UA112630C2 - GLP-1 RECEPTOR AGENCY AGENTS AND peptide CONCEPTS - Google Patents

Abstract

The present is a conjunction with the HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF-NH2, and their use in the treatment of various diseases or disorders, including diabetes (type 1 and / or type 2), and diseases or disorders caused by diabetes.

Description

during islet neogenesis, i.e. stimulation of the growth of insulin-secreting VDV cells of pancreatic islets | see, for example, Kogs, M., 9. Siip. Ipmevi., 92: 1113-1114 (1993); Nootap sei ai. Journal 51: 686-690 (2002)|, and thereby help regulate blood glucose levels.

Gastrin shares a receptor with another peptide gastrointestinal hormone, cholecystokinin (CSK). CSK-A K and CSK-B E receptors have different affinities for variants of gastrin and CSK. SSK-A K (or

SSK KI) acts mainly as a receptor for sulfated SSK, while SSK-B EC (or SSK 2) binds SSK and gastrin equally well. It is believed that SSK-B K is a "gastrin receptor" due to a higher level of gastrin compared to SSK in plasma (Boisatsa ei aiYi. Ked.

Reriide5 145: 17-23 (2008).

CSC-BK can trigger several intracellular pathways after ligand binding, which is considered to be the reason for various physiological functions of CSC. The key way, which is regulated by SSK-B

E, there is the MAPK (mitogen-activated protein kinase) or EKK (extracellular regulated kinase) pathway, which is also activated by several growth hormones. This is a key feature of gastrin's cell proliferation function. Since CSK-B K is expressed in the pancreas, gastrin can participate in cell proliferation and islet regeneration in this tissue.

In humans, gastrin occurs mainly in three forms, namely: Gastrin-34, Gastrin-17 and

Gastrin-14 (depending on the total number of amino acids in the sequence under consideration).

Gastrin-b6 was also found. Shorter forms are obtained by cleavage of the C-terminal amidate

Gastrin-34, thus, Gastrin-17 consists of the C-terminal last 17 residues of Gastrin-34 (which correspond to progastrin residues (55-71)), Gastrin-14 from the C-terminal last 14 residues (which correspond to progastrin residues (58 -71)) and Gastrin-b6 consists only of the C-terminal last 6 residues (which correspond to the residues of progastrin (66-71)). They are amidated forms of gastrin that bind with high affinity to SOK-B E and perform the function of cell proliferation.

In human Gastrin-17, the M-terminal amino acid residue is a residue of pyroglutamic acid (RugoSiImy). Amidated C-terminal 6 amino acids are key receptor-binding residues of gastrin.

UMO publication 2005/072045 describes, in particular, combinations of "SI P-1 agonists" and "gastrin compounds", which probably have a beneficial effect on the prevention and/or treatment of conditions and/or diseases in which the therapeutic effect of the "SI agonist P-1" or "gastrin compounds". UMO publication 2007/095737 describes, among other things, similar combinations of "exendin agonists" and "gastrin compounds", which also presumably show a beneficial effect on the prevention and/or treatment of conditions and/or diseases in which the therapeutic effect of "exendin agonists" has been shown " or "gastrin compounds".

Data (obtained from studies using non-obese diabetic mice (MBD), which are widely used as an animal model of human type 1 diabetes), presented in publication M/O 2005/072045, clearly indicate that some combinations of "CI P agonist -1" and "gastrin compounds" according to the description can show a beneficial effect on the normalization of blood glucose levels in the mouse model with acute diabetes MY in comparison with the effect observed when using the considered "CI P-1 agonist" (or "gastrin compound ") separately. The data (also obtained from studies using non-obese diabetic mice (NOB)|presented in UMO publication 2007/095737) clearly indicate that some of the described "exendin agonist"/"gastrin compound" combinations exhibit beneficial effects on normalization of glucose and insulin levels in the blood in a mouse model with acute MYO diabetes compared to the effect observed when using the considered "exendin agonist" (or "gastrin compound") separately, and that some combinations of "si pP-1 receptor agonist"/ tastrin" according to the description may have a beneficial effect on the induction of islet cell regeneration compared to the effect observed when using the "CI P-1 receptor agonist" alone.

Publications UMO 2005/072045 and UMO 2007/095737 also describe the possibility of forming conjugates containing "agonist SI P-1" or "agonist exendin", respectively, and "gastrin compound", covalently paired or linked (i.e. con' yoked)) to each other is possible with the help of an intermediate linker or spacer. A suitable spacer is a mono- or disaccharide, amino acid, sulfate, succinate, acetate, or oligomeric polymeric spacer or linker that contains one or more of these groups. Also described are the intended methods by which it is possible to obtain the considered types of conjugates. However, none of the recent documents reviewed provided preparative or other data to substantiate that any type of conjugate under consideration had actually been prepared and characterized or had its biological/physiological properties or activity tested - at the time of the filing of the relevant international application.

It can also be noted that neither IMO publication 2005/072045 nor MO publication 2007/095737 provides data on ip mimo, ip migo, or other data confirming that the combinations "SI P-1 agonist"/"gastrin compound" or "exendin agonist"/"gastrin compound" as described and used herein may be useful in the treatment of, for example, type 2 diabetes.

BRIEF DESCRIPTION OF THE INVENTION

According to the present invention, it was found that some conjugates that contain two covalently paired or linked peptide groups can exhibit unexpectedly high therapeutic activity in the treatment of, for example, diabetes (type 1 and/or type 2 diabetes) or various diseases or conditions caused by diabetes compared to the therapeutic activity of the combination of the two individual peptides under consideration.

In a broader aspect, the present invention provides a peptide conjugate of an agonist of the CI P-1 receptor and gastrin, in particular, gastrin with a substitution at position 15 selected from Ge, Miee, Rpe and TNg. More specifically, the present invention provides peptide conjugates of Exendin-4 and gastrin, as well as peptide conjugates of SI P-1 and gastrin.

According to the first aspect, the present invention thus provides a peptide conjugate having the formula I:

B1-2-I-x-82 (I), in which

K1 represents H, Si. alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

B2 is OH or MH2; 2 contains the sequence of exendin-4 (1-39), which has the sequence

Nibz-Spu-spty-spu- Gpiy-Ripe-Tnyg-Zeg-Azr-I ey-Zeg-I uz-SITp-Mei-Sspy-spty-spty-Aia-Ma!I-Ag9-Gey-RNe-Pe- C1y-

Tr-Hets-G uv-Avp-Spu-Sptu-Rgo-Zeg-Zeg-Spu-AIa-Rgo-Rgo-Rgo-5eg (ZEO IO MO: 115), or its analogue 74;

It is an optional linker group; and

U contains the sequence of Gastrin-17, which has the sequence

Sip-Spu-Rgo-Ttr-Gey-s1y-spty-sp1y-s1y-s1y-Aia-Tuk-Spu-Ggr-M15-Avr-Rpe (Z5EO IO MO: 116), in which U15 is chosen from I em, Mie , Re and TNg, or its analogue Ua.

Also, the present invention provides a peptide conjugate in which: () 7a has up to 10 substitutions in positions and/or contains a shortening of the C-terminus by 1-12 amino acids compared to the exendin sequence; and/or (ii) Ma has up to 5 substitutions compared to the sequence of Gastrin-17 and/or contains a shortening of the M-terminus by 1-13 amino acids compared to the sequence of Gastrin-17.

According to one embodiment, the present invention provides a peptide conjugate in which 7a is a peptide sequence having the formula Ia:

Niv-22-23-S1u- Gpi-Rpe- TNg-Zeg-29-210-211-212-713-2714-с21y-216-217-2718-719-220- (pa) 221-222-7223-724 -725-7265-727-728-729-730-2731-2y 32-72 33-734-735-736-737-238-739 and in which 22 is chosen from su, Aa, 5eg, AB, TAg, I em and Pe; 23 chosen from Sim and A5r; 29 chosen from A5r and Sim; 2710 chosen from I em, Mai, Pe ii AIa; 211 selected from Zeg and AiB; 2712 chosen from Zeg, Sp, Agou, Suv, I uv, Sim and Ogp; 713 chosen from Ago, Zeg, Sip, Toogi Sim; 214 selected from Su, Su, Re, Tug, Tgr, Guv, Mei, Gei, Mie and Pe; 2716 chosen from Ar, Su, Aib, Shem, Guz, and Suv; 2717 chosen from Sim, Sub, I uv, Zeg and Sp; 718 chosen from Ai and AiB; 2719 chosen from Mai, I ey, Pe and Aa; 220 chosen from Ago, Gu, Sub, Ot and Sim; 2721 chosen from I ei and Sim; 222 selected from RNe and Aa; 223 chosen from Pe and I ey; 224 chosen from Sim, Sub, I uv, Aa and Ago; 225 selected from Tgr, Suv, I uz and Rpe; 226 chosen from I ei and Pe; 227 chosen from Pe, Mai, SiIp, Gu, Suv, Ago and Ogp; 228 is chosen from Avp, 5eg, A5r, AB, Sp, Gu, Sub, Ago, Tug, BAia, Sim, Ot and I ey or it is absent; 229 is selected from Su, AIIB and BAia or it is absent; 230 is selected from Su, Suv, I uz and Agd or it is absent; 231 is selected from Rgo, Zeg and A5r or it is absent; 232 is selected from Zeg and I uh or it is absent; 233 represents 5Zeg or it is absent;

234 is selected from Su and Guz or it is absent; 235 is Aa or absent; 236 represents Rgo or it is absent; 237 represents Rgo or it is absent; 238 is Rgo or it is absent; 239 represents 5Zeg or it is absent;

It is a peptide sequence that has the formula Pr:

I1-i12-I5-14 (PB), in which

Y1 is selected from Zeg, Aa, Gu, Ogp, BAia, vAss, OBE, Red3, Suzh and SiIp or is absent;

Y2 is selected from Zeg, Aa, Gu, Ogp, BAPIa, vAss, OBE, Red3, Suzh and SiIp or is absent;

YZ is selected from Zeg, Aa, Gu, Ogp, BAPIa, vAss, OBE, Red3, Suzh and SiIp or it is absent;

And 4 is selected from Zeg, Aa, Gu, Ogp, BAPIa, vAss, OBE, Red3, Suzh and SiIp or it is absent;

Ma is a peptide sequence that has the formula Ps:

U1-m2-U3-u4-u5-U6-u7-U8-U9-U10-u11-u12-u13-u14-u15-A5r-Uu17 (Ps), in which

U1 is a sp or it is absent;

U2 is su or absent;

UZ is Rgo or it is absent;

U4 is Tgr or it is absent;

У5 represents I ей or it is absent;

У6 represents сСиы or it is absent;

У7 represents сСий or it is absent;

У8 represents сСиы or it is absent;

У9 represents сСий or it is absent;

U10 is Sy or it is absent;

U11 is A|Pa or it is absent;

U12 is selected from AP and Tug or it is absent;

U13 is selected from Su and Aia or is absent;

U14 is selected from Tgr, Re, 1 Mai and Mei;

U15 is selected from I em, Mie, Rpe and TAg, and

U17 is selected from Re and 3-(3-pyridyl)-alanine.

According to another embodiment, the present invention provides a peptide conjugate in which 7a is a peptide sequence having the formula Sha:

Nibz-Spu-spty-spu- Gpg-Rpe-TNi-5eg-29-I ei-5ei-212-213-214-S1y-216-s1y-AIa-Ma!I-220-I ei- (Sha)

РНе-ІІе-224-225-ІІ ей-227-228 " in which 29 is selected from A5r and Sim; 712 is selected from Gu, Ago and Ogp; 713 is selected from Sip and Tug; 214 is selected from Mei and I ей; 2716 is selected from Sim, Suz and I uv; 220 chosen from Ago, Huz and Ogp; 224 chosen from I uv and Sm; 225 chosen from Tgr, Gu, Suz and Re; 221 chosen from Gu, Ago and Ogp; 2728 chosen from Avp and Azr or it is absent;

It is a peptide sequence that has the formula PSHB:

I1-i12-I5-14 (full name), in which

Y1 is selected from Opt, Red3, Sub, I uz and SiP or it is absent;

Y2 is selected from Ot, Red3, Sub, I uz and SiIp or it is absent;

IZ is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

And 4 is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

Ma is a peptide sequence that has the formula Ps:

U12-413-uU14-U15-Avr-u17 (She), in which

U12 is selected from Tug and Aa or absent;

U13 is selected from Su and Aia or is absent;

U14 is selected from Tgr, May 1 and Re;

U15 is selected from I ei, Mie, Tig and RNe; and

U17 is selected from Re and 3-(3-pyridyl)-alanine.

According to another embodiment, the present invention provides a peptide conjugate in which 7a is a peptide sequence having the formula IMa:

Nibz-Spu-spty-spu- Gpy-Ripe-Tng-5eg-29-I ei-5eg-212-S1p-Mei-Spy-216-s1y-Aia-Ma!I-Ag9-I ei- (Ma)

РПе-Пе-Спы-Тгр-Й ей-227-228 ' in which 29 is chosen from Sim and A5r; 712 chosen from Guz and Ogp; 2716 chosen from Sim and G uv; 221 selected from GI universities and OGP; 2728 is selected from Avp and Azr or it is absent;

It is a peptide sequence that has the IMB formula:

Y1-i2-I 3-14 (IMB), in which

Y1 is selected from Opt, Red3, Sub, I uz and SiP or it is absent;

Y2 is selected from Ot, Red3, Sub, I uz and SiIp or it is absent;

IZ is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

And 4 is selected from Opt, Red3, Sub, I uz and SiP or it is absent;

Ma is a peptide sequence that has the formula IMc:

U12-Zh413-Tr-I ei-A5r-Rpe (IMs), in which

U12 represents Tug or it is absent; and

U13 is su or absent.

According to another embodiment, the present invention provides a peptide conjugate in which 7a is a peptide sequence having the formula Ma:

Nibz-Spu-spty-spu- Gp-Ripe-Tni-5eg-29-I ei-5eg-212-Tui-I esh-S1y-216-S1y-AIa-Ma!I-Agod-I ei- (ma)

РПе-Пе-СШ-РНе-ЙИ ей-227-228 ' in which 29 is chosen from Sim and A5r; 712 selected from I uz and Op; 2716 chosen from Sim and G uv; 221 selected from GI universities and OGP; 2728 is selected from Avp and Azr or it is absent;

It is a peptide sequence that has the formula MB:

Y1-i2-I 3-14 (MB), in which

Y1 is selected from Opt, Red3, Sub, I uz and SiP or it is absent;

Y2 is selected from Ot, Red3, Sub, I uz and SiIp or it is absent;

IZ is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

And 4 is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

Ma is a peptide sequence that has the formula Mc:

У12-Ж13-Тр-И ей-А5р-РнНе (Us), in which

U12 represents Tug or it is absent; and

U13 is su or absent.

Moreover, the present invention provides a peptide conjugate in which the peptide sequence of formula I contains one or more intramolecular bridges.

The present invention also provides a peptide conjugate according to which the specified intramolecular bridge is formed between the side chains of two amino acid residues separated by three amino acids in a linear amino acid sequence according to formula I.

According to a certain implementation variant, the present invention provides a peptide conjugate in which an intramolecular bridge is formed between the side chains of pairs of residues x and x3, x4, x5, etc.

According to another specific embodiment, the present invention provides a peptide conjugate in which the specified intramolecular bridge is a lactam ring.

According to another specific implementation option, the present invention provides a peptide conjugate in which the specified intramolecular bridge includes pairs of residues, while: 712 is I uv, and 716 is sy; 212 represents si, and 216 represents I uv; 716 represents si, and 220 represents I uv; 716 represents | uv, and 220 is SIy; 220 represents Sy, and 724 represents I uv; 2720 represents | uv, and 224 is sy.

According to another aspect of the present invention, a peptide conjugate having the formula is provided

E:

V" X-I -x-8e (MI), in which

BAV" is H, C alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

B2 is OH or МНе;

X contains the sequence SI P-1 (7-36), which has the following sequence:

Nibz-AIa-SITy-S1tu- Hyg-Rpe-Tng-5eg-Avzr-Ma!I-Zeg-Zeg- Tug-Gey-Sspty-sptu-s1p-Aia-Aia-Y uv-SIy-Rpe-PPe-Aia -Tgr-

Gei-Ma!I-Guv-Spu-Agu (ZEO 10 MO: 114), or its analogue Kha;

It is a linker that contains up to 4 natural or unnatural amino acids or their combination, or it is absent;

U contains the sequence of Gastrin-17, which has the sequence:

Spp-Spu-Rgo-Ttr-Yi-Sty-sti-s1y-s1y-s1y-Aia-Tug-Spu-Ggr-U15-Avr-RnNe, while U15 is selected from I em, Mie, Re and ТНg, or its analogue Ua.

According to one variant of implementation, the present invention provides a peptide conjugate in which: (Y) Xa has up to 5 substitutions in positions and/or has a shortening at the C-terminus by 1-2 amino acids compared to the sequence of CI P-1; and/or (i) Ma has up to 5 substitutions in positions compared to the sequence of Gastrin-17 and/or contains a shortening at the M-terminus of 1-13 amino acids compared to the sequence of Gastrin-17.

According to another embodiment, the present invention provides a peptide conjugate in which:

Xa is a peptide sequence that has the formula MiIa:

Nib-X8-Spi-Ss1u- Gpi-Rpe- Tii-Zeg-Azr-Ma!I-Zeg-Zeg- Tug-G ei-Ssti-sSptu-siP-Aia-Aia- (ia) х26-С1y-РПе- IPe-AiIa-Ttr-I ei-MaI-X34-Sst1u-x36 " in which

XV is selected from Aa, AB and su;

X26 is selected from Aga and I uv;

X34 is selected from Agu and I uv;

X36 is selected from Aga and I uv;

It is a peptide sequence that has the formula MIIB:

G1-12-I5-14 (MB), in which

Y1 is selected from Zeg, Aa, Gu, Ogp, BAiIa, vAss, OBE, Red3, Su", SiIp or it is absent;

Y2 is selected from Zeg, Aa, Gu, Ogp, BAiIa, vAss, OBE, Red3, Suv, SiIp or it is absent;

YZ is selected from Zeg, Aa, Gu, Ogp, BAiIa, vAss, OVE, Red3, Su», SiIp or it is absent;

And 4 is selected from Zeg, Aa, Gu, Ogp, BAiIa, vAss, OVE, Red3, Su», SiIp or it is absent;

Ma is a peptide sequence that has the formula Mys:

U1-42-73-u4-u5-6-u7-8-U9-U1.0-u11-m412-u13-u14-u15-A5r-u17 (Miss), in which

U1 is a rash or it is absent;

U2 is su or absent;

UZ is Rgo or it is absent;

U4 is Tgr or it is absent;

U5 represents I em or it is absent;

У6 represents сСиы or it is absent;

У7 represents сСий or it is absent;

У8 represents сСиы or it is absent;

У9 represents сСий or it is absent;

U10 is Sy or it is absent;

U1 1 is AIa or it is absent;

U12 is selected from Aa, Tug or absent;

U13 is selected from Su, Aa or absent;

U14 is selected from Tgr, Re, 1 Mai and Mei;

U15 is chosen from I em, Mie, Re and TNg, and

U17 is selected from Re and 3-(3-pyridyl)-alanine.

According to another embodiment, the present invention provides a peptide conjugate in which:

Xa is a peptide sequence having the formula MPa:

Nib-X8-Spi-Ss1u- Gpg-Rpe- Tii-Zeg-Avzr-Ma!-Zeg-Zeg- Tut-Hei-Ssti-sSptu-sIp-AIa-Aia-X26- (MPa) sui-Rpe-Pe- AIa-Ttr-I ei-MaI-X34-Spu-X36 ' in which

XV is selected from Aa, AB and su;

X26 is selected from Aga and I uv;

X34 is selected from Aga and I uv;

X36 is selected from Aga and I uv;

It is a peptide sequence that has the formula MB:

I1-i12-I5-14 (MPIB), in which

Y1 is selected from Red3, Ot, Suh, I uv, SiIp or it is absent;

Y2 is selected from Zeg, Aa, Ogp, Su, I y, SiIp or it is absent;

YZ is selected from I uh, Aa, Su, Op, SiIp or it is absent;

And 4 is selected from I uh, Opt, Aa, Red3, Suv, Gu, SiIp or it is absent;

Ma is a peptide sequence that has the formula MPs:

У12-413-уУ14-У15-А5р-РНе (MP), in which

U12 is selected from Tug, Aa or absent;

U13 is selected from Su, Aa or absent;

U14 is selected from Tgr and Re; and

U15 is selected from I ei, TNg and Re.

According to a certain embodiment, the present invention provides a peptide conjugate in which:

Xa is a peptide sequence that has the formula IXa:

Nib-X8-Spi-Ss1u- Gpi-Rpe- Tii-Zeg-Azr-Ma!I-Zeg-Zeg- Tug-G ey-Ssti-sSptu-sIp-Aia-Aia- (kha) х26-С1y-РПе- IPe-AiIa-Ttr-I ei-MaI-X34-Sst1u-x36 " in which

XV is selected from Aa, AB and su;

X26 is selected from Aga and I uv;

X34 is selected from Aga and I uv;

X36 is selected from Aga and I uv;

It is a peptide sequence that has the formula ICB:

I1-i12-I5-14 (IKB),

In which

Y1 is selected from Opt, Red3, Sub, I uz and SiP or it is absent;

Y2 is selected from Ot, Red3, Sub, I uz and SiIp or it is absent;

IZ is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

And 4 is selected from Opt, Red3, Sub, I uz and SiIp or it is absent;

Ma is a peptide sequence that has the formula IXc:

У12-Ж413-Тр-И ей-А5р-Рпе (Хс), in which

U12 represents Tug or it is absent; and

U13 is su or absent.

According to another specific embodiment, the present invention provides a peptide conjugate in which: at least one of I uh or Suh is also conjugated with a lipophilic substituent.

