 9 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 10 Lys Lys Lys Xaa Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> 11 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 10 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 11 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Xaa Ala 1 5 10 <210> 12 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 11 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 12 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa 1 5 10 <210> 13 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 12 <220> <221> misc_feature <222> (4) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> Homocysteine <400> 13 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Xaa 1 5 10 <210> 14 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 13 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 14 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Xaa 1 5 10 <210> 15 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 14 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 15 Lys Lys Lys Xaa Val Pro Arg Gly Asp Asn Phe Xaa 1 5 10 <210> 16 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 15 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(14) <223> Thioether bond between residues 4 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 16 Lys Lys Lys Xaa Ala Ile Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 15 <210> 17 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 16 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(14) <223> Thioether bond between residues 4 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 17 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Ala Xaa Ala 1 5 10 15 <210> 18 <211> 16 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 17 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(15) <223> Thioether bond between residues 4 and 15 <220> <221> misc_feature <222> (15) <223> 2-Amino-4-(acetylamino)butyric acid <400> 18 Lys Lys Lys Xaa Ala Ile Pro Arg Gly Asp Asn Phe Arg Ala Xaa Ala 1 5 10 15 <210> 19 <211> 16 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 18 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(15) <223> Thioether bond between residues 4 and 15 <220> <221> misc_feature <222> (15) <223> 2-Amino-4-(acetylamino)butyric acid <400> 19 Lys Lys Lys Xaa Ala Ala Ile Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 15 <210> 20 <211> 16 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 19 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(15) <223> Thioether bond between residues 4 and 15 <220> <221> misc_feature <222> (15) <223> 2-Amino-4-(acetylamino)butyric acid <400> 20 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Phe Arg Ala Ala Xaa Ala 1 5 10 15 <210> twenty one <211> 17 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 20 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(16) <223> Thioether bond between residues 5 and 16 <220> <221> misc_feature <222> (16) <223> 2-Amino-4-(acetylamino)butyric acid <400> twenty one Lys Lys Lys Gly Xaa Ala Ile Pro Arg Gly Asp Asn Phe Arg Ala Xaa 1 5 10 15 Ala <210> twenty two <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 21 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> twenty two Lys Lys Lys Xaa Val Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> twenty three <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 22 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> twenty three Lys Lys Lys Xaa Asp Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> twenty four <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 23 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> twenty four Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> 25 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 24 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 25 Lys Lys Lys Xaa Tyr Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 <210> 26 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 25 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 26 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Ser Phe Arg Xaa Ala 1 5 10 <210> 27 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 26 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 27 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Asn Tyr Arg Xaa Ala 1 5 10 <210> 28 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 27 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 28 Lys Lys Lys Gly Xaa Leu Pro Arg Gly Asp Asn Phe Arg Xaa Ala 1 5 10 15 <210> 29 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 28 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 29 Lys Lys Lys Gly Xaa Leu Pro Arg Gly Asp Ser Phe Arg Xaa Ala 1 5 10 15 <210> 30 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 29 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 30 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 31 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 30 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 31 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 32 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 31 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 32 Lys Lys Lys Ala Xaa Leu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 33 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 32 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 33 Lys Lys Lys Ala Xaa Tyr Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 34 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 33 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 34 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Ser Tyr Arg Xaa Asp 1 5 10 15 <210> 35 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 34 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 35 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Phe Arg Xaa Asp 1 5 10 15 <210> 36 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 35 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 36 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Asp Xaa Asp 1 5 10 15 <210> 37 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 36 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 37 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Glu Xaa Asp 1 5 10 15 <210> 38 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 37 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 38 Lys Lys Lys Gly Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 39 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 38 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 39 Lys Lys Lys Asp Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 40 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 39 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 40 Lys Lys Lys Glu Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 41 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 40 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 41 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Gly 1 5 10 15 <210> 42 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 41 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 42 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Ala 1 5 10 15 <210> 43 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 42 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 43 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 44 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 