According to another aspect, the present invention relates to a peptide conjugate having the formula:

Exendin-4(1-39)-Rea93-Rea3-|SiIp1, Hei15|Gastrin-17, (1)

Exendin-4(1-39)-(Sip1, Hei15|Gastrin-17, (2)

Exendin-4(1-39)-K-I (SiIp1, Hets15|Gastrin-17, (3)

Exendin-4(1-39)-AAA-|(Sip1, Hei15|Gastrin-17, (4)

Exendin-4(1-39)-5KK-|Sip1, Hei15|Gastrin-17, (5)

Exendin-4(1-39)-Re93-5KK-|(SIP1, G ey15|Gastrin-17, (6)

Exendin-4(1-39)-8Aos-5KK-|СИп1 ГГ ей15|Gastrin-17, (7)

Exendin-4(1-39)-OVE-Z5KK-|SIP1, I en15|Gastrin-17, (8)

Exendin-4(1-39)-v8Aos-vAos-|SiIp1, ei15|Gastrin-17, (9)

Exendin-4(1-39)-(Gesh4|Gastrin-b, (10)

Exendin-4(1-39)-K-(Hetz4|Gastrin-6, (11)

Exendin-4(1-39)-AAA-(Gesh4|Gastrin-6, (12)

Exendin-4(1-39)-5KK-I(Hetz4|Gastrin-6, (15)

Exendin-4(1-39)-Rea3-5KK-( ec4|Gastrin-6, (14)

Exendin-4(1-39)-Rea3-Re93-(Hei4|Gastrin-6, (15)

Exendin-4(1-39)-8Aos-5KK-| ets4|Gastrin-6b, (16)

Exendin-4(1-39)-OVE-5KK-|Hets4|Gastrin-b, (17)

Exendin-4(1-39)-8Aos-v8Aos-I ets4|Gastrin-6, (18)

Exendin-4(1-28)-|(Sip1, Hei15|Gastrin-17, (19)

Exendin-4(1-28)-K-ISiIp1, Hets15|Gastrin-17, (20)

Exendin-4(1-28)-AAA-|SIP1 and ei15|Gastrin-17, (21)

Exendin-4(1-28)-5KK-|Sip1 and ei15|Gastrin-1 7 (22)

Exendin-4(1-28)-Re93-5KK-|Sip1, Hei15|Gastrin-17 (23)

Exendin-4(1-28)-Rea3-Rea3-|SiIp1, Hei15|Gastrin-17, (24)

Exendin-4(1-28)-8Aos-5KK-|СИп1 ГГ ей15|Gastrin-17 (25)

Exendin-4(1-28)-OVE-ZKK-|SIP1, I en15|Gastrin-17 (26)

Exendin-4(1-28)-8Aos-v8Aos-|SiIp1,ei15|Gastrin-17 (27)

Exendin-4(1-28)-(Hech4|Gastrin-b (28)

Exendin-4(1-28)-K-(Hetz4|Gastrin-6 (29)

Exendin-4(1-28)-AAA-I (Heshi4 | Gastrin-b, (30)

Exendin-4(1-28)-5KK-I(Hetz4|Gastrin-6, (31)

Exendin-4(1-28)-Re93-5KK-I (Hech4|Gastrin-6, (32)

Exendin-4(1-28)-Rea3Z-Re93-(Hei4|Gastrin-6, (33)

Exendin-4(1-28)-8Aos-5KK-| ets4|Gastrin-6b, (34)

Exendin-4(1-28)-OVE-5KK-|Hets4|Gastrin-b, (35)

Exendin-4(1-28)-8Aos-v8Aos-I ets4|Gastrin-6, (36) and P-1(7-36)-(SIP1, Gen15|Gastrin-17, (37) and P-1( 7-36)-K-(SIP1,Y en15|Gastrin-17, (38)

C, P-1(7-36)-AADA-|СИпП1, I ей15|Gastrin- 17, (39)

Si P-1(7-36)-5KK-|SIP1, ey15|Gastrin-17, (40) a, P-1(7-36)-Red3-5KK-|SIPP1 I ei15|Gastrin- 17, (41 ) a, P-1(7-36)-Red3-Reaz-|SIP1, I e15|Gastrin-17, (42) a P-1(7-36)-8Aos-5KK-|SIP1, e15|Gastrin- 17, (43) and P-1(7-36)-ОВЕ-5КК-|СИп1,ей15|Gastrin-17, (44)

Si P-1(7-36)-8Aos-8Aos-|(SiIp1, Hei15|Gastrin-17, (45)

Si R-1(7-36)-(Hets4|Gastrin-b, (46)

C, P-1(7-36)-K-(ec4|Gastrin-6, (47)

SI P-1(7-36)-AAA-( ec4|Gastrin-6, (48) and P-1(7-36)-5KK-( ec4|Gastrin-6, (49)

Si R-1(7-36)-Re93-5KK-( ec4|Gastrin-b, (50)

SI P-1(7-36)-Red3-Re93-Iesh4|Gastrin-6, (51) and P-1(7-36)-8Aos-5KK-( ec4|Gastrin-6, (52) and P- 1(7-36)-OVE-ZKK-|Hets4|Gastrin-6 (53) or

C P-1(7-36)-8Aos-8Aos-|(Hets4|Gastrin-6, (54) while each peptide group from Exendin-4(1-39), Exendin-4(1-28) and SI P-1(7-36) is covalently attached (i.e., linked or paired) to the remaining part of the corresponding conjugate molecule through its C-terminal part, and each peptide group from (Sip1,e15|Gastrin-17 and |ey4|Gastrin-6b is covalently attached (ie linked or paired) to the remaining portion of the corresponding conjugate molecule through its M-terminal portion; or a pharmaceutically acceptable salt or solvate thereof.

According to a certain aspect, the peptide conjugates according to the present invention can be obtained using standard synthetic methods using recombinant expression systems or any other suitable method. Thus, conjugates can be synthesized in a variety of ways, including, for example, methods that include: (a) synthesizing the peptide conjugate using standard solid-phase or liquid-phase methodology, stepwise or by fragment assembly, and isolating and purifying the final peptide product; conjugate; (b) expressing the nucleic acid construct encoding the peptide conjugate in a host cell and isolating the expression product or host cell culture; or (c) carrying out the expression of ip migo in a cell-free system of a nucleic acid construct that encodes a peptide conjugate, and isolating the expression product; or using any combination of the specified methods (a), (b) or (c) to obtain fragments of a peptide conjugate, subsequent doping of fragments to obtain a peptide conjugate and isolation of a peptide conjugate.

Among other aspects of the present invention are methods of treating various conditions, diseases or disorders (including diabetes (type 1 and type 2) and various conditions, diseases and disorders associated with diabetes) that comprise the administration of a peptide conjugate according to the present invention (in free form or in the form of its pharmaceutically acceptable salt or solvate), as well as pharmaceutical compositions containing a peptide conjugate or its pharmaceutically acceptable salt or solvate according to the present invention.

According to a specific aspect, the peptide conjugates of the present invention can also be used as pharmaceutical agents for the treatment of insulin resistance, glucose intolerance, prediabetes, elevated fasting glucose levels, type 1 and type 2 diabetes, hypertension and/or dyslipidemia (or a combination of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary artery disease, peripheral artery disease, and stroke. They may also be used to prevent weight gain, promote weight loss, reduce excess body weight, and/or treat obesity (eg, by controlling appetite, nutrition, food intake, caloric intake, and/or energy expenditure), including morbid obesity, as well as related diseases, disorders and conditions, including but not limited to obesity-related inflammation, obesity-related gallbladder disease, and obesity-related sleep apnea. The effect of the peptide conjugates according to the present invention on the specified conditions may be mediated in whole or in part by the effect on body weight or may not depend on it.

BRIEF DESCRIPTION OF FIGURES

Figure 1. Average plasma concentration as a function of time (directly proportional) after intravenous and subcutaneous administration to mice of 100 nmol/kg. A: Compounds 33, B: Compounds 1. Data are presented as the mean of 50, n-Z/hook measurements.

Figure 2. Mean plasma concentration as a function of time (directly proportional) after subcutaneous administration of 100 nmol/kg Compounds 33, 74, 76, 77, 78 and 80 to mice. p-2/measurement hook.

Figure C shows the data of the total content of pancreatic insulin (in μg) in diabetic YAB/aB mice after administration of three concentrations (1.10 and 50 nmol/kg) of Compound 1 according to the present invention IExendin-4(1- 39)-Redz-Read3-|(CIP1,Hei15|Gastrin-17; see below), (ii) three corresponding concentrations of 1:1 additive combination of peptides Exendin-4(1-39) and pei15|Gastrin-17 ( 1, 10 and 50 nmol/kg of each peptide) and (ii) carrier.

Figure 4. D-glucose in the blood of mice. Data were processed using the Kruskal-Wallis test followed by multiple comparisons using Dunn's test, "p" 0.001. Comparison

Compounds 33, Exendin-4, combinations of Exendin-4(1-39) and пей15|Gastrin-17 and carrier, respectively; p-16-19 in the group.

Exendin-4(1-39)-Rea93-Rea3-|SiIp1, Hei15|Gastrin-17, (1)

Exendin-4A(1-39)-(SIP1, Гей 15|Gastrin-17, (2)

Exendin-4(1-39)-K-I (SiIp1, Hets15|Gastrin-17, (3)

Exendin-4(1-39)-AAA-|Sip1, Hei15|Gastrin-17, (4)

Exendin-4(1-39)-5KK-|Sip1, Hei15|Gastrin-17, (5)

Exendin-4(1-39)-Re93-5KK-|(SIP1, G ey15|Gastrin-17, (6)

Exendin-4(1-39)-8Aos-5KK-|СИп1 ГГ ей15|Gastrin-17, (7)

Exendin-4(1-39)-OVE-5KK-|Sip1, Hei15|Gastrin-17, (8)

Exendin-4(1-39)-v8Aos-vAos-|SiIp1, ei15|Gastrin-17, (9)

Exendin-4(1-39)-(Gesh4|Gastrin-b, (10)

Exendin-4(1-39)-K-(Hetz4|Gastrin-6, (11)

Exendin-4(1-39)-AAA-(Gesh4|Gastrin-6, (12)

Exendin-4(1-39)-5KK-I(Hetz4|Gastrin-6, (15)

Exendin-4(1-39)-Rea3-5KK-( ec4|Gastrin-6, (14)

Exendin-4(1-39)-Rea3-Re93-(Hei4|Gastrin-6, (15)

Exendin-4(1-39)-8Aos-5KK-| ets4|Gastrin-6b, (16)

Exendin-4(1-39)-OVE-5KK-|Hets4|Gastrin-b, (17)

Exendin-4(1-39)-8Aos-v8Aos-I ets4|Gastrin-6, (18)

Exendin-4(1-28)-|(Sip1, Hei15|Gastrin-17, (19)

Exendin-4(1-28)-K-ISiIp1, Hets15|Gastrin-17, (20)

Exendin-4(1-28)-AAA-|Sip1, Hei15|Gastrin-17, (21)

Exendin-4(1-28)-5KK-|Sip1, Hei15|Gastrin-17, (22)

Exendin-4(1-28)-Re93-5KK-|SIP1, G ey15|Gastrin-17, (23)

Exendin-4(1-28)-Rea3-Rea3-|SiIp1, Hei15|Gastrin-17, (24)

Exendin-4(1-28)-8Aos-5KK-|СИп1 ГГ ей15|Gastrin-17, (25)

Exendin-4(1-28)-OVE-5KK-|Sip1, Gey15|Gastrin-17, (26)

Exendin-4(1-28)-8Aos-vAos-|SiIp1,ei15|Gastrin-17, (27)

Exendin-4(1-28)-(Gesh4|Gastrin-b, (28)

Exendin-4(1-28)-K-(IHec4|Gastrin-6, (29)

Exendin-4(1-28)-AAA-(Gesh4|Gastrin-6, (30)

Exendin-4(1-28)-5KK-I(Hetz4|Gastrin-6, (31)

Exendin-4(1-28)-Re93-5KK-I (Hech4|Gastrin-6, (32)

Exendin-4(1-28)-Rea3Z-Re93-(Hei4|Gastrin-6, (33)

Exendin-4(1-28)-8Aos-5KK-| ets4|Gastrin-6b, (34)

Exendin-4(1-28)-OVE-5KK-|Hets4|Gastrin-b, (35)

Exendin-4(1-28)-8Aos-v8Aos-I ets4|Gastrin-6, (36)

SG R-1(7-36)-(ISIp1, Gay15|Gastrin-17, (37)

C P-1(7-36)-K-(SIP1, Hei15|Gastrin-17, (38)

Si P-1(7-36)-AADA-|SIP1, Gay15|Gastrin-17, (39)

Si P-1(7-36)-5KK-|SiP1, Hei15|Gastrin-17, (40)

SI P-1(7-36)-Red3-5KK-|SIP1, Hei15|Gastrin-17, (41)

SG R-1(7-36)-Red3-Re93-|SIP1, Hei15|Gastrin-17, (42)

Si P-1(7-36)-8Aos-5KK-|(SIP1, Sey15|Gastrin-17, (43)

Si P-1(7-36)-OVE-5KK-|(SIP1, Sey15|Gastrin-17, (44)

Si P-1(7-36)-8Aos-v8Aos-|SiP1, Hei15|Gastrin-17, (45)

Si R-1(7-36)-(SGey4|Gastrin-6, (46)

Si P-1(7-36)-K-(Gen4|Gastrin-6, (47)

SI P-1(7-36)-AAA-|Hei4|Gastrin-6, (48)

Si P-1(7-36)-5KK-IGey4|Gastrin-6, (49)

SI R-1(7-36)-Red93-5KK-I(Hets4|Gastrin-b, (50)

SI R-1(7-36)-Red3-Re93-Iesh4|Gastrin-6, (51)

SI P-1(7-36)-8Aos-5KK-(Hets4|Gastrin-6, (52)

Si P-1(7-36)-OVE-5KK-I(Gesh4|Gastrin-6 (53) or

C P-1(7-36)-8Aos-8Aos-|(Hetz4|Gastrin-6, (54)

Figure 5. A-insulin in plasma in mice. Data were processed using the Kruskal-Wallis test followed by multiple comparisons using Dunn's test, "p" 0.001. Comparison

Compounds 33, Exendin-4, combinations of Exendin-4(1-39) and пей15|Gastrin-17 and carrier, respectively; p-16-19 in the group.

Figure 6. Pancreatic insulin content in mice. The data were processed using the criterion

Kruskal-Wallis with subsequent multiple comparison using Dunn's test, "p" 0.01.

Comparison of Compound 33, Exendin-4, the combination of Exendin-4(1-39) and pei15|Gastrin-17 and the carrier, respectively; n-16-19 in the group.

Figure 7. D-NrBAISS in mice. Data were processed using the Kruskal-Wallis test followed by multiple comparisons using Dunn's test, "p" 0.01, "p" 0.001.

Comparison of Compound 33, Exendin-4, the combination of Exendin-4(1-39) and pei15|Gastrin-17 and the carrier, respectively; n-16-19 in the group.

Figure 8. D-C-peptide in plasma in mice. The data were processed using the Kruskal test-

Wallis with subsequent multiple comparison using Dunn's test, "p " 0.05. Comparison

Compounds 33, Exendin-4, combinations of Exendin-4(1-39) and пей15|Gastrin-17 and carrier, respectively; p-16-19 in the group.

Figure 9. Effect of subcutaneous administration of Exendin-4, Liraglutide, or Compound 33 on glucose tolerance as measured by area under the curve (AC) after glucose loading in ar/aB mice. Three modes of administration were used (A) Prevention, (B) Treatment or (C) Vacation. The data are presented in the form of average and ZEM (n-8-13Z/group). Statistics: data were compared using two-factor AMOMA analysis with the following Bonferroni correction: "p" 0.05; "p" 0.01; p « 0.001 against the carrier.

Figure 10. Effect of subcutaneous administration of Exendin-4, Liraglutide, or Compound 33 on fasting blood glucose levels 8 hours after the last meal in dr/ydB mice. Three modes of administration were used: (A) Prevention, (B) Treatment, or (C) Vacation. The data are presented in the form of average and ZEM (n-8-13/group). Statistics: Data were compared using AMOMA two-way analysis with the following Bonferroni correction: p < 0.05; cancer 0.01; p < 0.001 vs vehicle.

Figure 11. Effect of subcutaneous administration of Exendin-4, Liraglutide, or Compound 33 on final values (day 93) of (A) plasma C-peptide, (B) plasma insulin, or (C) NATc (95). The data are presented in the form of the average and 5EM (n-8-13/group)". Statistics: data were compared using the AMOMA univariate analysis, the Kruskal-Wallis test with the following Dunn's analysis: хр 0.001, p«0.01, "p « 0.05 against the carrier.

DETAILED DESCRIPTION OF THE INVENTION

As already shown above, one aspect of this invention relates to a peptide conjugate having the formula: while each of the peptide groups of Exendin-4(1-39), Exendin-4(1-28) and SI P-1(7 -36) is covalently connected to the remaining part of the corresponding conjugate molecule through its C-end, and each of the peptide groups |SiIp1, Hei15|Gastrin-17 and (Gen4|Gastrin-b6) is covalently connected to a part , remaining of the corresponding conjugate molecule via its M-terminus; or a pharmaceutically acceptable salt or solvate thereof.

According to another aspect, the present invention relates to a peptide conjugate having the formula:

Exendin-4(1-28)-ReaZz-Re93-(GeizZ|Gastrin-5 (55)

Exendin-4(1-28)-Rea3-Reaz3-|Aia1,H ec4|Gastrin-6 (56)

Exendin-4(1-28)-Rea3-Reaz-|Aia2,H ec4|Gastrin-6 (57)

Exendin-4(1-27)-ReaZz-Re93-(Gastrin-b (58)

Exendin-4(1-28)-Rea3-Rea3-|(Hep2|Gastrin-4 (59)

ISen14|Exendin-4(1-28)-Redz3-Reaz3-(Gay4|Gastrin-6 (60)

Iogp12|Exendin-4(1-28)-Reaz-Rea3-(Hesh4|Gastrin-6 (61) (Iogp27|Exendin-4(1-28)-Red3-Rea93-(Hesh4|Gastrin-6 (62)

IRpe25|Exendin-4(1-28)-Red3-Re93-(Hec4|Gastrin-b (63)

IA5zr28|Exendin-4(1-28)-Rea3z-Re93-(Hei4|Gastrin-b (64) (Tug13)Exendin-4(1-28)-Red3-Re93-(Gen4|Gastrin-b (65)

IOgtp29|Exendin-4(1-28)-Reaz-Rea3-(Gesh4|Gastrin-6 (66)

Exendin-4(1-28)-Rea3-(Gesh4|Gastrin-b (67)

Exendin-4(1-28)-(Hech4|Gastrin-b (68)

Exendin-4(1-27)-(Hech4|Gastrin-11 (69)

Exendin-4(1-27)-Rea3-(Gesh4|Gastrin-b (70)

Exendin-4(1-27)-Rea3-(GeizZ|Gastrin-5 (71)

Exendin-4(1-26)-Rea3-(GeizZ|Gastrin-5 (72)

Exendin-4(1-27)-Rea3-(Gesh2|Gastrin-4 (73)

ITuUg13, GSei14|Exendin-4(1-27)-Red3z-Re93-(Hec4|Gastrin-6 (74) (Tug13,Rpe25|Exendin-4(1-27)-Red3z-Re93-(Gen4|Gastrin-6) (75)

ISey14, Rpe25|Exendin-4A(1-27)-Red3z-Re93-(Gen4|Gastrin-6 (76)

ITUg13, Sey14, Rpe25|Exendin-A(1-27)-Red3z-Re93-(Hets4|Gastrin-6 (77)

Side chain-cyclo (SG uz12,051y16|Exendin-4(1-28)-Red3-Re93-|(Gen4|Gastrin-b (78)

Side chain-cycloC(OIsh16,G uz29|Exendin-4(1-28)-Red3-Re93-|(Gen4|Gastrin-b (79)

Side chain-cyclo((Huz20,1024|Exendin-4(1-28)-Red3-Re93-|(Gen4|Gastrin-b (80)

ISuz16|Exendin-4(1-28)-Red3-Re93-|(G en4|Gastrin-b (81)

Exendin-4(1-28)-Rea3-K-Re93-(Gesh4|Gastrin-b (82)

Exendin-4(1-28)-(Tpg4|Gastrin-b (83)

Exendin-4(1-28)-IRpe4|Gastrin-b (84)

ISen14|Exendin-4(1-28)-P1 MaiIZ, Gech4|Gastrin-6 (85)

ISey14|Exendin-4(1-28)-IMIeye4|Gastrin-6 (86)

ISen14|Exendin-4(1-28)-( ей4(3-(3-Pyridyl)-AIa|b|Gastrin-b (87)

ISIn9, Hei14, Rpe25, Tug13|) Exendin-4(1-27)-Redz-Re93-(Gesh4|Gastrin-6 (88)

ISey14, Rpe25, Tug13|Exendin-4(1-27)-Red3z-Reaz-(Gesh4,Rpez|Gastrin-6 (89)

ISIn9, Hei14, Rpe25, Tug13|Exendin-4(1-27)-Red3z-Reaz-I(Gesh4, Rpez|Gastrin-6 (90)

IAgd927 I ei14 Rpe25, Tug13|Exendin-4(1-27)-Re93-( ec4|Gastrin-6 (91)

IAg912,27,I ey14 I uh16,Rpe25, Tug13|Exendin-4(1-27)-Re93-(ec4|Gastrin-b (92)

IAg912,27,I ey14 I u520,Rpe25, Tug13|Exendin-4(1-27)-Re93-(ec4|Gastrin-b (93)

IAg912,27,I ey14 I uz24, Rpe25, Tug13|Exendin-4(1-27)-Re93-(ec4|Gastrin-b (94)

IAg912, Hei14, Rpe25, Tug13|) Exendin-4(1-27)-Re93-(ec4|Gastrin-6 (95)

ISiSh9 and ei14, Rpe25, Tup13|Exendin-4(1-27)-(IHec2|Gastrin-4 (96)

ISIn9, Hei14, Rpe25, Tug13|)Exendin-4(1-27)-Re93-IHei2|Gastrin-4 (97)

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Og-Re93-( ei2|Gastrin-4 (98)

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Rea3-Ot-|( ei2|Gastrin-4 (99)

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Ogp-Ogp-I ei2|Gastrin-4 (100)

ISIn9, ei14, Rpe25, Tug13|Exendin-4(1-27)-(IHec4|Gastrin-b (101)

ISIn9, Hei14, Rpe25, Tug13|)Exendin-4(1-27)-Re93-I(Gesh4|Gastrin-b (102)

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Og-Re93-( ec4|Gastrin-b (103)

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Rea3-Ot-|( ec4|Gastrin-b (104)

ISIsh9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Ogp-Ogp-I( en4|Gastrin-b (105)

Isuz(Hexadecanoyl-isoIm)Z4|C P-1(7-37)-RedZz-Rea93-(Hex4|Gastrin-6 (106)

IAgo34 Gus(Hexadecanoyl-isos1Iy)26|I P-1(7-37)-Rea3-Rea93-(He4|Gastrin-b (107)

IAgo926,34 I uz(Hexadecanoyl-isosyl)36|SI P-1(7-37)-Red3-Re93-(IGa4|Gastrin-b (108)

Isuz(Hexadecanoyl-iso1I1)26|SI P-1(7-37)-RedZz-Rea93-(Hex4|Gastrin-6 (109)

IAgo26,34, Suv, I uz(Hexadecanoyl-isosyl)36|SI P-1(7-37)-Red3-Re93-(IGhe4|Gastrin-b (110)

IAILB, Ago34 I uz(Hexadecanoyl-isos1Iy)26|C I P-1(7-37)-Redz-Re93-(eshy4|Gastrin-6 (111)

IAiB8, AgazAai P-1(7-37)-Rea3-Rea3-(ec4|Gastrin-b) (112)

IAhaZzCai P-1(7-37)-Red3-Re93-(en4|Gastrin-6, (113) or its pharmaceutically acceptable salt or solvate.

The above formulas for the peptide conjugates of the present invention are written using traditional and widely used abbreviations/notations for the various peptide groups considered (eg Exendin-4(1-39), Exendin-4(1-28) and CI P-1(7-36)), can be written in the form of a traditional complete amino acid sequence, as presented below (linker groups are highlighted in bold): (ZEO IO MO: 1) Н-НаЕСТЕТ5ОИ ЗБКОМЕЕЕАМВИ РЕМИ КМССРЗОАРРРО-РедЗ-Редаз-

OSRUM ЕЕЕЕЕАМОаУ ЮБ-МН2 (ZEO IO MO: 2) n-

NOaeESTET5OI ZKOMEEEEAMVI RIEMI KMSSRZZIARRRBZOSTRUM EEEEEEAMSUMI OB-MNA (without linker) (ZEO IO MO: З) N-NSESTET5OI ZKOMEEEEAMVI RIBYEMI KM RZBOARRRB-K-

OSRUM EEEEEAMOaU UB-MN2 (ZEO IO MO: 4) N-NOESTET5OI ZKOMEEEEAMVI RIEMI KM RBZBOARRRBO-ADA-

OSRUM EEEEEAMOaU UB-MN2 (ZEO IO MO: 5) N-NOESTET5OI ZKOMEEEEAMVI RIEMI KM ROBOARRRUB-5KK-

OSRUM EEEEEAMOaU YUB-MN2 (ZEO IO MO: b) N-NaESTET5OYI BKOMEEEEAMVI RIBEMI KMSD RZZOARRRO-Red3-5KK-

OSRUM EEEEEAMOaU UB-MN2 (ZEO IO MO: 7) N-NSOESTET5OI ZKOMEEEAMVI RIEMI KMSROZIARRRO-vaAos-KK-

OSRUM EEEEEAMOaU YUB-MN2 (ZEO IO MO: 8)

OSRUM EEEEEAMOaU YUB-MN2 (ZEO IO MO: 9) N-NaESTET5OYI ZBKOMEEEEAMVI RIBMI KM RZBZOARRRO-8Aos-vaAos-

OSRUM ЕЕЕЕЕАМОаУ ЮБ-МН2 (ZEBEO AND MO: 10) Н-НСЕЕЕЕАМВИ RIEMI KMSSRZBSARRRBOZUSUUI OB-МНО2 (without linker) (ZEO IU MO: 11) NNNEESTET5ОI 5KOMEEEEAMVI RIEMI KM RZBOARRRI-K-MSUMI OB-MN2

(ZEO and MO: 12) NNNOVICEMUEIA and RIEEAMVY RIEUMI KM RZBORRRRO-YU-UU-MN2 (ZEO and M MN: 13) Rea3-ZKK-MSMMI OB-

Mna (ZEO 10 MO: 15)

Mna (ZEO and MO: 16)

Mna (ZEO and MO: 17)

Mna (ZEO 10 MO: 18)

Mna (ZEBEO AND MO: 19) N-NOaESTET5OYI BKOMEEEEAMVI REM KMOSTRUUL EEEEEAMOUUUI OB-MNa2 (without linker) (ZEO AND MO: 20) NNNEESTET5OI 5KOMEEEEAMVI RIEUMI KM-K-OSRU/L EEEEEAMSUMI OB-MN2 (ZEO IYU MO: 21) NNNEEAIEAIA COMEEMEEAMVY RIEUI CM-AAAAAAA-OSRUME EEEEMSAUAUA OB-MN2 (Zeo and M: 22) EEEEEEAMSUMI OB-

Mna (ZEO IU MO: 24) N-NSESaTET5OI BKOMEEEEAMVI RIEMI KM-Rea3-Rea3-OSRU/L EEEEEEAMSUMI OB-

Mna (ZEO 10 MO: 25)

Mna (ZEO 10 MO: 26) N-NOESaSTET5OI ZKOMEEEEAMVI RIEUMI KM-OVE-5KK-OSRUM EEEEEEAMSOUMI OB-

Mna (ZEO 10 MO: 27)

Mna (ZEO AND MO: 28) NNNEESTET5OI ZKOMEEEAMVI RIEUMI KM-USUMI OB-MNA (without linker) (ZEO IU MO: 29) NNNN EU TET5OI ZKOMEEEEAMVAI RIEU KM-K-USUM OB-MN2 (ZEO IU MO: 30) NNNE EU TET5OYI ZKOMEEEAMVI REM KM-AAA-USUM OB-MN2 (ZEO IO MO: 31) N-N-NEBESaITET5OYI ZKOMEEEEAMVI RIEU KM-5KK-USUM OB-MNa (ZEO IR MO: 32) NNNEEEEESTET5OI ZKOMEEEEAMVI RIEUI KM-Red3Z3-5KK-MSUMI OB-MNa (ZEO Ir MO: 33) NNNEESTET5OYI ZKOMEEEEAMVI RIEUI KM-RedZz-Red3-ZhaUM OB-MN2 (ZEO Ir MO: 34) NNNEEEESTET5OYI ZKOMEEEEAMVI RIEUUI KM-VAos-5KK-USAU OB-MNa2 (ZEO Ir MO: 35) NN-NEESTET5OI 5KOM EEEAMVI RI EM KM-OVE-5KK-MSaUM OB-MN2 (ZEO Ir MO: 36) N-noestetzoua55555555555555Ma Ukevosrum Eeeemimum Ob-Mnea (without Linker) (Zeo and MO: 38) NN "NNAIEUNOSUM55MA MNa (ZEO IU MO: 40) NNNAEEESTETZOM55MI ESOAADAKERIAUMI UKaV-5KK-OSRU/L EEEEEAMOIaU OB-MNa (ZEO IO MO: 441) N-NAESTET5OU5ZMUI ESOAAKERIAMI UKaV-Reaz-5KK-

OSRUM EEEEEAMOaU YUB-MN2 (ZEO IO MO: 42) N-NAESTET5OU5ZMUI ESOAAKERIAMI UKOaV-Reaz-Reaz-

OSRUM EEEEEAMOaU YUB-MN2 (ZEO IO MO: 43) N-NAESTET5OU5ZMUI ESOAAKERIAMI UKOaV-vaAos-5KK-

OSRUM EEEEEAMOaU UB-MN2 (ZEO and MO: 44) NN NAESTETZOU5Z5MI ESOADAKERIAM/I UKAV-OVE-5KK-OSRUM EEEEEAMSOUMI OB-

Mna (ZEO IO MO: 45)

OSRUM EEEEEAMOaU UB-MN2 (ZEO I O MO: 46) N"NAESTETZOU5ZMUI ESOADAKERIAUMI UKa VMS OB-M Na (without linker; (ZEO IU MO: 47) NNNAYESTETZOM55ZMI ESOAADAKERIAUMI UKav-k-Mau oB-MNa (ZEO IU MO: 48 () ZEO IYU MO: 51) NN"NNAEESTETZOM55MUI ESOADAKERIAMI UKaV-Red3-RediZ-mSaU OBE-MNa2 (ZEO IU MO: 52) NN"NNAESTETZOM55MI ESOADAKERIAUMI UKaV-8Aos-5KK-USUMI OB-MNa (ZEO IYU MO: 53) NNNAMISIE ESOZOU5 UKIAv-OVE-ZKK-MaUm OB-MN2 (ZEO I MO: 54) NNNAEESTETZOM55MUI ESODAKERIAMI UKaV-8Aos-vaAos-uSsUMI OB-MN2 (ZEO Ir MO: 55) NNNEESTET5OI ZKOMEEEAMVI RI EMMI KM-Rea3-Rea3-SMMI OB-MN2 (ZEO and MO: 56) NN-NEESTET5OYI ZKOMEEEEAMVI RI EI KM-Rea3-Rea3-ASMU OB-MN2

(5EO IO MO: 57) NN-NOESTET5OI BKOMEEEEAMVI RI EM KM-RedZz-Re93-MAMMI OB-M H2 (5EO IO MO: 58) NNNOESTET5OI BKOMEEEEAMVI RI EM K-RedZz-Rea3-MSUMI OB-M Na (5EO IO MO : 59) NN-NOESTET5OYI BKOMEEEEAMVI RIEMLI KM-Red3-Red3-ZhMI OB-MN2 (5EO IO MO: 60) N-NOESTET5OYII 5KOI EEEAMVI RIEUMI KM-Reaz3-Red3-HSUMI OB-MN2 (5EO IO MO: 61) N- N-NOESTET5OI 5-Ot-OMEEEEAMVI RIEM/LI KM-RedZz-Red3-mMaUMI OB-MN2 (5EO IO MO: 62) NNNOESTET5OI BKOMEEEEAMVI RIEMI "Ogp-M-RedZz-Red3-MaUMI OB-MN2 (5EO IO MO: 63 () - RedZ3-RedZz-MSsUMI YUB-MNa. (5EO IU MO: 66) NNNOESTET5OI BKOMEEEEAM-Ottp- I RIEMMI KM-Red3-Red3-MSUMI OB-MN2 (ZEO IU MO: 67) NNNOESTET5OI BKOMEEEEAMVI GRIE KM-Red3-MaUMG OB-MNa (ZEO IU MO: 68) N -NNE EU TET5OYI ZKOMEEEAMVI RIEU KMMOaMUM OB-MN2 (ZEO IYU MO: 69) H-"NOEESTET50I 5KO EEEEAMVI RIEMI KEEEEEAMOaUMMI OB-MN2 (ZEO IYU MO: 70) NNNOESTET5OI BKOMEEEEAMVI RIEMI K-Redz-MaUMZEO OB-MYU : 71) NN"NOESTET50ОI BKOMEEEEAMVI HEAT K-Red3-SUMI OB-МН2 (ZEO IYU MO: 72) Н-"NOESTET50ОИ BKOMEEEEAMVI HIRE -Red3-SUMI OB-МН2 (ZEO IYU MO: 73) NNNOESTET5ОИ BKOMEEEEAMVI RIEM K-Red3- ЖМ ОБ-МН2 (5EO ИО МО: 74) Н-НОЕСТЕТ5ОИИ 5КМИ ЕЕЕАМВИ РЕММИ K-RedЗз-Red3-МСсУМИ OB-МН2 (5EO ИО МО МО: 75) Н-Н-НОЕСТЕТ5ОИ 5БКУМЕЕЕАМВИ RIERI K-Red3-Ре93-ЖSUMI ОБ-МН2 MH2 (5EO IO MO: 76) H-N-NOESTET5OII 5KOI EEEAMVI RIERI K-Red3-Red3-MaUMI OB-MH2 (5EO IO MO: 77) N-NOESTET5OIII 5KMI EEEAMVI RIERI K-Rea3-Re93-HSUMI OB-MH2 ( 5EO IO MO: 78) H-NOESTET5OYI 5-K()-OME-E()-EAMVI RIEMMI KM-Redi3-RedZz-ZhSUMI OB-MNa. (5EO IO MO: 79) H-N-NOESTET5OYI BKOME-E( )-EAM-K(O-SEIEUMI KM-EdZ-Ed Zz-MaUM OB-MNa. (ZEO IO MO: 80) N"NOEESTET5OI BKOMEEEEAM-KO)-I RI-EO-U/L KM-RedZz-Rea3-MOUMI OB-MN2 (5EO IO MO: 81) NNNOESTET5OI BKOMEKEAMVI RIEMI KM-Rea3-Red3-MSUMI OB-MN2 (5EO IU MO: 82) NNNOESTET5OYI BKOMEEEEAMVI RIEMI KM-Red3-K-Red3-ZhS UM OB-MN2 (5EO IYU MO: 83) NNNOESTET5OI 5KO EEEAMVI RIEUMI KMUSUMTOB-MN2 (ZEO IYU MO: 84) N-НNE EU TET5OYI ZKOMEEEEAMVI RIEU KMU RO B-MNa2 (ZEO IO MO: 85) N-"NEESTET5OI 5KOI EEEAMVI IEM KMMa-1 MaI- OB-MNa (ZEO IYU MO: 86) N-NNEEESTET5OI 5KOI EEEAMVIETEMMI KMMSMU-Mie-OB-MNa (5EO IO MO: 87) N-NOESTET5OI 5KOI EEEAMVI RITEUI KMMSUMI O-(3-(3-Pyridyl)-alanyl|-MH2. (5EO IO MO: 88) N-NACETETH5EII 5KMI EEEAMVI RIERI K-Red3-RedZ-MSUMI OB-MNa (5EO 10 MO: 89) N-NOESTET5OI KM EEEAMVI RIERI K-Red3-Red3-Zhag OB-MN2 (5EO IO MO: 90) N-NOESTET5EI 5KMUI EEEAMVI RIERI K-Red3-RedZz-MavgRI OB-MN2 ( 5EO 0 MO: 91) N-NOESTET5OI ZKU EEEAMVI RIERI K-Re93-HSUMI OB-MN2 (5EO IO MO: 92) N-NOESTET5OI 5AMI EKEAMVI RIERI V-RedZz-Ж SUM OB-MNa (5EO IO MO: 93) H -NOESTET5OI ZAM EEEAMKI RIERI V-Red3-MaUMI OB-MN2 (5 EO IO MO: 94) N-NSESTET5OYI ZAM EEEAMVI RICRI V-RedZz-Ж SUM OB-MNa (5EO IO MO: 95) N-NOESTET5OYI ZAM EEEAMVI RIERI K-Red3-MSUM OB-MN2 (5EO IO MO: 96) N -NOESTET5EI 5KMUI EEEAMVI RIERI KUM OB-MN2 (5EO IO MO: 97) N-NOESTET5EI 5KMI EEEAMVI RIERI K-Red3-MI OB-MN2 (5EO IO MO: 98) N-NSESTET5EI 5KMI EEEAMVI RIERI K-Ogp-Red3-UMI OB-MN2 (5EO IO MO: 99) N-NSESTET5EI 5KMI EEEAMVI RIERI K-Red3-Ogp-UMI OB-MN2 (5EO IO MO: 100) N"NOESTET5EI ZKU EEEAMVI RIERI K-Ogt-Ogp-MmI OB-MN2 ( 5EO IO MO: 101) NN-NOESTET5EI ZKU EEEAMVI RIERI KMSUMI OB-MN2 (5EO IO MO: 102) NN-NOESTET5EI ZKU EEEAMVI RIERI K-Red3-MSUMI OB-MN2 (5EO IO MO: 103) N"NOESTET5EI ZKU EEEAMVI ERI K-Ogt-Red3-MsUMI OB-MN2 (5EO IO MO: 104) N-NOESTET5EI ZKU EEEAMVI RIERI K-Red3-Ogp-USUMI OB-MN2 (5EO IO MO: 105) N"-NOESTET5EI ZKU EEEAMVI RIERI K-Og -Ogp-MaUM OB-MH2 (ZEBEO 10 MO: 106) H-NAESTET5OUBZBMI ESOAA-K(Hexadecanoyl-isosIsh)-SsvaAa-RedzZ-Redz-

MUSU OB-MNa2 (5EBEO AND MO: 107) H-"NAESTET5OM55UI ESOAA-K(Hexadecanoyl-isoI0)-ERIAMI UVaAOI-Redz-

Rea3-MSUMI OB-MH2 (5EBEO AND MO: 108) H-NAESTET5OU55UI ESOAAVERIAMI UVO-K(Hexadecanoyl-isos1Iy)-c-Redyava-

Rea3-MSUMI OB-MH2 (5EBEO 10 MO: 109) H-NAESTET5OMU55UI ESOAA-K(Hexadecanoyl-isoSy)-ERIAUMLI UKaVa-Redz-

Rea3-MSUMI OB-MH2 (5EBEO 10 MO: 110) N-NOESTET5OU55UI ESOAAVERIAMI UVO-K(Hexadecanoyl-isos1Iy)-c-Rediva-

Rea3-MSUMI OB-MH2 (5EO AND MO: 111) H-N-AIB-ESTET5OM55MI ESOAA-K(Hexadecanoyl-isocyIsh)-ERIAMI MNaNO-Redz-

Rea3-MSUMI OB-MH2 (ZEO IO MO: 112) N-N-AI-ESTET5OM55MU ESOADAKERIAMI UVaVa-Redz-Red3-MaUmI OB-MH2

(ZEO IU MO: 113) NNNAYESTETZOU55ZMI ESOAAKERIAMI Ua Va-Reaz-Rea3-USaUMI OB-MNa, while the abbreviations Red3, vAos, OBE, 1 Mai, rBAia, Ogp, ORK, OBy, Saba and Aib denote the following amino acid groups, which not found in nature:

Reds: - "МН-СН2-СН2-0-СН2-СН2г-0-СН2-С(0)- (obtained from 8-amino-3,6-dioxaoctanoic acid); vAos: -"МН-СН2-СН2-СН2г-СН2-СН2г-СН2г-СН2г-О(0)-(obtained from 8-aminooctanoic acid);

OBE: "MH - o (obtained from 4-(2-aminoethyl)-6-dibenzofuranpropanoic acid); 1 Ma!: 1-naphthylalanine; pAia: beta-alanine;

Saba: y-aminobutanoic acid; holes: α-amino-isobutanoic acid; rBy: diaminobutanoic acid;

ORE: diaminopropionic acid;

From: ornithine.

Thus, taking into account the location of the linker group in the peptide conjugate according to the present invention, the linker group -Red3z-Redz3-, for example, denotes the following chemical group: -MnH-CH2g-SnHg-o-Cng-CHg-o-CHg -с(0)-МН-СН2г-СнНг-о-СнН2г-СнНГ-о-СН2г-С(О)-, while the group -МН-.... to the left of the linker group under consideration is covalently attached to the group , obtained from Exendin-4- or SI P-1, - the peptide conjugate under consideration; and the group ...-

C(O)- to the right of the linker group under consideration is attached to a group derived from gastrin, the peptide conjugate under consideration.

In the marked linker groups remaining, -K- denotes the residue of the amino acid lysine, -АДА- denotes the tripeptide residue -АИа-АИа-Аия-, and -"ЗКК-" denotes the tripeptide residue -5е1-И ув-и ув-.

It should be understood that in some peptide conjugates according to the present invention, listed above, the group of the peptide sequence CI P-1(7-36) is derived from the sequence CI P-1 of a person (PS P-1) or its analogue.

It should be understood that in some peptide conjugates according to the present invention, listed above, the group of the peptide sequence of Exendin-4(1-39) is derived from the sequence of Exendin-4 NeIodegtta zizresisht or is its analogue.

Similarly, the groups (SiIp1, ei15|Gastrin-17 and (Hech4|IGastrin-6) in the indicated conjugates are obtained from human gastrin.

It should be understood that 5EO IYU MO: 1 is equivalent to Compound 1, ZEO IYUO MO: 2 is equivalent to Compound 2, etc.

It should be understood that each of the above peptide conjugates 1-54 individually, i.e., Compound 1 or Compound 2 or Compound C (etc. up to Compound 54), and in addition each of the peptide conjugates 55 -113 listed below (see Table 2 and C in Example 2), separately, i.e., Compound 55 or Compound 56 ".. (etc. to Compound 113) or a pharmaceutically acceptable salt or solvate thereof also constitute a separate aspect of the present invention .

In the context of the present invention, when amino acids are not designated by their full name (e.g., alanine, arginine, etc.), they are designated by their traditional three-letter and/or one-letter abbreviations (e.g., Aia or A for alanine, Ag or K for arginine, etc.).

The term "peptide conjugate" in the context of this invention refers to a molecule in which a first peptide group is attached (i.e., linked or connected) directly or via a linker chemical group (i.e., a bridge or spacer) by means of a covalent chemical bond with the second peptide group.

The compounds according to the present invention may carry one or more intramolecular lactam rings in the peptide sequence. Each such bridge in the compounds listed in Table 2 (denoted by the prefix "cyclo side chain") is formed between a side chain that contains a carboxylic acid and another side chain that contains an amine. Two amino acid residues are usually separated by three amino acids in a linear sequence.

In the peptide conjugates of the present invention, Exendin-4 or 74 may overlap at least 75 95 with natural Exendin-4, for example, at least 80, 85, 90 or 95 9.

In the peptide conjugates of the present invention, gastrin or Ua may overlap by at least 7095 with native gastrin, for example, at least 75, 80, 85, 90, or 95 95. In the peptide conjugates of the present invention, si P-1 or Ha can match at least 85 95 with natural

SI P-1, for example, at least 90 or 95 9.

According to one embodiment, the polypeptide according to 3 of the present invention may contain an amino acid sequence represented by one of ""EO IU MO: 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 , 39, 40, 41, 42, 43, 44, 45, Ab, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 , 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 , 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 113 , or a functional fragment/variant thereof that is at least approximately 80 bps, 85 95, 90 Fo, 95 95, 97 Us, 98 95, 99 Fo, 99.5 90 identical to one or more of the specified sequences or their functional fragments/variants , which has no more than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitution compared to one or more specified sequences, without signal sequence or with it, without replacing one or more cysteine residues with another residue, such as serine, or with it, and their continuous segments having at least 2 amino acid residues in length.

According to one variant of implementation, the polypeptide according to the present invention (ii) coincides in the amino acid sequence at least 99 95 with one of the ZEO IUO MO: 1,2, 3,4, 5,6, 7, 8, 9, 10, 11 , 12,13, 14,15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36 , 37, 38, 39, 40, 41, 42, AZ, 44, 45, Ab, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 , 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111 , 112 and 113 or its part; or (iii) contains at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, Ab, A7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 continuous amino acids of any of the FEO IU MO: 1,2,3,4,5,6, 7, 8, 9, 1 0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, C8, 39, 40, 41, 42, 43, 44, 45, Ab, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112 113; or (iiii) both.

The term "pharmaceutically acceptable salt" in the context of the present invention (a pharmaceutically acceptable salt of a peptide conjugate according to the present invention) refers to a salt that is safe for the patient or person to whom said salt is administered. It can be a salt selected from acid-addition salts and basic salts. Examples of acid addition salts include chlorides, citrates, and acetates.