43 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 44 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Glu 1 5 10 15 <210> 45 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 44 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 45 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 46 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 45 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 46 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 47 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 46 <220> <221> misc_feature <222> (4) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> Homocysteine <400> 47 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 48 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 47 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 48 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 49 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 48 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 49 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa Asp 1 5 10 15 <210> 50 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 49 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MOD_RES <222> (13) <223> Amidation <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 50 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 51 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 50 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> MOD_RES <222> (14)..(14) <223> Amidation <400> 51 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 52 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 51 <220> <221> misc_feature <222> (4) <223> β-Alanine <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> MOD_RES <222> (14)..(14) <223> Amidation <400> 52 Lys Lys Lys Xaa Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 53 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 52 <220> <221> misc_feature <222> (4) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> Homocysteine <220> <221> MOD_RES <222> (13) <223> Amidation <400> 53 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 54 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 53 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <220> <221> MOD_RES <222> (14)..(14) <223> Amidation <400> 54 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Xaa 1 5 10 <210> 55 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 54 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 55 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 56 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 55 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 56 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Gly 1 5 10 15 <210> 57 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 56 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 57 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 58 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 57 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 58 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 <210> 59 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 58 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(13) <223> Thioether bond between residues 5 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 59 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Xaa Ala 1 5 10 <210> 60 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 59 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 60 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa 1 5 10 <210> 61 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 60 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 61 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Thr Phe Xaa Ala 1 5 10 <210> 62 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 61 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 62 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa 1 5 10 <210> 63 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 62 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 63 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 64 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 63 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 64 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Thr Phe Xaa 1 5 10 <210> 65 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 64 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 65 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Xaa 1 5 10 <210> 66 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 65 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 66 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Val Phe Xaa 1 5 10 <210> 67 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 66 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <220> <221> misc_feature <222> (12)..(12) <223> 2-Amino-4-(acetylamino)butyric acid <400> 67 Lys Lys Lys Xaa Val Pro Arg Gly Asp Val Phe Xaa 1 5 10 <210> 68 <211> 17 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 67 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(16) <223> Thioether bond between residues 5 and 16 <220> <221> misc_feature <222> (16) <223> 2-Amino-4-(acetylamino)butyric acid <400> 68 Lys Lys Lys Gly Xaa Ala Ile Pro Arg Gly Asp Thr Phe Arg Ala Xaa 1 5 10 15 Ala <210> 69 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 68 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (6) <223> Homotyrosine <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 69 Lys Lys Lys Gly Xaa Xaa Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 70 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 69 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 70 Lys Lys Lys Gly Xaa Glu Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 71 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 70 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 71 Lys Lys Lys Gly Xaa Val Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 72 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 71 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 72 Lys Lys Lys Gly Xaa Leu Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 73 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 72 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 73 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Ser Phe Arg Xaa Ala 1 5 10 15 <210> 74 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 73 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (11)..