Examples of basic salts include salts in which the cation is selected from alkali metal ions such as sodium or potassium ions, alkaline earth metal cations such as calcium or magnesium, and ammonium ions such as M(K1ХК2)(КЗ3)( K4), where K1, K2, KZ and K4 independently usually denote hydrogen, optionally substituted C1-e alkyl or optionally substituted C1-e alkenyl. Examples of C1-E alkyl groups include methyl, ethyl, 1-propyl and 2-propyl. Examples of important C1-e alkenyl groups include vinyl, 1-propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in the publication 17th edition "Keptipdiopye Rpaptaseciisa! Zsieepse5", AMopzo V. Seppago (Ed.), Magk Rybiiznipa

Sotrapu, Easiop, RA, O5A, 1985 (and its earlier editions), in the third edition of Epsusioraedia oii

Rpaptaseshisa! Tesppoiodu", dchatev bulagrgisk (Ea.), Iptotpta Neainsage OA (Ips.), MM, OA, 2007, and 9.

React. 5 66:2 (1977).

The term "solvate" in the context of this invention refers to a complex with a certain stoichiometry formed between a solute (in this case, a peptide conjugate or a pharmaceutically acceptable salt according to this invention) and a solvent. The solvent in this case can be, for example, water, ethanol or other pharmaceutically acceptable, usually low molecular weight organic substances, such as, but not limited to, acetic acid or lactic acid.

If the considered solvent is water, then the solvate is usually denoted by the term hydrate.

Another aspect of the present invention relates to a peptide conjugate or a pharmaceutically acceptable salt thereof according to the present invention for use as a medicinal product. According to another aspect, the subject medicament is a medicament for use in the treatment of a patient in need thereof of one of the following diseases or disorders, or related conditions: type 1 diabetes, type 2 diabetes, prediabetes, insulin resistance syndrome, glucose tolerance disorder (IST), painful conditions associated with elevated blood glucose levels, hyperglycemia, hypertension, atherogenic dyslipidemia, arteriosclerosis (for example, atherosclerosis), coronary heart disease, peripheral artery disease, stroke, microangiopathy, stomach disease, metabolic syndrome, cancer (such as colon cancer), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).

Other diseases or disorders of possible relevance in this regard include obesity, morbid obesity, obesity-induced inflammation, obesity-induced gallbladder disease, and obesity-induced sleep apnea.

In yet another aspect, said medicament is a medicament for use in inducing pancreatic islet neogenesis in a patient in need thereof (eg, to promote the formation of new rD cells in pancreatic islets).

In yet another aspect, said medicament is a medicament for use in inducing in a patient in need thereof survival of β-cells in pancreatic islets (eg, to prevent loss of β-cells in pancreatic islets).

In yet another aspect, said medicament is a medicament for use in preventing B-cell apoptosis in pancreatic islets in a patient in need thereof (eg, to prevent loss of β-cells in pancreatic islets).

According to another aspect of the present invention, said drug is a drug for use in lowering hemoglobin levels in a patient in need thereof. B1TAc (glycosylated hemoglobin; NHA c) in the blood.

According to yet another aspect, the present invention relates to a peptide conjugate according to the present invention for the manufacture of a medicament for the treatment of a patient in need thereof of one or more of the following conditions, diseases or disorders: type 1 diabetes, type 2 diabetes , prediabetes, insulin resistance syndrome, glucose tolerance disorder (IST), disease states associated with elevated blood glucose levels, hyperglycemia, hypertension, atherogenic dyslipidemia, arteriosclerosis (for example, atherosclerosis), coronary heart disease, peripheral artery disease, stroke , microangiopathy, stomach disease, metabolic syndrome, cancer (eg, colon cancer), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).

The peptide conjugate according to the present invention can be used for: the manufacture of a medicinal product for inducing pancreatic islet neogenesis in a patient in need thereof; the manufacture of a medicament for preventing apoptosis of B cells in pancreatic islets in a patient in need thereof; or the manufacture of a medicinal product to reduce the levels of hemoglobin p1As (glycosylated hemoglobin; HbATc) in the blood of a patient in need.

Among other related aspects, additional aspects of the present invention are suitable methods of treating conditions, diseases or disorders other than those mentioned above. Thus, one such additional aspect of the present invention relates to a method of treating a patient in need thereof for one or more of the following diseases or disorders: type 1 diabetes, type 2 diabetes, prediabetes, insulin resistance syndrome, glucose tolerance disorder (GTI) , disease states associated with elevated blood glucose levels, hyperglycemia, hypertension, atherogenic dyslipidemia, arteriosclerosis (eg, atherosclerosis), coronary heart disease, peripheral artery disease, stroke, microangiopathy, stomach disease, metabolic syndrome, cancer (eg, colon cancer), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), said method includes administering to a patient a therapeutically effective amount of a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the present invention.

In addition, other possible underlying conditions, diseases or disorders in the context of the methods of treatment according to the present invention include obesity, morbid obesity, obesity-induced inflammation, obesity-induced gallbladder disease, and obesity-induced sleep apnea.

Another aspect of the present invention relates to a method of inducing pancreatic islet neogenesis in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the present invention.

An additional aspect of the present invention relates to a method of ensuring the survival of B cells in pancreatic islets in a patient in need thereof, said method includes administering to the patient a therapeutically effective amount of a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the present invention.

An additional aspect of the present invention relates to a method of reducing or preventing apoptosis of p-cells in pancreatic islets in a patient in need thereof, said method includes administering to the patient a therapeutically effective amount of a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the present invention.

Another aspect of the present invention relates to a method of reducing the levels of hemoglobin B1As (glycosylated hemoglobin; NATc) in the blood of a patient in need thereof, said method includes administering to the patient a therapeutically effective amount of a peptide conjugate or its pharmaceutically acceptable salt or solvate according to the present invention.

Other aspects of the present invention include the following: a method of treating a patient in need thereof for a condition caused by elevated glucose levels;

a way to lower glucose levels in a patient in need; a method of stimulating the release of insulin in a patient in need thereof; method of regulating gastric emptying in a patient who needs it; and a method of lowering plasma lipid levels in a patient in need thereof.

In each of the latter methods according to the present invention, said method includes administering to the patient a therapeutically effective amount of the peptide conjugate or its pharmaceutically acceptable salt or solvate according to the present invention.

The term "therapeutically effective amount" when used in the context of the above described methods of treatment or other therapeutic interventions in accordance with the invention refers to an amount sufficient to cure, ameliorate, alleviate or partially stop the clinical manifestations of a particular disease, disorder or condition that is object of treatment or other therapeutic intervention under consideration. An amount sufficient to achieve this goal is defined as a therapeutically effective amount. The amount administered and the method of administration can be adapted to achieve optimal effectiveness. The amount effective for this purpose will depend, in particular, on the severity of the disease, disorder or condition that is the subject of a particular treatment or other therapeutic intervention, the body weight and general condition of the patient under consideration, nutrition, possible concomitant treatment and other factors, well known to specialists in this field of medicine. The appropriate dose and dosage regimen most suitable for administration of a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the invention to a human can be determined by the results obtained using the present invention and can be confirmed in properly designed clinical trials. The effective dose and treatment protocol can be determined using traditional methods, starting with a low dose in laboratory animals and then increasing the dose while monitoring the effects and systematically changing the dosing regimen. Numerous factors can be taken into account by a doctor when determining the optimal dosage for a given object. Such considerations are well known to those skilled in the art.

The term "treatment" and its grammatical variants (e.g., "which is cured", "treatment", "treat" when used in this context refer to an approach for obtaining useful or desired clinical results. For the purposes of this invention, useful or desired clinical results include , but are not limited to, relief of symptoms, reduction of disease severity, stabilization (i.e., not worsening) of disease state, delay or slowing of disease progression, improvement or temporary improvement of disease state, and remission (partial or complete), both marked and unmarked." "Treatment" may also mean prolonging survival compared to the expected life expectancy in the absence of treatment. "Treatment" in some embodiments of the invention may be an intervention that is performed to prevent the development of or change the pathology of a condition, disease, or disorder. Accordingly, the term "treatment " can refer to both therapeutic intervention and profiles active or preventive measures. A subject (eg, a human) in need of treatment may thus be a subject already suffering from the disease or disorder in question, or a subject in whom the disorder is to be prevented.

The term "treatment" thus includes suppressing or reducing the severity of the pathological condition or symptoms (eg, weight gain or hyperglycemia) compared to no treatment and need not necessarily mean the complete cessation of the relevant disease, disorder or condition.

The term "agonist" in the context of this invention means a substance (ligand) that activates the type of receptor in question.

The term "CI P-1 receptor agonist" in the context of this invention means a substance (ligand) (which is sometimes referred to as a "CI P-1 agonist") that activates an OCI P-1 receptor, such as a human CI P-1 receptor.

Substances that activate the human SI P-1 receptor include natural peptide hormones SI P-1: SI P-1017-37), SI P-1(7-36)amide, oxyntomodulin, Exendin-3, Exendin-4, glucagon , gastric inhibitory polypeptide (SIP) and their functional analogs and derivatives.

The term "antagonist" when used in the context of this invention refers to a substance (ligand) that blocks, neutralizes or counteracts the effect of another substance (ligand) that functions as an agonist with respect to the type of receptor in question.

In the context of the present invention, a patient in need of a particular treatment or other therapeutic intervention and referred to in connection with the various aspects of the present invention described above is preferably a mammal and, more specifically, a human. An additional aspect of the present invention relates to a pharmaceutical composition comprising a peptide conjugate or a pharmaceutically acceptable salt or solvate thereof according to the present invention together with a pharmaceutically acceptable carrier, excipient or base.

Synthesis of peptide conjugates

Peptide conjugates according to the present invention can be produced using standard synthesis methods, using recombinant expression systems, or using any

any other suitable method. Thus, conjugates can be synthesized in a variety of ways, including, for example, a method that involves: (a) synthesizing the peptide conjugate by standard solid-phase or liquid-phase techniques, either stepwise or by fragment assembly and isolation and purification of the final product of the peptide conjugate; (b) expressing the nucleic acid construct encoding the peptide conjugate in a host cell and isolating the expression product from the host cell culture; or (c) expressing a nucleic acid construct encoding a peptide conjugate of migo in a cell-free system and purifying the expression product; or any combination of methods (a), (b) or (c) for obtaining fragments of a peptide conjugate, subsequent ligation of fragments to obtain a peptide conjugate and isolation of a peptide conjugate.

It may often be preferable to synthesize the conjugates of the present invention using solid-phase or liquid-phase peptide synthesis. In this regard, it is possible to cite as a reference the publication MO 98/11125 or, including, RieYid5, S.V. oh oh "Rgipsirie5 apa Rgasiise oi bZoiia-Rnaze

Reriide Zupipeviv"; in: Zupipeiiis Reriide5, Sgedogu A. sgapi (ea.), Ohtoga Opimegeyu Rge55 (2nd edition, 2002) and examples of synthesis in them.

One or more amino acid side chains in a compound according to the present invention may also be conjugated with a lipophilic substituent. Said lipophilic substituent may be covalently bound to an atom in the side chain of an amino acid or, alternatively, may be conjugated to the side chain of an amino acid by means of a spacer. The amino acid can be part of peptide 2 or part of peptide B.

Without wishing to be bound by theory, it is believed that the lipophilic substituent binds albumin in the bloodstream, thereby protecting the compound of the present invention from enzymatic degradation, which increases the half-life of the compound. A spacer, if present, is used to provide spacing between the compound and the lipophilic substituent.

Said lipophilic substituent can be attached to the amino acid side chain or spacer in the form of an ester, sulfonic ether, thioether, amide, or sulfonamide.

Accordingly, it will be clear that a preferably lipophilic substituent includes an acyl group, a sulfonyl group, an M atom, an O atom, or a 5 atom that forms part of an ester, thioether, amide, or sulfonamide.

Preferably, the acyl group in lipophilic substituents forms an amide or ester moiety with an amino acid side chain or spacer.

A lipophilic substituent can include a hydrocarbon chain that includes 4-30 atoms.

Preferably it has at least 8 or 12 C atoms, and preferably it has 24 C atoms or less or 20 C atoms or less. The hydrocarbon chain may be linear or branched or may be saturated or unsaturated. It will be clear that preferably the hydrocarbon chain is substituted with a group that forms part of the attachment to the amino acid side chain or spacer, for example, an acyl group, a sulfonyl group, an M atom, an O atom, or a 5 atom. Most preferably, the hydrocarbon chain is substituted with an acyl and, accordingly, the hydrocarbon chain may be part of an alkyl group, for example, palmityl, caproyl, lauroyl, myristoyl or stearoyl.

Accordingly, said lipophilic substituent may have the formula shown below:

CT

A lipophilic substituent can be, for example, an acyl group, a sulfonyl group, MH, M-alkyl, an O atom or a 5 atom, preferably acyl. n is an integer from C to 29, preferably at least 7 or at least 11, and preferably 23 or less, or more preferably 19 or less.

The hydrocarbon chain may be additionally substituted. For example, it may additionally have up to three substituents selected from MH2, OH, and COOH. If the hydrocarbon chain is additionally substituted, preferably it is additionally substituted with only one substituent. Alternatively, the hydrocarbon chain may include a cycloalkane or a heterocycloalkane, such as that shown below:

Kk MU

Preferably, the cycloalkane or heterocycloalkane is a six-membered ring. More preferably, it is a piperidine.

Alternatively, the lipophilic substituent may be based on a cyclopentanophenanthrene backbone, which may be partially or fully unsaturated or saturated. Each carbon atom in the backbone can be replaced by Me or OH. For example, a lipophilic substituent can be cholyl, deoxycholyl or lithocholyl.

As mentioned above, the lipophilic substituent can be conjugated to the side chain of the amino acid by means of a spacer. If present, the spacer is attached to the lipophilic substituent and to the side chain of the amino acid. The spacer may be attached to the lipophilic substituent and the amino acid side chain independently as an ester, sulfonyl ether, thioether, amide, or sulfonamide. Accordingly, it may include two groups independently selected from acyl, sulfonyl, atom

M, atom O or atom 5. The spacer can have the following formula: vo

At the same time, each of B and O is independently selected from acyl, sulfonyl, MH, M-alkyl, O atom or atom 5, preferably from acyl and MH. Preferably n is an integer from 1 to 10, preferably from 1 to 5. The spacer may be optionally substituted with one or more substituents selected from C0-6 alkyl, C0-6 alkylamine, C0-6 hydroxyalkyl and C0-6 carboxyalkyl.

Otherwise, the spacer may have two or more repeating units according to the formula above. Each of B, 0, and n is chosen independently for each repeating unit. Adjacent repeating units may be covalently linked to each other through their respective B and O groups. For example, groups B and O of adjacent repeating units together can form an ester, sulfonyl ether, thioether, amide, or sulfonamide. The free V and U units at each end of the spacer are attached to the amino acid side chain and the lipophilic substituent as described above.

Preferably, the spacer has five or fewer, four or fewer, or three or fewer repeating units. More preferably, the spacer has two repeating units or is a single unit.

The spacer (or one or more repeating units of the spacer, if it has repeating units) can be, for example, a natural or non-natural amino acid. It should be understood that in the case of amino acids having functional side chains, B and/or Y may represent a group in the side chain of the amino acid. The spacer can be a natural or non-natural amino acid.

For example, a spacer (or one or more repeating units of a spacer if it has repeating units) can be su, Rgo, Aa, MaiYi, Gei, Ne, Meii, Sub, Re, Tug, Tgr, Ni, Guv, Ago, Sp ,

Avp, "C-Sim, y-C1my, Avr, beg TNg, Sava, AIb, BAia, 5-aminopentanoyl, b-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminonanoyl or 10-aminoldecanoyl.

For example, the spacer can be one amino acid selected from y-Sia, Sava, B-Aia and ossu.

A lipophilic substituent may be conjugated to the side chain of an amino acid in the compounds of the present invention. Preferably, the amino acid side chain includes a carboxy, hydroxy, thiol, amide, or amino group to form an ester, sulfonic ester, thioether, amide, or sulfonamide with a spacer or lipophilic substituent. For example, a lipophilic substituent can be conjugated with Ar, SIM, ip, Ni, Guv, Agud, 5eg, TAg, Tug, Tgtr, Su5 or Yuri, Org or Ot. Preferably, the lipophilic substituent is conjugated with I uh or Su. However, any amino acid designated as Hus in the formulas herein may be replaced by UOBb, Yurg, or Ot if a lipophilic substituent is added.

An example of a lipophilic substitute and spacer is shown in the formula below:

VI Fr

WHAT

On it, Huz from the compound according to the present invention (for example, from X) is covalently attached to y-Si (spacer) through an amide group. Palmityl is covalently attached to the y-SiIsh spacer through an amide group.

Alternatively or additionally, one or more side chains of amino acids in a compound according to the present invention may be conjugated to a polymeric group, for example, to increase solubility and/or half-life (eg, in plasma) and/or bioavailability. Such modifications are also known to reduce clearance (eg, renal clearance) of therapeutic proteins and peptides.

The polymer group is mainly soluble in water (amphiphilic or hydrophilic), non-toxic and pharmaceutically inert. Suitable polymer groups include polyethylene glycol (PES), homo- or copolymers of PES, monomethyl-substituted polymer PES (tPES) or polyoxyethylene glycerol (PO).

See, for example, publications in Il. U. Netaioiodu 68:1 (1998); Viosopijdage Spet. 6:150 (1995); and Stia. Chem.

Tpegar. Ogyd Satyeg Zuv. 9:249 (1992).

Other suitable polymeric groups include polyamino acids such as polylysine, polyaspartic acid, and polyglutamic acid (see, e.g., Szotrboi'i (1995), Viosopishdaie

SNnet., mine. 6: 332-351; Nidesl, you ai. (1992), Viosopiidaiye Spet., my. 3, 49-57; TvyKkada, her a!. (1984), in

Mai! Sapseg Ipvi., mo! 73, 721-729; and Rgaiezi, ei a. (1985), Vg. 9. Sapseg, mine. 52: 841-848).

The polymer group can be linear or branched. It can have a molecular weight of 500-40,000 Da, for example, 500-10,000 Da, 1,000-5,000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

A compound may contain two or more such groups, in which case the total molecular weight of all such groups will generally be within the range indicated above.

The polymer group can be connected (using a covalent bond) to the amino, carboxy or thiol groups of the amino acid side chain. Preferred examples are the thiol groups of the residues Suzh and the epsilon-amino group of the residue Gu, and the carboxyl groups of the residues A5p and sim can also be used.

One skilled in the art will be well aware of suitable techniques that can be used to carry out the condensation reaction. For example, the RES group having a methoxy group can be linked to the thiol group Su5 by means of a maleimide bond using reagents commercially available in

Mekiag Tpegareshiisz AG. See also UMO 2008/101017 and the references above for a more detailed description of suitable chemistry.

Therapeutic methods of application

It will further be understood that reference to the use of peptide conjugates according to the present invention also includes the use of a pharmaceutically acceptable salt or solvate thereof.

Peptide conjugates of the present invention may provide an attractive treatment option for metabolic diseases or disorders, including diabetes, particularly type 1 and/or type 2 diabetes, and possibly obesity.

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from disorders in insulin secretion and/or insulin action. Acute symptoms of diabetes include excessive urine production, resulting compensatory thirst and increased fluid intake, visual disturbances, unexplained weight loss, lethargy, and changes in energy metabolism. Chronic hyperglycemia of diabetes is associated with macro- and microvascular disorders that can lead to long-term damage, dysfunction and - in some cases - failure of various organs, including the eyes (especially in the form of diabetic retinopathy), kidneys (in the form of diabetic nephropathy ), nerves (in the form of diabetic neuropathy), heart and blood vessels. Diabetes can be divided into three classes, namely, type 1 diabetes, type 2 diabetes, and gestational diabetes, based on their pathogenetic features.

Type 1 diabetes accounts for 5-10 95 of all cases of diabetes and is caused by autoimmune destruction of insulin-secreting pancreatic HD cells.

Type 2 diabetes accounts for 90-95% of cases of diabetes and is the result of a complex set of metabolic disorders. Type 2 diabetes is the result of the body's own insulin production and/or insulin sensitivity becoming insufficient to maintain blood plasma glucose levels below the diagnostic threshold.

Gestational diabetes refers to any degree of glucose tolerance found during pregnancy.

A condition known as prediabetes is also recognized. It includes, for example, impaired fasting glucose and impaired glucose tolerance and generally refers to those conditions that occur when the blood glucose level is elevated but below the levels established for a clinical diagnosis of diabetes.

A large proportion of patients with type 2 diabetes and prediabetes are at increased risk of morbidity and mortality due to the high prevalence of additional metabolic risk factors, including abdominal obesity (excess adipose tissue around the internal organs of the abdominal cavity), atherogenic dyslipidemia (disordered levels of fat in the blood , including high levels of triglycerides, low levels of HDL cholesterol and/or high levels of LDL cholesterol, which contributes to the formation of plaques in the walls of arteries), high blood pressure (hypertension), prothrombotic conditions

(for example, high levels of fibrinogen or plasminogen activator inhibitor-1 in the blood) and pro-inflammatory conditions (for example, increased levels of C-reactive protein in the blood).

In turn, obesity leads to an increased risk of developing, for example, prediabetes, type 2 diabetes, certain types of cancer, obstructive sleep apnea, and gallbladder disease.

Dyslipidemia is associated with an increased risk of cardiovascular disease. High-density lipoproteins (HDL) are of clinical importance because there is an inverse correlation between plasma HDL concentrations and the risk of atherosclerosis. Most of the cholesterol deposited in atherosclerotic plaques comes from low-density lipoproteins (LDLs) and, therefore, elevated concentrations of LDLs are strongly associated with atherosclerosis. The ratio of LDL/LDL parameters is used to assess the clinical risk of developing atherosclerosis and coronary atherosclerosis in particular.

Without being bound by any particular theory, it appears that the peptide conjugates of the present invention may unexpectedly combine the physiological action of agonists of the CI P-1 receptor with the action of gastrin peptides, see above, so that the observed activity can be significantly greater than when using the corresponding additive combination of (unconjugated) individual peptide components. Therefore, it is believed that the peptide conjugates of the present invention may be particularly useful in the treatment of prediabetes, diabetes (especially type 1 and/or type 2 diabetes) and diabetes-induced conditions, diseases or disorders such as those discussed above. , including treatment to ensure the formation of Bp cells of the pancreatic islets (islet regeneration) and thereby the production of insulin, which will be useful in regulating the concentration of glucose in the blood. Therefore, the peptide conjugates according to the present invention may be important, in particular, for limiting or inhibiting the progression of diabetes mellitus type 1 and/or type 2.

Peptides of the present invention may additionally be useful in promoting survival and suppressing apoptosis of D cells in pancreatic islets. The effect of CI P-1 and gastrin includes not only the effect on the proliferation and maturation of B cells, but also the prevention of apoptosis of DV cells and the enhancement of neogenesis, thus, the effect of the peptides according to the present invention may include such effects and their effect on improved insulin regulation and glucose.

Peptide conjugates of the present invention may thus be useful as drugs for the treatment of insulin resistance, impaired glucose tolerance, prediabetes, elevated fasting glucose, type 1 and/or type 2 diabetes, hypertension and/or dyslipidemia ( or combinations of these metabolic risk factors), atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, and stroke. They may also be useful in preventing weight gain, achieving weight loss, reducing excess body weight, and/or treating obesity (eg, controlling appetite, nutrition, food intake, caloric intake, and/or energy expenditure), including morbid obesity, as well as comorbidities diseases, disorders and health conditions, including but not limited to obesity-induced inflammation, obesity-induced gallbladder disease, and obesity-induced sleep apnea. The effect of the peptide conjugates according to the present invention on these conditions may be mediated in whole or in part by the effect on body weight or may be independent of them.

Pharmaceutical compositions

In the description below, it should be understood that the inclusion of one or more peptide conjugates according to the present invention in pharmaceutical compositions also includes a pharmaceutically acceptable salt or solvate of the peptide conjugate according to the present invention.

Peptide conjugates of the present invention may be formulated as pharmaceutical compositions which are suitable for use with or without storage and which typically contain a therapeutically effective amount of at least one peptide conjugate of the present invention together with a pharmaceutically acceptable carrier, excipient or basis

The term "pharmaceutically acceptable carrier" includes any standard pharmaceutical carrier.

Pharmaceutically acceptable carriers for therapeutic use are well known in the field of pharmaceuticals and are described, for example, in Ketipdiopye Rpaptaseciisa! Zsiepsev, 17th edition, Ayopzo K.

Seppago (Ea.), Mac Rybiiznipd Sotrapu, Eaviop, RA, O5A, 1985. For example, you can use sterile physiological solution and phosphate-salt buffer at slightly acidic or physiological pH values. Acceptable pH-buffering agents can be, for example, phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TKI5), M-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TARbB), ammonium bicarbonate, diethanolamine, histidine, arginine , lysine or acetic acid (for example, in the form of sodium acetate), or their mixtures. The term also includes any carrier listed in the United States Pharmacopeia for use in animals, including humans.

The pharmaceutical composition according to the invention can be in a single dosage form. In this form, the composition is divided into unit doses, which contain appropriate amounts of the active component or components. A single dosage form may be presented as a packaged drug, with the package containing discrete amounts of the drug, for example, packaged tablets, capsules, or powders in vials or ampoules. A unit dosage form may be, for example, capsules, wafers, or tablets per se, or it may be an appropriate amount of any of these packaged forms. A unit dosage form may also be provided in the form of a form for injection of a single dose, for example, in the form of a pen, which contains a liquid phase composition (usually aqueous). The compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in compositions suitable for, for example, oral, intravitreal, rectal, vaginal, nasal, topical, enteral, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration or administration by inhalation. The compositions can be presented in the form of a single dosage form and can be obtained by any of the well-known methods in the field of pharmaceutical preparation.

Subcutaneous or transdermal routes of administration may be particularly suitable for the peptide conjugates of the present invention.

Another aspect of the present invention relates to devices, dosage forms and packaging used to deliver the pharmaceuticals of the present invention. Thus, at least one specified peptide conjugate or a portion or variant thereof in stable or preserved formulations or solutions according to this description can be administered to a patient according to the present invention by various methods, including subcutaneous or intramuscular injections; transdermal, pulmonary, transmucosal routes of administration, implantation, osmotic pump, cartridge, micropump, or other means known to those skilled in the art and also known in the art.

Another aspect of the invention relates to compositions for oral administration. Oral preparations may include co-administration of excipients (e.g., resorcinol and nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the intestinal wall, as well as co-administration of enzyme inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (OBERE) and trasylol) to suppress degradation by enzymes.

The active compound of the solid dosage form for oral administration may be mixed with at least one additive, including lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, arginates, chitins, chitosans, pectins, tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer and glyceride. These dosage forms may also contain other type(s) of additives such as inactive diluent, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrant, a thickening agent, a thickener, a buffering agent, a sweetener, a flavoring agent, a flavoring agent, etc.

Doses

A typical dose of a peptide conjugate of the present invention used in the context of the present invention may range from 0.001 to 100 mg/kg body weight per day, for example from about 0.01 to about 50 mg/kg body weight per day , for example, from about 0.05 to about 10 mg/kg of body weight per day, which is administered as one or more doses, for example, from one to three doses. As already indicated to some extent above, the exact dose used will depend, in particular, on the nature and severity of the disease or disorder, sex, age, body weight and general condition of the subject to be treated; possible other co-morbidities or disorders that are or should be treated, and other factors that would be known to one of ordinary skill in the art.

Combined therapy

As noted above, it should be understood that reference to the following peptide conjugates of the invention also extends to a pharmaceutically acceptable salt or solvate thereof, as well as a composition containing more than one of the various peptide conjugates according to the present invention.

A peptide conjugate of the present invention may be administered as part of a combination therapy together with another active agent for the treatment of a disease or disorder under consideration, for example, diabetes, obesity, metabolic syndrome, dyslipidemia, or hypertension, and in such cases the two active agents may to enter together or separately, for example, as components in the same pharmaceutical composition or dosage form, or in the form of separate dosage forms.

Thus, the peptide conjugate can be used in combination with an anti-diabetic agent of a known type, including, but not limited to, metformin, a sulfonylurea, glint, OPR-IM inhibitors, glitazone, or insulin, or an insulin analog. In a preferred embodiment of the invention, the peptide conjugate according to the present invention is administered in combination with insulin or its analogue, an OPP-IM inhibitor, a sulfonylurea or metformin, in particular a sulfonylurea or metformin to achieve adequate glycemic control. In a more preferred embodiment, the peptide conjugate is administered in combination with insulin or an insulin analog to achieve adequate glycemic control. Examples of acceptable insulin analogs include, but are not limited to, Lantus"M, Novorapid"M, Humalog"M, NovoMix"Mm, Aktrafan"M NM, Levemir M,

Degludec"mM and Apidra m. Other significant antidiabetic drugs in this case include agonists of the CI P-1 receptor, such as exenatide (Buetta "m; Exendin-4) and liraglutide (Victose "M),

The peptide conjugate of the present invention can also be used in combination with an anti-obesity agent of known type, including, but not limited to, UU peptide or its analog, neuropeptide M (MRU) or its analog, cannabinoid receptor 1 antagonist, lipase inhibitor, human preislet peptide (PIP), melanocortin 4 receptor agonist, or melanin-concentrating hormone receptor 1 antagonist.

The peptide conjugate of the present invention can also be used in combination with an antihypertensive agent of known type, including, but not limited to, an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta blocker, or calcium channel blocker.

The peptide conjugate of the present invention can also be used in combination with an anti-dyslipidemia agent of known type, including, but not limited to, a statin, fibrate, niacin, and/or a cholesterol absorption inhibitor.

A peptide conjugate of the present invention may also be used in combination with a proton pump inhibitor (ie, a pharmaceutical agent having pharmacological activity as an H7K:α-ATPase inhibitor) of known type, including, but not limited to, a benzimidazole derivative type agent or imidazopyridine, for example, Omeprazole"M, Lansoprazole"M, Dexlansoprazole")|,

Esomeprazole "M, Pantoprazole "M, Rabeprazole "M, Zolpidem "M, Alpidem "M, Saripidem "M or Nekopidem "M,

The peptide conjugate according to the present invention, moreover, can be used in combination with an anti-inflammatory agent of a known type, including, but not limited to: - steroids and corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone and hydrocortisone; - non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (eg alaminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pyrprofen, pranoprofen, suprofen , tiaprofenic acid and thioxaprofen); acetic acid derivatives (eg, indomethacin, acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclosic acid, fentiazac, furofenac, ibufenac, isoxepac, oxipinac, sulindac, thiopinac, tolmetin, zidomethacin, and zomepirac); fenamic acid (eg, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid); biphenylcarboxylic acid (for example, diflunisal and flufenizal); oxicams (eg, isoxicam, piroxicam, sudoxicam, and tenoxicam); salicylates (eg, acetylsalicylic acid and sulfasalazine) and pyrazolones (eg, apazone, bezpiperylone, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone); COX II inhibitors such as rofecoxib and celecoxib; - interferon beta preparations (for example, interferon beta-1a or interferon beta-16); and - certain other compounds, such as 5-aminosalicylic acid and prodrugs, and their pharmaceutically acceptable salts.

Metformin has been shown to have anti-inflammatory properties |(see Naipeg et al., Ophthalmology 54: 1566-1572 (2005)) and therefore may also be useful in this context.

Each of the cited publications and patent applications is incorporated herein by reference in its entirety.

The following examples demonstrate some specific embodiments of the present invention. The following examples were performed using standard techniques well known to those skilled in the art, except as otherwise described in detail. It should be understood that these examples are provided for illustration only and are not intended to limit the scope or scope of the invention. Therefore, they should not be construed as limiting the scope of this invention.

EXAMPLES

Abbreviations used in these examples include:

MMP: M-methylpyrrolidone

OSM: dichloromethane

OME: M, M-dimethylformamide

NAT: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

OI REA: diisopropylethylamine

EUN: ethanol

EFO: diethyl ether

Reds: 8-amino-3,6-dioxaoctanoyl vAos: 8-aminooctanoyl

OE: 4-(2-aminoethyl)-6b-dibenzofuranpropanoyl

TEA: trifluoroacetic acid mesm: acetonitrile

HPLC: high performance liquid chromatography

MS: mass spectrometry

IVMH: 3-isobutyl-1-methylxanthine

BSA: bovine serum albumin

CAMP: cyclic adenosine monophosphate

OMEM: Igla's environment in Dulbecco's modification

EC5: fetal calf serum

HERE5: M-2-hydroxyetipiperazine-M'-2-ethanesulfonic acid p-ECK: phosphorylated extracellular regulated kinase

РВ5: phosphate-salt buffer

Vos: I-butoxycarbonyl

MER: M-methylpyrrolidone

Liraglutide: (Аг9о34 ГГ уз(hexadecanoyl-isosyIc)26|I P-1(7-37)

EXAMPLE 1: Compound synthesis and peptide properties

MATERIALS AND METHODS

Unless otherwise noted, the reagents and solvents used below were commercially available as standard laboratory reagent grade or analytical grade and were used without further purification.

General method of synthesis of peptide conjugates according to the present invention

Solid-phase synthesis of peptides was carried out on a Girepu Reriide Zupipezigeg SEM using standard Etos chemistry. Tepiase resin! m 5 Cat (1 g; 0.25 mmol/g) was soaked in MMP (10 ml) before use and transferred from the test tube to the reaction vessel using UOSM and MMP.

Pseudoprolines, which are dipeptides used to minimize aggregation during peptide synthesis, such as Ethos-Ppe-Tpg(f-Me, Me-Pho)-OH and Ethos-Azr-Zeg(f-Me, Me-Pho) -OH, used as necessary, and artificial amino acids forming linker groups Red3, v8Ass and

OE (see above), used as Ethos-protected amino acids (i.e., Ethos-Rea3-OH, Ethos-vAos-

OH and Gitos-OVE-OH, respectively) without changing the general methodology.

Condensation:

Amino acid-Etos in MMP/OME/OSM (1:1:1; 0.2 M; 5 mL) was added to the resin in a microwave oven

SEM bi5someg together with NATO/MMR (0.5 M; 2 ml) and OIREA/MR (2.0 M; 1 ml). The mixture was heated to 757 for 5 minutes while passing nitrogen bubbles through the mixture. Then the mixture was washed with MMP (4 x 10

ML).

Removing protection:

Piperidine/MMP (20 95; 10 mL) was added to the initial deprotection resin and the mixture was heated in a microwave oven (40 °C; 30 sec). The reaction vessel was dried and a second portion of piperidine/MMP (20 90; 10 mL) was added and heated again (75 "C; 3 min). The resin was then washed with MMP (6 x 10

ML).

Splitting:

The resin was washed with EN (3 x 10 ml) and E20O (3 x 10 ml) and dried to constant weight at room temperature (g). The crude peptide was cleaved from the resin by treatment with TEA/ethanedithiol (95/5, 40 mL, 2 h; g-). Most of the TEA was removed under reduced pressure and the crude peptide was precipitated, washed three times with Et2O and dried to constant weight at room temperature.

Cleaning and characterization:

The crude peptide was purified to a purity greater than 90,956 by preparative reverse-phase HPLC using a Regzeriime Viozuviet5 MIBIOM workstation equipped with an appropriate column and fraction collector, and passed through a gradient of buffer A (0.1 95 TEA, aqueous) and buffer B (0.1 95 TEA, 90 95 Mesm, aqueous).

The fractions were analyzed by analytical HPLC and MS, and the corresponding fractions were accumulated and lyophilized. The final product was characterized by HPLC and MS.

An example of synthesis

Exendin-4(1-39)-Rea3-Re93-|Сип1,Гей15|Gastrin-17 (Compound 1) was synthesized on the peptide synthesizer SEM GG Iregu Reriide Zupipe5хи7ег using Tepiaceae resin 5 Cat (0.67 g; 0.23 mmol /d) and Ethos chemistry as described above. Riptos-8-amino-3,6-dioxaoctanoic acid and pseudoprolines Ethos-Rpe-Tyg(f-Me, Me-Pho)-OH and Ethos-zeciVy)-Zeg(f-Me, Me-Pho)-OH were used.

The peptide was cleaved from the resin as described above and purified on a Septi-

МХ (5 x 25 cm; 10 μm; С18) while passing 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 20 95 to 95 for 47 min and fractions (9 mL) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (122 mg), which was characterized as 58 95 pure according to analytical HPLC.

The product was purified again on a IPA column (1 x 25 cm; 5 μm; C8) with a flow of 4 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; water). The product was eluted with a linear gradient of buffer B from 20 95 to 50 95 for 47 min and fractions (2 ml) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (63 mg), which was characterized as 82 95 pure according to analytical HPLC.

The other part of Compound 1 was synthesized using Tepiaceae resin! 5 Cat (0.70 g; 0.23 mmol/g) and used the same conditions for synthesis and cleavage as described above.

Purification was carried out on a Setipi-MX column (5 x 25 cm; 10 μm; C18) at a flow rate of 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; water). The product was eluted with a linear gradient of buffer B from 2095 to 50 95 for 47 min and fractions (9 mL) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (113 mg), which was characterized as 57 95 pure according to analytical HPLC.

The product was purified again on a IPA column (1 x 25 cm; 5 μm; C8) with a flow of 4 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; water). The product was eluted with a linear gradient of buffer B from 20 95 to 55 95 for 47 min and fractions (2 ml) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (29 mg), which according to the results of analytical HPLC was characterized as 77 95 pure.

The products of the first synthesis (63 mg; 82 965) and the second synthesis (29 mg; 77 90) were combined and purified once again on a Kgopavbvia column (1 x 25 cm; 10 μm; C8) at a flow rate of 4 ml/min of a mixture of buffer A (0.1 95

TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 25 95 to 65 95 for 47 min and fractions (2 mL) were collected using a fraction collector.

The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (33 mg), which according to the results of analytical HPLC was characterized as 94 95 pure. The mass was 6553.39 Da according to MS results (calculated 6553.06 Da).

Exendin-4(1-28)-Rea3-Re93-(Hei4|Gastrin-b6 (Compound 33) was synthesized on a peptide synthesizer

SEVEN reps of Reriide Zupipezigeg using Tepiase resin! 5 Cat (0.55 g; 0.23 mmol/) and chemicals

Ethos as described above. Etos-8-amino-3,6-dioxaoctanoic acid and pseudoproline Etos-RNpe-Tyg(f-Me, Me-Pho)-OH were used.

The peptide was cleaved from the resin as described above and purified on a Septi-

МХ (5 x 25 cm; 10 μm; С18) while passing 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 25 95 to 55 95 for 47 min and fractions (9 mL) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (70 mg), which according to the results of analytical HPLC was characterized as 90 95 pure. The mass was 4364.08 Da according to MS results (calculated 4364.11 Da).

ISIn9, Hei14, Rpe25, Tug13|)Exendin-4(1-27)-(Gen4|Gastrin-b6 (Compound 101) were synthesized on a peptide synthesizer SEM Girbegpu Reriide Zupipe5i7eg using Tepiaceae resin 5 Kat (1.15 g; 0, 25 mmol/g) and ERtos chemistry as described above.Etos-Rpe-Tpg(f-Me, Me-Pho)-OH was used.

MER was used instead of MMP during conjugation and deprotection.

The peptide was cleaved from the resin as described above and purified on a cSetipi column.

МХ (5 x 25 cm; 10 μm; С18) while passing 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 20 95 to 50 95 for 47 min and fractions (ZU ml) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (50 mg), which according to the results of analytical HPLC was characterized as 85-95 pure. The mass was 3952.00.08 Da according to MS results (calculated 3951.97 Da). a, P-1(7-36)-Red3-Rease-|Сип1, I em15|Gastrin-17 (Compound 42) were synthesized on a peptide synthesizer

SAM Pbrepu Reriide Zupipezi7eg using Tepiase resin! 5 Cat (1.16 g; 0.23 mmol/g) and chemicals

Ethos as described above. Etos-8-amino-3,6-dioxaoctanoic acid and pseudoproline Etos-5ecyl)-5eg(RzMe, Me-Prho)-OH were used.

The peptide was cleaved from the resin as described above and purified on a Zetipi column.

МХ (5 x 25 cm; 10 μm; С18) while passing 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 25 95 to 95 for 47 min and fractions (ZU ml) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (172 mg), which was characterized as 86 95 pure according to analytical HPLC. The mass was 5664.72 Da according to MS results (calculated 5664.70 Da).

IAgo34 I uz(hexadecanoyl-isos1Ii)26|С P-1(7-37)-Red3-Re93-(ей4|Gastrin-b (Compound 107) was synthesized on the peptide synthesizer SEM GG Iregiu Reriide Zupipezi2eg using Tepiacea resin

With Cat (1.30 g; 0.25 mmol/) and Ethos chemistry as described above. MER was used instead of MMP during condensation and deprotection. Ethos-8-amino-3,6-dioxaoctanoic acid and pseudoproline Ethos-Rpe-Tpg(f-Me, Me-Pho)-OH, as well as Ethos-I uv(rae)-OH were used at the attachment stage for acylation.

The M-terminus of the peptide attached to the solid phase was protected with Bos using Bos20 (330 mg) and

PIREA (54 μl) in OSM. Then the Ode protecting group was cleaved using hydrazine hydrate/MER (4 90; 2 x 15 min) and the resin was washed with MER (8 x 2 min), OIEA/MER (10 90; 5 x 5 min) and MER (8 x 2 min) . The synthesis was carried out on SEM and Reride Zupipevsieg according to the description above using Ethos-C1y-OyVy and hexadecanoic acid. MER was used instead of MMP during condensation and deprotection.

The peptide was cleaved from the resin as described above and purified on a cSetipi column.

МХ (5 x 25 cm; 10 μm; С18) while passing 35 ml/min of a mixture of buffer A (0.1 95 TEA; aqueous) and buffer B (0.1 95 TEA; 90 95 Mesm; aqueous). The product was eluted with a linear gradient of buffer B from 30 95 to 70 95 for 47 min and fractions (9 mL) were collected using a fraction collector. The corresponding fractions were analyzed by analytical HPLC and MS, accumulated and lyophilized to obtain a white powder (60 mg), which according to the results of analytical HPLC was characterized as 88 95 pure. The mass was 4819.95 Da according to MS results (calculated 4819.45 Da).

EXAMPLE 2: Activation (ESvo) of the CI P-1 receptor and the gastrin receptor SSK-B by migo peptide conjugates according to the present invention

MATERIALS AND METHODS

Analysis of the effectiveness of the SI P-1 receptor (С P-1 K) of a person:

The immediate effect of the peptide conjugates according to the present invention was evaluated by measuring CAMP induction after stimulation of the CI receptor P-1(7-36), Exendin-4(1-39) or the studied conjugates according to the present invention using a kit Biazproietm cSAMP production

Recap-EITeg. Briefly, HEK293 cells expressing human CI P-1 K (a stable cell line obtained by transfection of CI P-1 K cDNA and selection of stable clones) were seeded at a concentration of 40,000 cells/well in 9b-well microtiter plates coated with 0.01 95 poly-1-lysine, and cultivated for one day in 100 μl nutrient medium |OMEM, 10 95 EC5, penicillin (100 IU/ml), streptomycin (100 μg/ml))І. On the day of the analysis, the nutrient medium was removed and the cells were washed once with 200 μl of Tyrode buffer (Tyrode salt (9.6 g/l), 10 mM

NEREFH, rn 7.41. Cells were incubated in 100 μl of Tyrode buffer containing increasing concentrations of the test compounds, 100 μM IVMX and 0.1 95 B5A for 15 min at 37 °C. The reaction was stopped by adding 25 μl of 0.5 M NOSI and incubated on ice for 60 min. For details of the methodology, see UMO publication 2008/152403.

Analysis of the effectiveness of the CSK-B receptor (CSK-B B):

To study the binding and activation of CSK-B K, we obtained stable cell lines that express one of the human or mouse CSK receptors in the same way as the P-1 K cell lines were obtained (see above). Briefly, the authors used HEK293 cells for cDNA transfection

CSK-A K or CSK-B B (PSSK-A K (gene ID: 19315), NSSK-B B (MM 1 76875), toSK-A B (MM 009827) and toSK-B KE (MM 007627)| or mice, all cloned into the rIKE5-peoghamMmoOvgkK transfection plasmid. Cells were cultured according to a standard protocol in a nutrient medium and transfected with a plasmid using II iroiesiatip (Ipigodep). Cells stably expressing CSK receptors were selected by adding (418 to the nutrient medium (survival only those cells that had taken up and internalized the cDNA expression plasmid) and cultured them Stock cell suspensions were frozen for subsequent use.

The efficacy of the peptide conjugates according to the present invention was evaluated by measuring p-

ECC (using the AiIrpazZsgeep'"Mm ZyugeRige p-ECK assay) in NEK293 cells stably expressing human and mouse CSK-B K (high-affinity gastrin receptor), respectively.