(11) <223> Homoserine <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 74 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Xaa Phe Arg Xaa Ala 1 5 10 15 <210> 75 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 74 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 75 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 76 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 75 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 76 Lys Lys Lys Ala Xaa Thr Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 77 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 76 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 77 Lys Lys Lys Ala Xaa Ile Thr Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 78 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 77 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 78 Lys Lys Lys Ala Xaa Ile Ser Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 79 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 78 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 79 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Val Phe Arg Xaa Ala 1 5 10 15 <210> 80 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 79 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 80 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ala Phe Arg Xaa Ala 1 5 10 15 <210> 81 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 80 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 81 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Pro Arg Xaa Ala 1 5 10 15 <210> 82 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 81 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 82 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Tyr Arg Xaa Ala 1 5 10 15 <210> 83 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 82 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 83 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Thr Xaa Ala 1 5 10 15 <210> 84 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 83 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 84 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Ser Xaa Ala 1 5 10 15 <210> 85 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 84 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 85 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Ala Xaa Gly 1 5 10 15 <210> 86 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 85 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 86 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Ala Xaa Gly 1 5 10 15 <210> 87 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 86 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 87 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 88 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 87 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 88 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 89 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 88 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 89 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Thr Phe Gly Xaa Ala 1 5 10 15 <210> 90 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 89 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 90 Lys Lys Lys Ala Xaa Val Thr Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 91 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 90 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 91 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ala Phe Ala Xaa Ala 1 5 10 15 <210> 92 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 91 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 92 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Ala Phe Ala Xaa Ala 1 5 10 15 <210> 93 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 92 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 93 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 94 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 93 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 94 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Gly 1 5 10 15 <210> 95 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 94 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 95 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 96 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 95 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 96 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Gly 1 5 10 15 <210> 97 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 96 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 97 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 98 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 97 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 98 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Ser Phe Ala Xaa Gly 1 5 10 15 <210> 99 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 98 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 99 Lys Lys Lys Gly Xaa Val Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 100 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin Binding Cyclic Peptide 99 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 100 Lys Lys Lys Gly Xaa Val Pro Arg Gly Asp Ser Phe Ala Xaa Gly 1 5 10 15 <210> 101 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin Binding Cyclic Peptide 100 <220> <221> misc_feature <222> (2)..(2) <223> Homocysteine <220> <221> thioeth <222> (2)..(11) <223> Thioether bond between residues 2 and 11 <220> <221> misc_feature <222> (11)..(11) <223> 2-Amino-4-(acetylamino)butyric acid <400> 101 Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala Lys Lys Lys 1 5 10 15 <210> 102 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 101 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 102 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa 1 5 10 <210> 103 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 102 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 103 Lys Lys Lys Xaa Val Pro Arg Gly Asp Ser Phe Ala Xaa 1 5 10 <210> 104 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 103 <220> <221> misc_feature <222> (1) <223> Homocysteine <220> <221> thioeth <222> (1)..(10) <223> Thioether bond between residues 1 and 10 <220> <221> misc_feature <222> (10)..(10) <223> 2-Amino-4-(acetylamino)butyric acid <400> 104 Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Lys Lys Lys 1 5 10 <210> 105 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 104 <220> <221> misc_feature <222> (4) <223> Homocysteine <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> misc_feature <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 105 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 106 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 105 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 106 Lys Lys Lys Gly Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Gly 1 5 10 15 <210> 107 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 106 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 107 Lys Lys Lys Gly Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 108 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin-binding cyclic peptide 107 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 108 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Gly 1 5 10 15 <210> 109 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 108 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 109 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 110 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 109 <220> <221> misc_feature <222> (2)..(2) <223> Homocysteine <220> <221> thioeth <222> (2)..(11) <223> Thioether bond between residues 2 and 11 <220> <221> misc_feature <222> (11)..(11) <223> 2-Amino-4-(acetylamino)butyric acid <400> 110 Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala Lys Lys Lys 1 5 10 15 <210> 111 <211> 16 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 110 <220> <221> misc_feature <222> (6) <223> Homocysteine <220> <221> thioeth <222> (6)..(15) <223> Thioether bond between residues 6 and 15 <220> <221> misc_feature <222> (15) <223> 2-Amino-4-(acetylamino)butyric acid <400> 111 Lys Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 112 <211> 17 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 111 <220> <221> misc_feature <222> (7) <223> Homocysteine <220> <221> thioeth <222> (7)..(16) <223> Thioether bond between residues 7 and 16 <220> <221> misc_feature <222> (16) <223> 2-Amino-4-(acetylamino)butyric acid <400> 112 Lys Lys Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 15 Ala <210> 113 <211> 18 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 112 <220> <221> misc_feature <222> (8) <223> Homocysteine <220> <221> thioeth <222> (8)..(17) <223> Thioether bond between residues 8 and 17 <220> <221> misc_feature <222> (17) <223> 2-Amino-4-(acetylamino)butyric acid <400> 113 Lys Lys Lys Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala 1 5 10 15 Xaa Ala <210> 114 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 113 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 114 Lys Lys Lys Ala Xaa Val Thr Arg Gly Asp Val Phe Thr Xaa Ala 1 5 10 15 <210> 115 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 114 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-3-(acetylamino)propionic acid <400> 115 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 116 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 115 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-δ-Acetyl-Ornithine <400> 116 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 117 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 116 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-ε-acetyl-lysine <400> 117 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 118 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 117 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 118 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 119 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 118 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 119 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 120 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 119 <220> <221> misc_feature <222> (5) <223> N-δ-Acetyl-Ornithine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 120 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 121 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 120 <220> <221> misc_feature <222> (5) <223> N-ε-acetyl-lysine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 121 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 122 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 121 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-ε-o-acetyl-lysine <400> 122 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 123 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 122 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 123 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 124 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 123 <220> <221> misc_feature <222> (5) <223> Homocysteine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-ε-acetyl-lysine <400> 124 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 125 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 124 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Homocysteine <400> 125 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 126 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 125 <220> <221> misc_feature <222> (2)..(2) <223> Homocysteine <220> <221> thioeth <222> (2)..(11) <223> Thioether bond between residues 2 and 11 <220> <221> misc_feature <222> (11)..(11) <223> 2-Amino-4-(acetylamino)butyric acid <400> 126 Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 <210> 127 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 126 <220> <221> misc_feature <222> (2)..(2) <223> Homocysteine <220> <221> thioeth <222> (2)..(11) <223> Thioether bond between residues 2 and 11 <220> <221> misc_feature <222> (11)..(11) <223> 2-Amino-4-(acetylamino)butyric acid <400> 127 Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 <210> 128 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 127 <220> <221> misc_feature <222> (2)..(2) <223> Homocysteine <220> <221> thioeth <222> (2)..(11) <223> Thioether bond between residues 2 and 11 <220> <221> misc_feature <222> (11)..(11) <223> 2-Amino-4-(acetylamino)butyric acid <400> 128 Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Gly 1 5 10 <210> 129 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 128 <220> <221> misc_feature <222> (5) <223> Penicillamine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-3-(acetylamino)propionic acid <400> 129 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 130 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 129 <220> <221> misc_feature <222> (5) <223> Penicillamine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 130 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 131 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 130 <220> <221> misc_feature <222> (5) <223> Penicillamine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-δ-Acetyl-Ornithine <400> 131 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 132 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 131 <220> <221> misc_feature <222> (5) <223> Penicillamine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> N-ε-acetyl-lysine <400> 132 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 133 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 132 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 133 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 134 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 133 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 134 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 135 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 134 <220> <221> misc_feature <222> (5) <223> N-δ-Acetyl-Ornithine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 135 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 136 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 135 <220> <221> misc_feature <222> (5) <223> N-ε-acetyl-lysine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 136 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Xaa Ala 1 5 10 15 <210> 137 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 136 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 137 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 138 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 137 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> misc_feature <222> (14)..(14) <223> Penicillamine <400> 138 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 139 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 138 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <400> 139 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Cys Ala 1 5 10 15 <210> 140 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 139 <220> <221> misc_feature <222> (5) <223> N-δ-Acetyl-Ornithine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <400> 140 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Cys Ala 1 5 10 15 <210> 141 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 140 <220> <221> misc_feature <222> (5) <223> N-ε-acetyl-lysine <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <400> 141 Lys Lys Lys Gly Xaa Ile Pro Arg Gly Asp Thr Phe Arg Cys Ala 1 5 10 15 <210> 142 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 141 <220> <221> misc_feature <222> (4) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <400> 142 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Ala Cys 1 5 10 <210> 143 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 142 <220> <221> misc_feature <222> (5) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <400> 143 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Cys Ala 1 5 10 15 <210> 144 <211> 12 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 143 <220> <221> misc_feature <222> (4) <223> 2-Amino-4-(acetylamino)butyric acid <220> <221> thioeth <222> (4)..