Analyzes of the efficiency of gastrin receptors (analyses of AIrpazsgteep"m 5ugegige p-ECK) were carried out according to the following description:

Day 1: cell seeding

The described cells that expressed CSK-B K were seeded at a concentration of 20,000 cells/well in 100 μl of nutrient medium |OMEM, 10 95 EC5, penicillin (100 IU/ml), streptomycin (100 μg/ml)) in 96-well plates , coated with poly-O-lysine. The cells were incubated in an incubator (37 "С, 5 95 СО") for two days.

Day 3: changing the medium to serum-free

The nutrient medium was changed to 80 μl of serum-free medium |OMEM, penicillin (100

IU/ml), streptomycin (100 μg/ml)). per well and continued to incubate the cells for 19 hours in an incubator (37 "С, 5 95 СО").

Day 4: Peptide Conjugate Stimulation and Analysis of AIirpazsgeep m ZugegBige r-EVK 1. After 19 hours, 20 μl of serum-free medium containing one of 5 different concentrations of peptide conjugate (in triplicate for each concentration) was added and the cells were incubated for 5 min at room temperature. 2. Stimulation medium was removed by quickly turning the plate upside down, and 60 μl of their lysis buffer (from the 5igerige assay kit) was added to each well.

3. The tablet was mixed on a tablet shaker for 5 min and placed on ice. 4. BZygeBie P-ECK analysis: 4 μl of each supernatant was transferred to a 384-well proxy plate (Regkeep EITeg). 5. 4 μl of each of the two control lysates (unstimulated and stimulated) was added to the proxy plate in two replicates. b. 60 parts of reaction buffer, 10 parts of activation buffer, 1 part of acceptor beads and 1 part of donor beads were mixed (reaction buffer and activation buffer "- beads). 7 μl of the obtained reaction buffer - zhbusin activation buffer was added to the wells of the proxy tablet, the mixture was carefully resuspended before adding to the wells. 7. The tablet was incubated for 2 hours in a dark box at 22 "С in an incubator. 8. The tablet was analyzed on a light-emission tablet reader Epmiziop'm (RegKip-EIteg) using the appropriate reading program (RegkKkip-EIteg).

Peptide conjugates according to the present invention were studied in the above-described assays (ie, activation efficiency of human CSK-1K, activation efficiency of human CSK-B and activation efficiency of mouse CSK-B).

Human SI P-1(7-36) and Exendin-4(1-39u) were used as a positive control in the analysis of the effectiveness of the activation of the human SI P-1 receptor (PO P-1K), and Н(IСИп1, Iей15|Gastrin- 17 and CSK-8 (which consists of the C-terminal 8 active amino acid residues of CSK) were used as positive controls in the human CSK-B receptor efficiency assay (PSSK-B K) and mouse CSK-B receptor assay (tSssSkK-B B).

In this study, the activation of the SSK receptor, pICIP1, EI15|Gastrin-17 (which has the sequence

H-OSRU/L EEEEEEAMSUMI OB-MH2) was used as a control compound. The glutamine residue (Cp) could be changed to some extent to RugosSiim, but without loss of binding activity of the receptor.

The results (ESbzo values in mol/L) are presented below in Tables 1, 1 and 2.

Table 1

The efficiency (ESvo, mol/l) of the compounds (peptide conjugates) according to this invention in the activation of P-1 B, PSSK-B K and toSsK-B B and , ESvo ESvo ESvo

Exendin-4(1-39)-Red3-Redz3 was 5.4 x 108! (SIP1 and em15) Gastrin-17 5.8 x 10 1.90 x 10

Exendin-4(1-28)-Red3-Red3 in 7.15 x 108

Z3 Pei4 | Gastrin-6 7.714 x 10 3.8 x 10

SY P-1(7-36)-(Sip1, Gesh15|Gastrin-17 1.45 x 1070 | 2.59 x 108 7.31 x 108

SY P-1(7-36)-K-(SIP1,Hei15|Gastrin-17 | 8.42 x 10-! 7.73 x 108 1.14 x 107 a, P-1(7-36)-ADA -(СИ1Й1, lo v v 39 Hem15IGastrin-17 1.14 x 10 1.88 x 10 5.41 x 10

VIRY 96) VKK VIY eit5) Gastrinzlv'h 107 | 1.56 x 108 5.86 x 109

SI R-1(7-36)-Red3-5KK- li 9 c

A (SIP1 and esh151 Gastrin-17 9.26 x 10 8.76 x 10 5.11 x 10

C, R-1(7-36)-Red3-Reazli 9 in 42 (SIP1 esh151 Gastrin-17 7.718 x 10 8.20 x 10 5.83 x 10 and R-1(7-36)-8Aos-5KK - lo v v 43 SiP1, sesh15 | Gastrin-17 tzbhlog r vlyakhlot | vav hto a P-1(7-36)-OVE-5KK- lo v v 44 (SiP1 em 5) Gastrin-17 1.37 x 10 2 .57 x 10 8.69 x 10

SI P-1(7-36)-BAos-8Aoslo in in (SIP1 and esh151 Gastrin-17 1.22 x 10 1.28 x 10 7.14 x 10

SI-R-1C (7-36 yivbhtot 7171111

Exendin-4(1-39 yivzhtou 77711111 pISIPP1, Hei15|Gastrin-17 0001 489x109 1.82 x 108 sec-V 77717171 vho | T6zhto7

Table That

I measured the effectiveness (ECvo, mol/l) of compounds (peptide conjugates) according to this invention in the activation of P-1 B, PSSK-B K and toSsK-B B

Mo. and ESvo ESvo ESzo

Exendin-4(1-39)-Red3-Redz3-Y. 5.4 x 1038 7 Peptemvuastn oon | fighting MYT

Exendin-4(1-28)-Red3-Red3- Y Y 7.1x107 va (rea ozvyun | my

Table 2

The effectiveness (ECvo, mol/l) of the following compounds (peptide conjugates) according to the present invention in the activation of P-1 K and pSSsK-B B

Mo. and ESvo ESvo 60 CSesh14Exendin-4(1-28)-Re93-Rea3-(Gesh4|Gastrin-6b

Iogp12) Exendin-4(1-28)-Re93-Rea3Z-(Sei4|Gastrin-6

IRpe25|Exendin-4(1-28)-ReaZ3-Re93-I(Sech4|Gastrin-6

IAzr281Exendin-(1-28)-Red3-Reo3-I(Sec4|Gastrin-6 (Tug13|Exendin-4(1-28)-Rea3-Re93-(Hesh4|Gastrin-6 66 TsOght209|Exendin-4(1- 28)-ReaZ-Rea3-(Sesh4|Gastrin-6b 68 |Exendin-4(1-28)-Iesh4|Gastrin-6i /-:/ | bihlom | 14х1о8 69 |Exendin-4(1-27)-Shey4| Gastrin-iiii -:/ | yokhlo"m | 43x109

ITUg13, ей14) Exendin-4(1-27)-Red3-Redz-

ISen4|Gastryn-b

ITug13, Rpe25|Exendin-4(1-27)-Re93-Red3-

ISen4|Gastryn-b

Ie14, Rpe25|Exendin-4(1-27)-Red3-Redz-

ISen4|Gastryn-b

ITUG13, G ei14, Rpe25|Exendin-4(1-27)-Red3-Re9d3-

And enm4IGastrin-b

Side chain-cyclo (I uz12,1i16|Exendin-4(1-28)-

Re93-Re93-I(Heiy4|Gastrin-b'

Side chain-cyclo((СИм16,И х201Exendin-4(1-28)-

Re93-Re93-I(Heiy4|Gastrin-b' in Side chain-cyclo((uz20,Ich24|Exendin-4(1-28)-

Re93-Re93-I(Heiy4|Gastrin-b'

ISuz16) Exendin-4(1-28)-Red3-Reo3-I(Hets4|Gastrin-6b

ISei14Exendin-4(1-28)-G1 MaiZ,Gesh4|Gastrin-6 86 2 TSei14Exendin-4(1-28)-(Mie4|Gastrin-6)

I ei14Exendin-4(1-28)-(I ec4,(3-(3-pyridyl)-

AiIa|b|Gastrin-b '

ISIn9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Redz-

Rea3-(Sec4|Gastrin-b'

Y emn14, Rpe25, Tug13|Exendin-4(1-27)-Red3-Red3- Y Y ve |demrpesatrynia

ISIn9, Hei14, Rpe25, Tug13|) Exendin-4(1-27)-Redzli v in Rea3-P-esh4, Rpez|Gastrin-b Zach 10 1.3 ho

IAg927, Hei14, Rpe25, Tug13|Exendin-4(1-27)-Red3- that 1.8 x 1039 91 6.8 x 10

ISen4|Gastrin-b to IAgo12,27 I ei14 I uz16, Rpe25, Tug13|Exendin-4(1-27)- 17 x 1070 2.6 x 1039

Rea3-(Sec4|Gastrin-b' (Ago12,27, ei14,-uz20,Rpe25, Tug1Z)Exendin-4(1-27)-| 5 in 101 2.6 x 1038

Reaz-(Sets4|Gastrin-b' 94 IAgo912,27 I ei14 I uz24, Rpe25, Tug13|Exendin-4(1-27)- 13 x 1070 3.6 x 1038

Rea3-(Sec4|Gastrin-b' 95 IAg912, Hei14, Rpe25, Tug13|Exendin-4(1-27)-Red3- 79 x 10-71 1.4 x 1038

ISen4|Gastrin-b'

ISIn9, I ei14, Rpe25, Tug13|Exendin-4(1-27)- 12 x 109 211 x 107

Ie2 | Gastrin-4 97 ISIn9, Hei14, Rpe25, Tug13 |) Exendin-4(1-27)-Redz- 6.0 x 10-" 1.3 x 103

Iey2|Gastrin-4

ISIsh9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Og-Redz- 46 x 10-! 1.0 x 103

Iey2|Gastrin-4

ISIsh9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Rea3-Ogp- 41 x 10-1 BI x 108

And en2 | Gastrin-4

ISISH9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Og-Ogplo 7 100 I eig|Gastrin-4 1.1 x 10 8.6 x 10 101 ISIn9, I ei14,Rpe25, Tug13| Exendin-4(1-27)- 11 x 1070 3.0 x 103

ISen4|Gastrin-b 102 ISIn9, Gay14, Rpe25, Tug13|) Exendin-4(1-27)-Redz- 91 x 107! 5.4 x 108

ISen4|Gastryn-b

ISIsh9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Og-Redz- with 1.0 x 107 103 1.2 x 1070

ISen4|Gastrin-b 104 ISIsh9, ei14, Rpe25, Tug13|Exendin-4(1-27)-Rea3-Ogp- 87 x 10 8.8 x 109

And enm4|IGastrin-b

ISiSh9 I ei14, Rpe25, Tug13 | Exendin-4(1-27)-Ogt-Ogplo in 105 | etsa|Gastrin-b Tl ho 16khto

Table C

The efficiency (ESvo, mol/l) of SI P-1 compounds (peptide conjugates) according to the present invention in the activation of PO P-1 B, NSSK-B E and toSK-B B (included only in the application of SI P- 1)

ESvo

M, ESvo ESvo

С R-1(7-36)-(Sip1, Hei15|Gastrin-17 3.0 x 107! 2.6 x 1038 7.3 x 108

SI P-1(7-36)-K-(SIP1, Seshi15|Gastrin-17 3.0 x 107! 7.7 x 108 1.1 x 107 -8

SI P-1(7-36)-AAA-|SIPI I e15|Gastrin-17 | FOR ho | l1ehlov | 5410 which is 5.9 x 1038

SG P-1(7-36)-5KK-|SIP1 GG ey15|Gastrin-17 3.1 x 10 1.6 x 10 - - - - - - -8 pir 1(7-36)-Red3-ZKKAISipt I ей151 Gastrin-| 25 3x40y | ear 5110

SI P-1(7-36)-Red3-Redz- i 9 5.8 x 108 42 ip esch15) Gastrin-17 28x1o 8.2 x10 - - - - - - -8 vir 1(7-36)-BAos -5KK-IVIpt et 5|Gastrin-| 4 9 x4071 | smells | 8310 - - - - - - -8 vir 1(7-36)-ОВЕ-5КК-|СИп1,Г ей15|Gastrin vho | 2 x 108 8.7 x 10

C, P-1(7-36)-8Aos-vAos- that in 7.1x108 45. Si sets15)IGastrin-17 cha ho 13 chlo

IGuz(hexadecanoyl-isosyl) 341 P-1(7-37)- ah

Red3-Re93-(Gesh4|Gastrin-b'

IAgo34,I uz(hexadecanoyl-isooxyIsh)26|SI P- lachlo | I 1(7-37)-Red93-Reaz- (ei4|Gastrin-b'

IAgd26,34.I uh(hexadecanoyl-isosyIm) 36) P- liho B 1(7-37)-Red3-Reaz- (Heshi4|Gastrin-b'

IS uz(hexadecanoyl-isosyIm) 261 P-1(7-37)- vakh 6

Red3-Re93-(Gesh4|Gastrin-b' o YAKE en 110 isosieIy)Z6 | P-1(7-37)-Red3-Redz- 1.2 x 10710'

ISen4|Gastrin-6b om uter 111 isoSim)26|SI P-1(7-37)-Red3-Redz- 8.8 x 107'

ISen4|Gastryn-6b

ISen4|Gastryn-6b

IagoaZAai R-1(7-37)-ReaZ3-Reazli 2.4 x 108 oz ema 00000 I

MT: not checked

The results

The results presented in Tables 1, 1, 2 and 3 above show that generally all peptide conjugates of the present invention are potent agonists at all three receptors considered and that they exhibit very similar levels of efficacy.

EXAMPLE 3: Screening analysis of Compound 73 on 92 selected peptide SPCs

Compound 73 was chosen to screen a large sample of ORSC-type peptide receptors in order to detect any receptor non-specificity at an early stage. These receptors belong to the class A and B ORSC families, and the analysis was performed using the Miijiroge using the ORSC screening platform. Each SRSC was activated with its control peptide ligand (a known activator of the corresponding receptors) or Compound 73 at a concentration of 100 nM. Receptor agonism is expressed in bo compared to the control peptide (which gives 100 95 activation by definition).

Only the expected CI P-1 receptor and the SSKV receptor (SSK2) were significantly activated (100 and 95 95, respectively) by Compound 73, indicating that the peptide is specific for these two receptors.

EXAMPLE 4: Pharmacokinetics (PC) of Compounds 1 and 33 in Mice

Method

Three C57VI mice were given 100 nmol of Compound 1 or 33 per kilogram as an intravenous or subcutaneous bolus injection and plasma samples were obtained 240 min after dosing.

Samples were obtained from three mice at each time point. Plasma samples were analyzed for presence

Compounds 33 using IR/MS/MS (10-1000 nm).

The results

Table 4

Parameters after intravenous and subcutaneous administration of 100 nmol/kg to mice 77111111111111171111111Spolukaz3/// | /////// Spoluma7//: 17711611 fishing | 7777-1111 9796 | 7-1

Both compounds showed excellent bioavailability (ER) after subcutaneous administration, while

Compound 33 showed an elevated PK profile, likely due to a longer half-life (Figure 1A, 18 and Table 4).

EXAMPLE 5: RK Compounds 33 and 74-80

Method

Two C57VI mice were injected with a single subcutaneous dose of 100 nmol/kg of each peptide. Blood samples were obtained after 5 and 30 min and after 1, 2, 4, 6, 16 and 24 hours. At each time point, samples were taken from two mice. Plasma samples were analyzed after solid-phase separation (5PE) by liquid chromatography mass spectrometry (-C-MS/MO).

Table 5

So, after subcutaneous administration of 100 nmol/kg of the mouse, we shhhhhhhhhhhhhhh

The peptides show promising TU profiles, with Compounds 74 and 77 outperforming other compounds in terms of half-life and potency (Table 5 and Figure 2).

EXAMPLE 6: Ip mimo activity of peptide conjugates according to this invention in aB/ar mice

MATERIALS AND METHODS

The ar/aB mouse model was previously used to evaluate the effect of possible therapeutic candidates on the preservation of B cells. U. Rpuzio. Epdoshypoi. Meyer. 283: E745-E752 (2002))|. Several studies showed a correlation between the content of pancreatic insulin and the mass of p-cells

IVoip, V. ei ai. (Ios.siy.); Ztsageg-Rip2op, MU.Yi. et al., Journal 54: 2596-2601 (2005); Zytsage2-Ripgop M/.Y.. yei a!., Oiareitez 57: 3281-3288 (2008).

In this study, b-week-old female mice ar/av (VK5.Sd-t --/-- And erg5/y) (Tasopis Epgore A/5,

And She 5Kepzmed, YuOeptagKk) were acclimatized to new living conditions and provided with unlimited access to normal feed and water. Mice were housed in pairs in a room with controlled lighting, temperature and humidity. The development of diabetes was monitored for 2 weeks by measuring blood glucose levels, and before treatment, diabetic mice were randomly assigned to treatment groups depending on their blood glucose levels (n-10/group).

Animals were then sham-injected subcutaneously with 100 μl of vehicle (once daily) for three days to acclimatize the animals to the handling and injections. After randomization and sham injection, the animals were then treated (5s, twice a day) for 16 days with combinations of pIgE15|Gastrin-17 (1, 10 and 50 nmol/kg) and Exendin-4(1-39) (1, 10 and 50 nmol/kg) or Compound 1 (peptide conjugate according to the present invention) |hobto exendin-4(1-39)-ReaZz-Reaz-|Cip1, I en15|Gastrin-17| (1, 10 and 50 nmol/kg), or a carrier (buffer RV5; injection volume 5 ml/kg). Daily injections were performed between 8:00 and 9:00 and between 15:00 and 16:00, while fresh solutions were prepared immediately before administration.

Blood samples (200 μl) were obtained from the orbital plexus and placed in EDTA tubes before dosing (day 1) and on days 8 and 16 of treatment. Each blood sample was centrifuged and plasma (100 μl) was stored at -80 "C for further analysis. Blood samples for determination of blood glucose levels were obtained from the tail vein. After the final day of dosing, the animals were sacrificed (day 16) under CO anesthesia with following cervical dislocation The pancreas of each animal was immediately removed, weighed, and stored for further analysis of insulin content.

Measurement

Glucose concentrations in whole blood (MM) were determined by the oxidase method of immobilized glucose (Eije Ashoapaiuzeg, Vaueg, OeptagkK). The level of C-peptide in plasma was determined using a kit for radioimmunoassay of C-peptide (Gypso/MiPiroge, KE KSR-21 K). The content of pancreatic insulin was determined using a kit for radioimmunoassay of rat insulin (I ipso/MiiProge, kit K1-13).

The results

As is clear from Figure C, a significantly increased pancreatic insulin content was observed in animals treated with the peptide conjugate of the present invention (Compound 1) compared to animals treated with a simple combination of Exendin-4(1-39) and NO Eshe15|Gastrin- 17 or treated with a carrier.

Thus, apparently, the action at the level of pancreatic insulin, which occurs as a result of covalent condensation or binding (conjugation) of the Exendin-4 group and the Gastrin group in the peptide conjugate according to the present invention, may be unexpectedly greater than when using the appropriate additive combination of two separate peptide components.

EXAMPLE 7: A six-week study

Protocol 125 female mice ar/aB (VK5.Sd-t «/-- I ergar/y)) (at the time of arrival 6b-weeks old) were obtained from Tasopis Eigore A/5. On the 4th day, blood was obtained from animals kept on a semi-starvation diet to determine the baseline level of C-peptide in plasma, insulin in plasma, glucose in blood, and levels of NATc.

Then the animals were divided into 5 treatment groups, p-20, depending on the basic level of C-peptide and

NATs in plasma. Animals were given subcutaneous injections of 100 μl of the carrier twice a day for at least

From days for acclimatization of animals to housing conditions and experimental procedures.

Animals were then injected subcutaneously twice daily with peptides or vehicle for 42 days according to

Table 6. Daily injections were made between 08:00-09:00 and 15:00-16:00 with freshly prepared solutions.

The last day of dosing was the morning of day 42.

Table 6

Groups and doses nn

Subcutaneously twice a day

The research was stopped on the 42nd day. Animals were maintained on a semi-fasted diet and received the last dose in the morning. Blood samples were taken to determine plasma C-peptide, insulin in blood plasma, glucose in blood, and HBV. After blood sampling, the animals were euthanized using

So" with subsequent dislocation of the cervical vertebrae. The pancreas was obtained, weighed, divided into three parts and transferred to test tubes containing 2 ml of cold acid alcohol, and insulin content was analyzed.

Compound 33 reduced blood glucose (Figure 4) and increased plasma insulin concentrations compared to vehicle in Jaar/aB mice (Figure 5). In addition, treatment with Compound 33 caused a statistically significant decrease in the levels of NVATs compared to animals that were injected with vehicle and Gastrin-17 and Exendin-4 (Figure 6). These results show that Compound 33 improved blood glycemic control in diabetic mice.

In addition, Compound 33 caused a statistically significant increase in pancreatic insulin content compared to vehicle (Figure 7). In addition, both Compound 33 and exendin-4 resulted in significant increases in delta C-peptide plasma levels, indicating improved pancreatic function in all groups (Figure 8).

Combined administration of Exendin-4 and Gastrin did not outperform Exendin-4 in improving glycemic control in ar/4r mice. Thus, the doses used in this study did not reveal a synergistic effect of Exendin-4 and Gastrin on glycemia.

Our data show that the peptide conjugate of Compound 33 significantly increases pancreatic insulin content and improves glycemic control in aB/db mice, resulting from a reduction in LVATbs.

EXAMPLE 8: Study of a medicinal product in the "vacation" mode

Protocol

150 male ar/ar mice at the age of 5-6 weeks were obtained. Animals were kept (5 mice/cage). under controlled conditions (20-22 "C, 55-85 95 humidity) with a 12:12 h light/dark cycle, lights on at 05:00 a.m. Animals were fed ad libitum, kept on a standard Aygotip Mo 1324 diet, and had free access to acidified tap water Animals were 8-9 weeks of age at initiation of the study All animals were acclimatized and handled daily for at least one week prior to the start of the experiment.

Blood samples: Blood samples (150 µL) were obtained from the orbital plexuses using an EDTA-coated micropipette from fasted mice (17 hours) prior to initiation of treatment and on day 93 (prior to termination). Blood samples were placed in EDTA-coated tubes and stored on ice. Blood samples were centrifuged and the obtained plasma (at least 50 μl) was stored (at -80 "С) for the next analysis of C-peptide and insulin levels. Also on day -10/12 (before the start of treatment) and day 93 (before the end) the analysis was performed of blood samples (50 μl), obtained from the orbital plexuses, for blood glucose (sticks) and NVATs.

Divide:

6-4 days before the administration of the first dose of the drug, animals that were fasted (17 hours) were subjected to an oral glucose tolerance test (OPT, see below). The area under the blood glucose concentration curve obtained over a 240-minute period (AOS, unit of measurement: mM'min) was used to divide the animals into 5 groups (A-E) of 26 animals each to obtain similar glucose tolerance in each from groups After the first 50 days of taking the drug (period 1), a second glucose tolerance test was performed. Based on this second OGTT, each group of mice was divided by AS (as above) into two subgroups reflecting similar glucose tolerance.

Administration of doses:

Animals were dosed once daily subcutaneously with a dose of vehicle (2"p-26), Exendin-4 (p-:26), or Compound 33 (p-26) and administered these doses according to Table b for 50 days. Doses were administered between 02.00 at 3:00 pm daily as an injection of 5 ml/kg.After 50 days of dosing, the animals were divided into 7 groups as shown in Table 1. This dosing regimen was continued for 40 days, and the animals were sacrificed on day 93.

Oral Glucose Tolerance Test (OGTT): OGTT was performed on days -6/4, 50, 65, 78 and 91 of the treatment period in animals fasted overnight (17 hours) after the last injection of vehicle or compound. Blood samples were taken from the tip of the tail and blood glucose levels were measured. To prevent mixed food intake, the animals were fasted throughout the oHTT. Immediately after the initial blood sample (1-0, fasting blood glucose level), an oral dose (1 g/kg) of glucose (glucose monohydrate, AYU 500 g/l) dissolved in water MO (5 ml/kg, 0.2 g/ml), and the animals were returned to their home cages (1-0). Then, blood glucose levels were determined at time 1-15, 30, 60, 120 and 240 minutes.

Fasting Glucose: To further monitor the diabetic status of the animals, fasting blood glucose levels were measured after an 8-hour fast on days 0, 37, 44, 58, 72 and 85. To minimize stress, the animals were fasted throughout the day (from 06.00 a.m., when the usual food intake was low), and the fasting blood glucose level was determined at 02.00 in the afternoon.

Table 6

Research groups

Period 1 Period 2 subcutaneously 1 dose/ 79051007.

Carrier: РВ5: Phosphate-salt buffer sirso (Mo 70011, pH-7.4).

Compound 33, a dual agonist of P-1-gastrin I, reduced the area under the glucose curve (AU) after an oral glucose challenge and also reduced fasting blood glucose compared to vehicle-treated controls, regardless of whether the paradigm preventive treatment, treatment or "vacation" (Figure 9-10). In addition, plasma insulin and C-peptide levels and blood NBAI levels were significantly lower in mice receiving Compound 33 compared to those receiving vehicle (Figure 11). These data show that Compound 33 improves glycemic control in αB/γB diabetic mice to a greater extent than exendin-4 and liraglutide. Notably, the effect of the compounds on glycemic control persisted for several days after discontinuation of treatment, and was most pronounced in mice treated with Compound 33.

LIST. SEQUENCES "1" ZEELAND PHARMA DCS "1505 PENTIDE CONJUGATES OF STR RETENTOR AGONISTS AND THEIR

APPLICATION

"1305 0612 ОИ "150" OK RA 2010 00379 "151 2010-04-27 "160 16 "170" Raipv uetvivv 33 "y" 1 "115 55 "a" RET "RIZ" TSHEguchna "ZY" "lyu" Sequence of synthetic peptide "DO" "221" DIFFERENT FEATURES "Va" АЙ ЯЯ "MOU" Zhvaa сх Rер3 "хх 1

TV SPU Siv SLU Tvg RNe Te Vei Akre ee Buye bii Mesbiv Siv i x 10 Te

SPI Aye Uvi Ahe em RNe Pe Sta to Beh Gu Ak Siu Su Ro 5eg 2a 53 v et Su Anu Riv Rto Ro bag Ha Ha Siv SPU Rgo Ter bi Siv SY 85 40 45

Siv Sp Si Aa Tut SBU Tr ev Ar Re "Action" "pI115 30 "212" RET

"213" Artificial "223" Consistency of synthetic petil "Mr

NIV bi Siy bi Tv RVE TV beg Ar Sey skh Tv Siv Messi Oh

И Z HB 15

On Aza Uvi Agv Seh Riv Pe Om Ttrobei uk Avo STU SPU Rico Beh

Z bek Snu Ag Rto Rgo Rgo bek Siv Oiu Rgo Rer ben OT Siv Sv ON

For 40 45

SP Aza Tu SIK Ter TGev Ar Re 50 55 ka" Z "ii" 57 "12" EC "2153" TSHNuchna "20 "Z25" Sequence of synthetic peptide "NKx Z

Ni Sh Om StTu Tok Rae Tu Zsg lyar en Zeg buh Op Me S Sv i Z 10 15 oi AV Ma Aga Gen Rne Le Sy Ttrets uh Aa STU SPU Ro et 20 25 za

Zeg Su Aa Ro Rgo Rgo Zeg Guh Siv Su Rgo TtrSev OT Se Sleep

Spy ma Ada Tu SPU Ttr Gets Akr RNe 5a 58 "2105 4 "11" 559 "y" RET

"213" Artificial. "223" The sequence of the synthetic hymn "Ah 4 vyh SIu Siv Su Tvg Rbe. Fri beg Avroivy et Guz Siv Me Os biv 1 5 ju 15

Oi Aa MagAte Gechp Re Tse Si Ter ev uh Ap Ou SLU. Rgo Zeg 20 35 zo bek Oiu Av Rgo Rgo Rgo heh Aa Aa Aa Siv Siu Rio Ter Gay Oi 33 40 45

Siv Siv Si Sto DIV Huk SIu Ttr ysi Ar Re 50 35 "2" 5 "oi" 59 "812" RET "213" Artificial "P "28" Sequence of synthetic peptide "a" 5

Ni SU si bi1h Te Ve Tng be Ar si veg i uv Si Mesbiv SIV 1 5 Y 15

Siv Av Ma! Ag be Rie Ne SlLyu Ttr Bec (Se5 Aby Sp u Su ro Zeg 2 25 30 beg SPu Aa Rgo Rgo Rgo Zeg 5et uh Mu Siv Sbu Re Ter Gev'Eiiy 35. Ya0 45

Siv SYA Soch Aya Tug Su Ter es Ahr Re 535 "2105 6 "MI" 60 "212" RET

"213" Artificial "ZD" "yy3" Sequence of synthetic peptide "VD "dl VARIOUS FEATURES "lo (APK) vda May t Rem "400" b

Ni Ou Spa SPU Te Rhee Te 5eg Avr Gcheveg Guk Si Me Sim Sn

Z Z 10 15

Sy Aa Uvi Ata Ten Rpe Pe Sy Ttr Bec Gu Ap Su Su Rgo Zeg r.) 28 30 vet Snu Ada Rgo Ro Rgb 5eg Hav Zet Guz Sub Sil SLU Rgo Tr be 3a 45

Siv spo sce Se Spo Aiva Tug Su Ttr em Ar ore 50. 53 Ge; "CI 7 "112" 60 "212" RET "3" Artificial "M "23" Sequence of synthetic peptide "oh "2212. VARIOUS FEATURES "oo" (401440) "la" Let's JSC "KO" 7

Niv SI» Siv bih Tvu Re Tv 5eg Ar Ben bet Bu Siyu Me biv Siv

From 5 to 10 of them

Dreams Av UVI Atgv without Re Don't SLEEP tr Ben buye Abi SPU Sp in Rio Beh

A) t5 for zet STU Aa Rgo Rg Red ve Hva Beg uk Guk Sp Siu Ro Tr Geo 35 ov, 45

S bin Sy Stos Aza Guye Su tr Gene Avr rve 50 55 0 "0" 8 "1" 60 "212" RET "5135 Artificial "ex "203" Synthetic peptide sequence "co "221 VISNI. FEATURES "ra" CO) "oda" Let there be OBE x 42 aminoestyl)-o-dibenzofuran-propane "00" 8

Niv Siu tb u Ts Re TA 5si Ar be: bet Bu Ota Me Ot Si

N Z 10 15

Siv Aa Uvi Age bep Rpye Pe Ttroibeo Su Abp bu Su Rto vet

B) 25 30

ZekOiu Aa Rto Rgo Rgo Bet Ha Tu Gu Guz Se Ou Rio Persi 33 40 45

Opeoch biv biv bij AEtuye Ou Ter ben Aer Rne 60 "Oh 5 "el1rh 58 "212" RET "13" NShiuchna "220 "2232" Sequence of synthetic peptide "g" "di VARIOUS FEATURES.

"shaft" (40 "OZ" Ha VAS. "AYU" 9

Ni Si biv Su Tv Re Te beg Avr ep et uv SY MebSio Siv

IR: 15

Siv Ave Uvi Ate ep Rie Pe Su Ttr Gets Gu5 Av Su Siu Rio beg ze SPU Aa Rgo Rio Ri Bek Hva Haa O1p 1 Ro To vv Oi So 4a 45

You are Obesta A! Here STU Ter Gay Avr. Re 35 "Z" 10 "kiiz" 45 "To" RE "Ia" Artificial "odOh "Y2Az. The sequence of the synthetic peptyl "00 10

Mk Ou Si Ou TV Rne Pe Zet Avr vy Beg Buk ST Mei Siyu SYA v i 5 yuYu 15

Siv Ada Uvi Ate ep Re Pe Si Ttr ev was Av Snu Snu Rgo- et 20 ra Zo ek SPU Av Rgo Rgo Rio bBeg Tuk SPU Gtrisy Ahr Re

Ba o 45 "lashes" and "2115 "b "125 RK "13" Artificial and" "293" Sequence of synthetic pehtych "0" 11

Nih Spu Sleep SPU Te Re Te Beg Ar Gay beg Buk biv Me siv S 1 Z to 15

Siv Aa Ua Atro so Rie Tse Sm Ter Geo Guk Avv Su Ou Rio 9eg

At 30

Beye Ou Aya Rgo Rgo Ro beg Su Ruth Su Ter bey AkroRve vu 45 "THIS" "their 48 "2125 VET "13" Artificial. "la" "23" Posidity of synthetic peptide "Az 13

NO SIU STI U TK RYE TV bei Ahr vn et muk Oiv Mein So

And Z Io 15

Siv Aa Ma! At Tsev.Rne Pe and Ttr Gei bukh Avko STU Su Rto Zei 20 23 30

Be Ou Aa Rgo Ro Ro 5eg Aa Aa Aa Tug SNU Tr ben Az" Re 35 0 43 "Ox 13 "11" av "213" RET "2135 Artificial "2295 "223" Sequence of synthetic peptide "400x 13

Ni biu Siv Su Tvh Be Te beg Avr Ti Zeg Tk STya Messte SPy

And 5 her IZ

Sn Aa Mag Ate See Rve Pe Siv Ttr be uh Ap Su Siu Ro Zeg 20 25 30

Zeg Oh Ada Rgo Rio Rgo et bsg u5 Buk Tuk Su Ter Geo Ar rve 3 B) 45 "210" 14 "211" 4 "a12y RET "213" Shkuchna "220" "oi" Sequence of synthetic peptide "2" "221" VARIOUS FEATURES "ad (401.30) "ia" Zhvah Re "A" TYA

Ou Sto Su TVh RBeE Tv Zeg Ar Gev BEK Suk siv Me Sm STI

And 5 yuYu 15

Sp Aa MagAge Ge Riye Ne Sy Ter Gev Guk Aby SNU SPu Rg bet

KO, 5eg Siu Aa Rgo Rgo Rgo begt Haa Zeg uv Gu TU Ou Ter vy Ar

Rie "Zhniz 15 "2112 47 "212" RET "215". Artificial; "rah" 33 Sequence of syvthetic time period "RO" "21" VARIOUS FEATURES "dod (40 "be" Haa - Revi "CYU" 15

NOTU OBESTu Tit Re TV Beh Ar Gen bet uv Siv Mesiv So i 5 10 I5

Sm Aza U Aga Gep Re fe Siv Ter Bvy G.u5 Akp Su Siu Rgo beg 95 Zo zeg bit Aa Rgo.Rgo Rgo Zeg Hna Hna Tut SPU Tr ev Avr Re "MO" 16. "2115 49 "12" RA "135 Artificial "Dr "db". The sequence of the snvtegic peptide "2" "221" is DIFFERENT. FEATURES "222" (4.40) "3" Hai "ZAS "4300" 16

Niv sYau Sat OH TVi Rie TV 5eg Ar ben 5ei Guz biv Me Obi S 1 5 Y 15

Siv Aa Ma! Agr Gei Rie De Oik Ter be buh Ap OT Ou Rio eh 20 ha 30 "vek Ou Aa Ro Rto Ro zet Ha et Buv Buv Guk STU Itr ben Ar 35 40 45

Rie "o" 17 "211zh 45 "12" RE "213" Artificial "ol" "223". The sequence of synthetic peptyl

"M" "2212 MISCELLANEOUS. FEATURES "2od" (40)-40) "ka Haa x BVE x 4402-aminoetnl-b-dibenzofuran-propanoia "NYU" 17

Nikstu Mi Spu Tag Rie. Tit Zeg Ahr Gen et Guz No Mega SL 1 5 Y 15

Sto Acha Uvi Agr Sey R Pe Oi Tr ep 1 u5 Avp Su SPU Vgo beg zo

Zeg SPU Aa Rio Rgo Rio Beh Haz be Gu Buv Rut Lu Tr Sei Acre 0 45

Re "21" 185 "Her" 47 "21225 RCT "213" Artificial "ex "doZ" Sequence of synthetic peptide "va "2215 DIFFERENT FEATURES "doz (SN) "203" Ha x VLOS "IV

Nib Spu Siv Su sg Re Te Zeg Avr Hepbeg Buv Si Me Si Oh i 5 juyu 15

Sun Ay Ma Atge Pec RNe Ne Ov Ter cezv Sat Aa SNU SPU Rgo ekh 20 2 30 beg SOIU Aa Rgo Rge Rgo Zeh Hna Hna Tut SPU Tr. ben Ar Re 33 v 45

"20" 19 "211 45 "oh VT "243" Artificial coa0" "OZ" Synthetic pentide sequence "00" 19

No Stu Sleep STU Tv Re Nu beh Ar iev Zeg buh Ov Me bi bii i 3 Yu 15

Siv Az Uvi At ep Re Pe bio Tr ev Gu Aza bij SPU Rio Tir 20 25 zv

Hek ich spa 1 Sn Se Aya tuye Su Ter ev Avr Re 40 45 "2" 50 "Iz Av "2125 RET "13" Artificial "M "223" MPosliptsovnost syvthetic peptnl "ah 20

RN OT se EIU Te RN Tig beg Ar vy be Buk Me Ot OT i 5 10 15

Siv Aa Ua Ate ep Reve Pe SL tr ev uh Avv Gu Siv Su Bgto

BI 23 30

Ttr vo Siv Om Sy Siv Aa uh STU Tur ev Avr Re "402 "15 48 "12" RE kl" Artificial "220" "023" Sequence of synuetic petisnd

"MU" 21

Pe STU ST Su, Tvh Rve Tit be Avr Bev 5eg 1u8 bij Me! Ов бий 1 5 юЮ 15

Siv AChe Uvi Ate Ge Rne Ce Su Ttr Be uh Av Aa Aa Aa bij

WITH

SYZH Ro Ter Gech Si Siv biv Se StY Aa Hugo Tgr be Ar Rv

For p 45 "0" 22 "21" I "oz RT "213" Artificial "ZD" "od Sequence of the pentide "I" 2

Nick SLU Siv Su Te Re Tvg beg Avr Gay Zet Guk Sp Meebiv Ob

From ІЙ 15

SLEEP Ah Ma! Ate ep Re Pe OV Ter re buh yap Zeg Sub Guk sp 20 28 30

SIu Reo Ter bev Si Siv biv Siv Sy Aa Tut Syau Ter Ge Avr Re "ii" 23 "211" 49 "12" RAT "IZ" Artificial "220" "2232" Sequence of synthetic pawn "BA" "2215 SPECIAL FEATURES "02 » (29)(29) "vo" Hai x RerZ "300" 23

Nih Oih Sich Spu Tit Re Te bet Awr Gen beg uv Sip Me! Siv Ov and Z 1 5

Oh Av Uyai, Ahd BepoRpe Pe Om Ttr ep uh Ako Hwa ve Gu Gu

For 25 tons,

Siv SYAu Ro tr Beo SYAv Siv SYA bo Si Aa Huk SpPu tr Sen Avr 35 40 45

Re "210" 24 "215 47 "Ia" ET "233 Pituchna "v" "bij" The sequence of the synthetic peptide "a" 221 VARIOUS FEATURES "Lo" (29).(30) "223" Hyai x Reri "AYU o

No SPU Siv Lu ve Rve Te Beg Avr Gen beg Buv Sp Mei Si STO 1 5 yuYu 15

St Av Uvi Aiv without RNe Tse biv Ter without 1.u5 Aby Hva Haz Siya Slu

Zo

Rg Tr ep sty STE Sny biv sly Aa Tu Su Ter ev Ar Rie "2105 25 "their 49 "2" RET "2135 Stuchna "220". "223" Synthetic peptyl sequence

"Y" "2215 VARIOUS FEATURES "23" 429)-(29) "DZ" Khmyv x AOS "00 25

Nik Siu Siv SYA U Te RNe To beg Akv eo Be gu Sil Me Oich O16 1 ih Yu 15 biz Az Ua! Atv so Re Tse vo Ttr Geo Buv Aby Haa bek Guye Buv

By

Siv Spu Rto Ttr Sev Op su Siv OZ STch Aa Tut Snu Ter Gay Ar 33 40 45

Rie "10" and "i" 49 "12" RET "Z13x Artificial "20" "235 Nosequence of synthetic peptide "DM "boi" DIFFERENT FEATURES "ro" (29). (29) "kdz3" Hai VE - 4-(2-Myoethiz)-e-dibenchofurav-propanoyl "Azh yes

Nih Shh Siv STU TV ve Ti be Avr Pec be? Su SYA Me Oto STI i Z 10 I5 si Aa Ma Aga Geo Re Pe On GerTwi Su yo Hwa zeg Buk uv 20 ah KO)

Siv Siu Rgo Ttr Sem Siv Siv Siv Siv Ste Aa Tukhg SPU Ter G.ep Avr

TBe "20 27 "from 47 "212" RET "21325 Artificial "DM" "a" Sequence of synthetic peptide "em" "their DIFFERENT FEATURES "pod" (29230) "223" Hva ek Zaos "A" 37

Niv SPU Siv Su Tag Rve GW Beh Ar Gen et bukh Siv Mei Siv STI i 5 10 IV

Aza Ma sat down! Agr Sev Re Pe Se Teren Guk Av Haa Hav siv STU zo

Ro To Ben Spo Si YTCH YELO Si Aa Tuk SPU Ttroben AvroRne "guid" 25 "-24112 34 "212" RKET "213" ЦЕгучна "вх "033" Sequence of synthetic peptide "Oi" 25 их С1у Сим Су Мв РНе Tweet beg Akr Gen es Tuye ST Me Ot Ev 1 5 TO) 15

Siv Aa Ma! Atebey Rre Ce SV) Ttr em Buv Avo Tut Su Ttr Gen 20 25 36

Auré Re

"21" 29 "8115 38 "12" RET "3" Artificial; "oh "223" The sequence of the synthetic peptide "ah 29

Niz Su Sim Su TE Re Te beg Ar Gen et 15 16 Messi St 1 2 juyu 15

Si Aa Ua Ago Be Riye Tse Si Ttr ysi Gu kv buye Tut O1U Ter 2 Z 30

Tem Avr Re: 35 "oi 3 koi15 37 "liz RKT "13" Cytuchna. "А" 2235 Sequence of synthetic peptide "00" 30

Niv Si; Siv O1U Te Rne Tin beg Ar sy Zhei bukh Sil Mesy ste 1 5 yuYu 15

Dreams Liv UA Aga ep Ra Ne OI Ter Sen Gl Avv Liv Aga Ada uh

MU 30

OK Ter Teo Ahro Re "SHTO 31 "M". 57 "2" RE "VZ" Pituchna.

"Ox "723" The sequence of the synthetic peptide "Ox 31

Nik stu Sn Stu Te Riye Tig bek Ayar vi Beh Guz biy Meebty Siv ! 5 July 15

Siv'Avv Mag Ate Bey Re Ne O by Ttr Beb Y u5 An be Guya uh Tuye

Ou tr ben Ar Roye "under" 35 "1 38 "42" RE "213" Pituchna "B "203" Sequence of synthetic peptide "oh "actions" VISUAL FEATURES "breeze" (29)(29) "223" Hvaah Revi " WHAT" 32

Nih Su Sy SPu Tk Rve Tve beh Ar. Gen beg Guz beat Messpv spy 1 z 10 15

OIo Av Uvi Ate Sen RBye Pe bin Teren Sub Ahy Hwa we was Buv

For 23 30

Tug slu Ttr Cez Akr.Rve 33 "2105 33 "11" 36 "12" RET "8135" Artificial "ee" "Zl3" Sequence of synthetic peptide

"00" "r" VARIOUS FEATURES "apoy (293.30) ka" Hai t Reva "400" 33

Ne SPU Sto S1u Tu RNe Gn be Avrisv bebi hv Ov Mes otv S

From 5 10 15

Sie Aiv Ua Ate Gvy Roe Pe STI Ter ev uh Akwa Hav Hwa Tuye SOIU

ZI 28 Za

Ter ev Avr. Rie "2105 Z "KI" "12" RT "13" Artificial "230" "aa" Sequence of synthetic peptide "2" "eyelashes" DIFFERENT FEATURES "Y (29429) "23" Zavt VAE "M" with

No OR St STU TVh Rie Tve beg Avr Gen zet Suk Siv Place STI 1 5 16 15

St Aa Uvi Ate Gen Rae Pe Siv Tir ep Gu AvpoHva beg Buk Buk 2 a zo

Tug Siu Ttr Gele Ave RVE "10" Za. "actions" 35 "2122 RET

"viz" Artificial "DO" "223" Sequence of synthetic peptyl "a" rah VARIOUS FEATURES "YO" (29429 "aa" Zhai with BVE with 4-yaMnostil)-b-dibenzoburanchyronanoy "ayu". 35

Ni pu Sat STU Te Rne Te Zeg Avr Ge eh Duh Xia MegOosie

H 5 io 15

Sleep Aba Uwi Ate; without Re Pe STy Ter ben Guv Avo Hva et Buv uv

Zo

Tug SYH Tiriyev Ahr Re "10" Zo "211" 36 "212" RET "2135 Shntuvva "M" "y3" Sequence of synthetic peutide "oo" "2215 VARIOUS FEATURES "dod" (21.30) "Za" Ha - VDOS "Zo

NE STU Siv Su TB Re Tu bet Ahr Ge eh 1u5 bip Me biv Siy

And 5 yuYu 15

Siv Aiv Mai Ake Se Rpe Ne Sty Tr ben Guz Aa Hav Haa Tug Su 20 25 30

Tto ben Havre Rieh

"2105 37 "2115 47 "12" RET "15" MNuchna "P" "oi" Sequence of synthetic peptyl "02 37

Ne Ata bish Si» Tre Re Grebeh Awr Ua Zeg be Tut vi Sv Ou

And there is 1 15

Sp Aiva ATa Su Obi Rve Tse Aza Ttr gy Mai Gu Tu Age biv Su 28 B

Rg Ttrev On biv Siv Spa Sto Aa Tukh OTu Ter en Avr. Rie "2102 38 "1" 45 "from PET "213" Artificial "MAE" "223" Sequence of synthetic peptide "4005 35

Niv Av bid Su Te Riye Te beg Avr Uvi Zet Beg Tuye Gay Ie Su

I 5 56) 15 biv Aiz Aa uh Sy Re Pe Quince Tr so ma) uk Su Ate Buk Op

ШЧИ 5 Зо

Ou Rio Ter ate Siv Ob styu Sto biv Ada Tuk su Ttr vi Ar Re

For I 45 "a "and 30 "2102 RKK "213 Artificial "20" "223" Synthetic peptide compatibility

"KyuYu" 39

Nih Aza fight Spu Te Re TVg Zeh Ahr Ma! Besbeg Tuye Ten sty would be 1 in 10 of her

Sip Aa Aa Was So Re Pe Az TtrGem Uvi Was Su Atya Av Aa 20 25 ke

Aa ST su Rgo Tr Geo in OV Se Siv Siv Aia Tu O1U Ttrivn

For 40 45

Avr Rieu "10 40 "ih 50 "From" RE "213" Artificial "2205 "223" Sequence of synthetic peptide "I

Niv Aiz Siv Spu Tvg Re Toh 5skhg AvroUN Zeg et Tut Gem Si Su 5 IU IZ

Siv Az Aiv I xx Sid rve Pe Aza Troe Ma uv Su Atr zegi de

Zo tuye bip Su Rio To ep So biv Siv Seven Siv Ava Gug S1U tri em

OZ 45

Avr Re "i" 41 "2115 51 "oz RET "IZ" SHERuchna "2" "23" Sequence of synthetic peptide

"Y" "r2i12 VARIOUS FEATURES "aa" (331 "233" Khva-RevZ "005 Ya.