(12) <223> Thioether bond between residues 4 and 12 <400> 144 Lys Lys Lys Xaa Val Pro Arg Gly Asp Asn Phe Cys 1 5 10 <210> 145 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 144 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 145 Lys Lys Lys Xaa Asp Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 146 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 145 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 146 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 147 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 146 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 147 Lys Lys Lys Xaa Leu Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 148 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 147 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 148 Lys Lys Lys Xaa Thr Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 149 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 148 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 149 Lys Lys Lys Xaa Tyr Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 150 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 149 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 150 Lys Lys Lys Xaa Val Ser Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 151 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin Binding Cyclic Peptide 150 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 151 Lys Lys Lys Xaa Val Thr Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 152 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 151 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 152 Lys Lys Lys Xaa Val Pro Arg Gly Asp Val Phe Ala Xaa 1 5 10 <210> 153 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 152 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 153 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Gly Xaa 1 5 10 <210> 154 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 153 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 154 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Ser Xaa 1 5 10 <210> 155 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 154 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 155 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Thr Xaa 1 5 10 <210> 156 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 155 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 156 Lys Lys Lys Xaa Thr Thr Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 157 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 156 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 157 Lys Lys Lys Xaa Thr Pro Arg Gly Asp Ser Phe Ala Xaa 1 5 10 <210> 158 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 157 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 158 Lys Lys Lys Xaa Thr Thr Arg Gly Asp Ser Phe Ala Xaa 1 5 10 <210> 159 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 158 <220> <221> MISC_FEATURE <222> (5) <223> Homocysteine <220> <221> THIOETH <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 159 Lys Lys Lys Ala Xaa Thr Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 160 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 159 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 160 Lys Lys Lys Xaa Thr Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 <210> 161 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 160 <220> <221> MISC_FEATURE <222> (5) <223> Homocysteine <220> <221> THIOETH <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 161 Lys Lys Lys Ala Xaa Thr Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 15 <210> 162 <211> 15 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 161 <220> <221> MISC_FEATURE <222> (5) <223> Homocysteine <220> <221> THIOETH <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 162 Lys Lys Lys Ala Xaa Thr Thr Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 15 <210> 163 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 162 <220> <221> MISC_FEATURE <222> (5) <223> Homocysteine <220> <221> THIOETH <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 163 Lys Lys Lys Ala Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa 1 5 10 <210> 164 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 163 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 164 Lys Lys Lys Xaa Ile Pro Arg Gly Asp Ser Phe Ala Xaa Ala 1 5 10 <210> 165 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 164 <220> <221> MISC_FEATURE <222> (5) <223> Homocysteine <220> <221> THIOETH <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Amino-4-(acetylamino)butyric acid <400> 165 Lys Lys Lys Ala Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa 1 5 10 <210> 166 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 165 <220> <221> MISC_FEATURE <222> (4) <223> Homocysteine <220> <221> THIOETH <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <220> <221> MISC_FEATURE <222> (13) <223> 2-Amino-4-(acetylamino)butyric acid <400> 166 Lys Lys Lys Xaa Val Pro Arg Gly Asp Thr Phe Ala Xaa Ala 1 5 10 <210> 167 <211> 14 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 166 <220> <221> misc_feature <222> (5) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (5)..(14) <223> Thioether bond between residues 5 and 14 <400> 167 Lys Lys Lys Ala Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Cys 1 5 10 <210> 168 <211> 13 <212> PRT <213> Artificial <220> <223> Integrin binding cyclic peptide 167 <220> <221> misc_feature <222> (4) <223> 2-Amino-3-(acetylamino)propionic acid <220> <221> thioeth <222> (4)..(13) <223> Thioether bond between residues 4 and 13 <400> 168 Lys Lys Lys Xaa Glu Pro Arg Gly Asp Asn Tyr Arg Cys 1 5 10 <210> 169 <211> 7 <212> PRT <213> Artificial <220> <223> Regions in the ring segments <400> 169 Ile Pro Arg Gly Asp Asn Phe 1 5 <210> 170 <211> 8 <212> PRT <213> Artificial <220> <223> Regions in the ring segments <400> 170 Ile Pro Arg Gly Asp Ser Phe Ala 1 5 <210> 171 <211> 8 <212> PRT <213> Artificial <220> <223> Regions in the ring segments <400> 171 Val Pro Arg Gly Asp Thr Phe Ala 1 5 <210> 172 <211> 8 <212> PRT <213> Artificial <220> <223> Regions in the ring segments <400> 172 Thr Pro Arg Gly Asp Thr Phe Ala 1 5

Claims

1. A cyclic peptide having an amino acid sequence of any one of SEQ ID NOs: 2 to 9, 11 to 33, 35, 37 to 50, 53 to 138, and 145 to 166.

2. The cyclic peptide according to claim 1, which is any one of the amino acid sequences of SEQ ID NOs: 2 to 9, 11 to 33, 35, 37 to 50, 53 to 128, and 145 to 166.

3. The cyclic peptide according to claim 2, which is any one of the amino acid sequences of SEQ ID NOs: 2, 93, 109, and 161. The cyclic peptide according to claim 3, which is any one of the amino acid sequences of SEQ ID NOs: 93, 109, and 161. 5 . A cell scaffold material comprising a substrate and the cyclic peptide according to any one of claims 1 to 4. 6 . A cell separation material comprising a holding material and the cyclic peptide according to claim 1 .

7. A culture medium comprising culture components and the cyclic peptide according to any one of claims 1 to 4.

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