EV AV STI su TV RAe TV ze Ahr Ma! vet ze Tut Ge Obid Su

H 5 iv 15

Syp Ay Az Buv Su Rpe Tse Aza Ttr ey Uvi Sub STU At Hva be

Glk was biv Siu Rez Ter ev OT Siu Siu Sim Si Av Tukh Su Ttr ho Ahr Rre "2105 43 "21st" 49 "125 RE "13" Artificial "in "YAZ" Sequence of synthetic peptitschu "r" "221 VARIOUS FEATURES "ra "(31).32) "roz" Mai x Rez "shЮю 42

Niv Aza So Siu Te Riye Te beh Avr Uvi be beg Hugo Siv Su i 5 juyu 15

Op.

Rne "Z" 43 "21" 51 "12" RE "3" Artificial "Spirit kg" Synietic peptide sequence "zh "231" VARIOUS FEATURES "dra" (3 "23" Zhave ZAS "ah 43

Nis Aa Sy Su Te Re TV bek Ar Mai bag beg Tug Geo Siv SPU 1 5 10 15

Sp Aza Ai Buv stv Rae Pe AV Ttrivn uv gu Ou Ag Hv God

Zo

Tu uz ОЙp Ou Rio Paris pe Ov Siv Si O1a Ana Tu SPU Tr 45 ist Avr rve za "105 8 "211" 51 ko" RET "2135 Artificial "oh yes" Sequence of synthetic nentide "M" "221" MISCELLANEOUS FEATURES "2225 (31323 "DOS" Kha x BVE "8-(5-aminoethyl and o-pibenzofuran-propane" 005 and

No Aa biv Su Gog Rbe Tvg o 5et Ahr Mi beg Zeg Tug vi Sim b1u i 5 10 15

Siv Aa ATa Gu Si RNe This Aa Ttr obi U Buv SPU Ago Hva be

Zo

Hm Was Sp Ou Rio Ter Seo bib Sat sin tv biv Aa Te Su Tr 0 45

I si Avr Re "zh 45 "2115 49 "212" REK "213" Artificial "Roof "23" The sequence of synthetic neptide "ad" "ei1i" VARIOUS FEATURES "al (3143) "23" Hai - ZAS. "NKYU" 45

NIV Aa SV STU Ti Ve Tu eh Ar uzi Begzek Tut Geo Sleep Su i 2 No IZ

St Aa Aa Buk OTo Riie Pes Aba Ter Bei Ua Buk Su Ag Hva Hna 20 25 30 Siu Siu Rgo Ter em Om Siv Siv Sat O19 Abu Tut SLU Ter Ge Avr 35 40 Yak

Re "0" 46 "I" k2idz RET "d13U" NShituchna

"оо3" The sequence of the sytegian peptide "0" 46

No Aza Sv Lu Tvg Rne TvVg beg yar Uvi beg be Tug ev Ov Su

From 10 to 15

Siv Av Aa buye Sim RNe Pe Aza Ter ev Ma B Su Aty Tu Su o) 75 Z

Ter Sen Ar Re 35 "2 47 "3115 37 "12" CT "213": Artificial "a" "aa". The sequence of the synthetic peptide "AYU" 7

Niz Aa biw biu Tweet Rie Te bek Ar Uzi Zeg eh Tut Be Siv Su

And 5 10 And 5

Op AV Aa 1 u5 0 Rpe Le Aza Ttrivy Ma bu Ou At Buv Tu 23 zo su Tr ben AkhroRve

For "ХО" 46 "их 39 "Mom REG "VRT3" PEGUuchNIa "22" "Ia" Sequence of the synthetic peptide "4005" 4K "Niz Aa Siv SiuU TNe Rie Track beg Akr Uvi Beh et Bug Gene Om biu 1 5 Yu 15 bii Aza At Guk Si Re Ne Az Ter Gay Mi Gu Su yo Aa Aa 29 25 30

Az Tut SLu Ter ep Avr Re. 35 "Z" 49 "211 39 "Ou" RCT "DU" Artificial ed0x "aha" Sequence of synthetic peptide "MY 49

NIV A Oish Oiu Te Rbe Tv bet Ar Uvi bek st Gut Sev Sy bih 1 5 yuyu 15

Op Aa Aa Suk OTa Ra Pe Aa str ben UVI Gu SPU At bot Gu ikh Guk SLU Ter Gay Av Re "MO" 50 "11" 80 "ice" RET "213" Artificial "00 "723" Sequence of synthetic zeptil "zh koyi » DIFFERENT FEATURES "aa" (313) "Ро3" Hai x Raya "MO" 50

Ni Az Si Su Te Rve Tvg bZeg Ar Ua bet be Tut Gen s STU 1 5 yuyu 15

Sp Aza Aza Buye Siv Ne Pe Aa Ter Ten Mai Bu Su Ah Haw vet

28 30

Buv Buv Huk Stu Ter Gen Avr Rie 40 "215 5 "1" 38 "212" RK "21U" Artificial "M" "ha" MPoslovity of synthetic peptide. «ех «22125 VZN FEATURES «ayu (U) «23» Khaz - REVZ «4005 51,

Niv Aich St Siu Te Rre Tv Zet Ahr Uvi beg Bei Tut Gen OTO Su 1 Z 10 z

Siv Av Av Buk Sim Re Pe Aa Tri Uvi Buv SPU At Ha Hai 28 25 30

TuyeSpu Ttr Gen Der Rre

According to "DM" 52 "DI" and "la RET "Viz" Artificial "A" "23" Sequence of the synystical pentad "am" "2012. VARIOUS FEATURES "Hai (3133 "223" Hva 5 AOS "4005 55

ENya Aa Siv Lu Te RBe: Te be Avr Uvi Zet veg Tuye Gen Sy SPu

At 10:15

St. Quince Aa Suh SYA Re Pe Aa Ter Ten Ma! zhk SO Ate Hai veg uv tsub Tut STU Ter yeo Akr rve 30 "21" 53 "iz 4) "Lyuh RKT "TYA" Artificial "dO" "223" Sequence of synthetic peptide of kich "221" DIFFERENT FEATURES "lad (131) " des" Hva PVE with 44 2-aminoethyl and o-dibenzofuran-propanoshes: "CYU" 53

No Ada Siv SPU Tk Re Tv beg Avro Uvi bee bab Huk Bey Siv Su a 10 I5 bij Ag Aiz bue bis Rne ie Aa Tgr.Gey Uvi Buv Siu Atr Hai be 2 a 30

Gu buye Tug Su Ter Bez Ar Rve 33 in "38105 54 "115 3 "2122 RET "piZ" Artificial "oh "03" Sequence of synthetic peptide "dach "22" SIGNIFICANT FEATURES "aa" 4333 "2232 Ha VAS

"WE" 5

Niv Aa Siv Siu Tpt Re Tykh bei Ar Uvi bei beg Tug pev biv bu i Z SHHI) 15

Sp Ah Az Buv Sto Re Ne Aa Ttr bech UaiSue STU Ato Ha Haa 29 25 ZO

Here SPU Tr Evy Avr Rie "2105 :35 "y1i1" 35 "217" RET "213" Artificial "2" "223" Sequence of synthetic peptide "205 "ali" VARIOUS FEATURES "b" (293.430) kra" Kai eh RerZ " I" 55

Nick Stj Siv SPU Tre Re Tbg beg Avr bey Zeg Gu bip Me bin biv

N Z 10 15

Saint Ah Ma! Ag ben Re Tse biv Ter ve Gu Av Haa Hav 15 Tr z2a 28 30

Ten-Ayar RNe 35 "0" 56 "7115 36 "212" ET "213" Nituchna "Od" "223" The sequence of the synthetic peptide

"at" VARIOUS FEATURES "232 (201.30) "232 Hai x ReyuZ "M" 56

No Snu On Slu TVu Re Tv bBeg Ar ev et Sub Siv May Siv bij 1 5 10 15

Op Aia UVI At rez Rae Pe Sich Tur ila Buv Abo Hwa Hai Aa Su 2 25 Zo

Tr Tsen Avr.RNe

ZU

"AYU" 27 "2115 36 "212" RET "13" Artificial "Z" "Z" Synthetic peptide sequence "20" "21 VARIOUS FEATURES "202" (29).(303 "o" Min x Rerd "409" 57

Ni Stu Si bih Te Rve TvVg be Ar Sei bek Su ip Me St i 5 10 Io

Siv Aa Ma! At vo RaE e Si Ttr ben Buk ko Hva Khaz Tug Av shcha 25 30

Tr Gay Ahr Re "2 5K "Ri" 35 "2" RET "215" Artificial

"a" "232 Synthetic peptide conformation "2" "ha" DIFFERENT FEATURES "200" (28).429) "223" Hna xx Reb3 "APOx 58

Ni Su Si SPU Ti Re Tig begAyar Gets Be u Sto Mesa Siv 1 5 10 IZ

Saint Ak Ma! At Gech Re Pe OTa Ter em uv Hva Hva tuye O1u tr

Vu and vyp Avr Rpe "21 55. "I Za "2155 RKK "213" Pihuchna "Di "223" Sequence of synthetic peptyl "lu" "kg2i" VARIOUS FEATURES "232" 42931 "y3" Hai Reri "a" 59

NSKU Ta STU Te RBE tТТ 5eg Ar ev bek Buv ip MegOiv Or i 5 Iv 15

Siv Aza Uai Atv en RBeliye Sich Ter be Gu zo Hwa Had Ttr Bey 20 25 30 der Re «25 6

"1" 36 "2125 RET "2135 Artificial "M "ol" Sequence of SYVUETNenOogO peptide "o" "221" DIFFERENT FEATURES "yo" (OK "o" Hai: Rob "CYU" 60

Ne SU OT Siu Te Reve TV et Ar ben Zeg Gu Xia Se) So OV 1 5 10 13

Si Lead Uvi Atr vi Rpe Ce Sto gr Gets Gu A hi Haya Ha Tut SP

Ter Ha Ahr Re "105 vi "21Y" 36 "12" RET "135 Artificial "MO" "03" Sequence of synthetic peptide "au" "321" MISCELLANEOUS FEATURES "ooo" (1232) "aa3Z" Hai Op "A" " 2212 VARIOUS FEATURES "222" (293.(30) "225" Khazve Rer3 "a o

Ni Spu Sy Su Tu Re Ti ZegAvrTey et Hav EP Mei Sio Siv 1 5 Io; 15

Si Ah Mar Ate Gei Ra Pe SN TtroGei uv Aky Haa Haa Tuk su

Ter Gay Ar Re

Ku "0" 62 "2115 Zb "2125 REK "213" Artificial "y" "dy" Sequence of synthetic peptide. "22Y" "221" DIFFERENT FEATURES kooo" (273,02) "a2U" Hai g "220 kli" DIFFERENT FEATURES "vai" (29). "AYU" Hv - ReO "4005 82

Nie S1uU Ov Ou TE RVE Tv Beh Ahr ev ze uv bip Mes Oso i Z 10 15

St Aiya Uvi Ago Geo Riye Ne ni Ttz Ben Haw Azy Haa Hwa Tut SU. 20 25 30

Ter ets Avr Re "2105 63 "2115 36 "d12z RET "213" Artificial "ah "2283" Spontaneous peptide sequence "o" "2215 VARIOUS FEATURES

"threw (29) (30) "23" Ma Reva ho" 63 niv tu Siy SIu Tag RN Tag beu Azr gen Zeg u SIV Me Si Siv 1 5 yuYu 15

SishAie Uvi Atv Tel Rie Pe Spi Re Gen Buk Avi Hai Haa Tut Su 70 25 for

Terihy Ar. Ries for "2105 654 "Her" 36 "2132" RKET "313" Artificial "code" "03" Synthetic peptide sequence "TO" "2215 MISCELLANEOUS FEATURES "bark" (29). "203" Hai - Reva "MUh b

No S1U Sy bu Tv Rve Te eh Avr Geo bek buh Ota Me Oto Sto 1 5 3) IZ

Om Aza Uai Ago Gen Re Pe Siv Ttr em uv Avr. Khaz Hwa Tut Siu zh zo

Tracks Avr Rieu "210" 65 "211" 36 "roz RKT "213" Artificial "ex "223" Synthesis of a synthetic peptide

"AD" "221" VARIOUS FEATURES "222" 429430) "MOU" May "Reru" 43005 05

No Su Siv Su Tbg Rbe. GWt 5et Avr Bez Zeu Was Here Mei Siv So 1 5 Yu I5 biv Aa Ma Asv Pe RBE Pe Oh Ter vo Was Av Hai Hai Tut SYA u yak) 25 Zo)

Ter Se Ar Re 35 "210" ob "11" 36 "122 ET "213" Artificial "VO" "vo3" Synthetic Peptide Sequence "2 "221" MISCELLANEOUS. FEATURES "yo" OO "sa" Hai x Op "M" "221" DIFFERENT FEATURES "rai" (29).430) "y" Masha Rev3 "WHAT" about

Vk SPU Osh STU TV Rpe Te Zeg Akr iey et Sat biv Me Sa SY i 3 I 15

St. Aya Oa! Khvya Pe Riye Pe S16Ltr ey Buv Ah Haa Hna Tug Ou za

Ter Gen Ar Re

"M 67 "215 35 "ma CANCER 213" Cellular "vah "sueoa MPOSLIDOVITY OF SYNTHETIC LENTTILL "a" "215. HIGHLIGHTS "20 (2).(29) "03" Hai - Reri "NO 7

Niv SLU Sv Si Tim Re Trust Avr Bay Zeg Buv Siv Me sin i 5 10 15

On Aa UagAto Ge Re Ne sb gr Geo uv Av Khaz Tug SPU r

Current AZr tears

For "210" 68 "2115 38 "12 RET "213" Artificial "220" "au". The sequence of synthetic peptyl "NO OV

Ni Ou So Ou TV Re TVh Beh Ler em vek Suk Si Mei ST OTO 1 c. 159) 15

SAT UVI te Sen Re Ne Ter ben Guz Aby Tut STU Ttrism 20 25 30

The tree is tearing

"210" 69 "115 38 "2125 RET "213" Artificial "220" "to" Sequence of synthetic peptic "nude" 69

No Su St STRU Yevi RBe Tvgbeg Ar Ben Zeg uv Siv Mebov bin 1 5 18 15

Spo Aa Uvi Ate Pen Rele beat Terobey Su Si beat Sp Spb A in Za

Tug Ou Ter vo Avr Roe "1 "i" Za kvi" RK "2132 Pikuchna "BA "23" Sequence of synthetic peptide kaDh "di" VISIBLE FEATURES "202" (28). (OKI "ia" Khan - RedZ "0"

Us SOU TV Re TV ZegAvrgen vek uv stv MesOto Oh 1 x Yu 15 bin Aiv Uzi Atr Hem Rie Pe Si Ter Gen Shuv Haa Guk Su Ter Tem 20 25 Zo

Aur. Re "21057 "211 33

"12" RET "213" Artificial "OY" "yaU" Sequence of synthetic peptide "A" "22157 MISCELLANEOUS FEATURES ky" (08) (OH) "223" High xx Bevs "005 71

Still spu Siv STU Te RNE Te 5eh Avr Gay BegTuk Siv Meg Om Siv

I. 5 Yu 15

Sleep Aza Ma Ate Te Re Pe Siv Ttr. It was Buv Haya S1u Ter Ge Avr | 25 30

Riee "210 7 "15 "a" REK "y" PUZna koch "2235 Sequence of synthetic peptide "OO" "221" DIFFERENT FEATURES "Vo (ILLI "2232 Khaz RerZ "SHHI" 72

Ni iu Spa pu Te Rie Tit Beh Avr ep bet Buv No Me Ov SYA 1 5 10 iz

Siv Ave Uvi Ate Bei Rie Ne spe Tri Haa Ou Ttr vi AhroRve 20 25 For "2102 73 "them 3

"12 RK "21525 Artificial "22" "223". Pestibility of the synthetic peptide "2" "221" VARIOUS FEATURES "ad" (28)428) "ka" zayt RevZ "A" 73

Than OTU Siv SI same Te Riv. Tvg Zeg Avr ep beg uv Xia Meg Ov So

I Z Yu 15

Sis Aa Uvi Aty yvi Rie Ne Spo Tgr without Gu Hai Ter ev Ar Re zo "MO" 74 "RE" 35 "212" RET "2135 Artificial. "yo" "U" The sequence of the peptide "o" "221" VARIOUS FEATURES "om (285:429) "203" May x Rev3 "MK"

Nick spu biv 'S1u TVi vve Te beg Ahr Geo Cheg Buv Tuye Be So Sat

It's 5 and 15

Siv Aya Mai Ag em Rne Ne Ta tr bec Was Hai zha Tug SNU Ter 25 for her der RNe 35. "20" 75 "11" 35

"212" RET "Il" Artificial "LYH "223" Sequence of synthetic pentide "paB" 2212. MISCELLANEOUS FEATURES "22 (28).2 "ai" Hwa - Rerd "ZO 75

Niv Schu Spo Su Tvg Re Te beh Ar without Zet Buv Tut Me biv Oh 1 and 53) 15

Spo Aza Uvi Akr Sev Re Pe Su Reve Geo Buv Ha Ha Guk O1u Tr sv Aho Re 33 "oh 76 "iz 5 "o KT "215" Artificial "dah "OA" Synthetic Peptide Sequence "220 "21" MISCELLANEOUS FEATURES "dai " (281.(29) "22U" Mai x Ber "MO" 76

Niv S1U 16 STU Pi Re Te Zei Avr Gep be Suv Siv Gay STO SNY 1 5 10 15

Siv Aa Uzi At ep Roe Pe SNY Rpe Gay Buk Hva Hza Bug SPU Tr 20 23 Za

Ge Arve

"20" 77 "115 35 "212" JSC "2132 Artificial "ko" "225" MPoslilovnst synthetic pentand "oh "221" VARIOUS FEATURES "Lo" (28329) "Viz" Ha Rev3 "Av 77

No STU STy SOIU Te RVe Tv et Avr Gey bet uv Tu Beshbiyu On 1 5 10 15

Stand Aa Uvi Ag Bey Rne Pe Siyu Riye en uh Hav ha Tut SPU Tr

Ka zo

HekAvr Re "1 78 "lashes" 36 "2" RCT "213" Artificial "B" "d2U" Synthetic peptide sequence "22" kR2125. DISTINCTIVE FEATURES "Water" (291.30) "aa" Hai RevZ eshtTSyuh V

NxIu Oin Siu TE rve Tvgbek Avr ben ep uv STA Me biv biv i 2 juyu 15

SPY Aa Uvi Ate Gen Rne Pe biz Ztr Ten uv Aa Ha Khvya Tut biu 20 25 0

Teriem Avr Rieu "20" 79 "211236 "12" RCT "visage Artificial "ka" "la3" Sequence of synthetic peptide "b" "groves VARIOUS FEATURES coffee" (29140) "ODA" ai Reva sMyuOh 79

Nick Siu Seven STU GWt Re Twe bag Ar ey bek u Siw Mesbvbe sti i Z 10 IV

PERSON ATa Mai was Bei Rne Pe bij Teo Was Ave Haz Haa Tug STU

Tr en Avr Re "2105 50 "her" Sv "122 RKT "213" Artificial "200" "223" Sequence of synthetic pentyl "Zh" "221" VARIOUS FEATURES "22" (29).430) "23" Hadosh Rerd " a00" VO

No Su Siv slu GT RNe Tv bet Ar Gen et uv Siya Mesoinsti i vi yuU 15

S AV Mag Was without RNe Pe SLo tr ben Was Ako Hai Hai Tug SP in 2O Be Zo

Hr Gene Or Re "Y y "Ani Zv "12" RET "c13" Artificial "230" "Y23" Sequence of synthetic peptide "a sho "2312 VARIOUS FEATURES o" (291.30) "223" Hav xx Revu "0" VI

Nv su sivOoiu Te Rve Te bei Ar ben 5ei Buv SYA Messi Gu

I 5 Yu 15 siy Az MagAte Gay Rve Tse Oto Ttr Gen buh Aa Hva Hai Tu Su a 23 30

Ter Geo Avr Re 35 "g" input "1" 37 "12" RK "2135 Artificial "220" "Roy" Sequence of synthetic pentide "y" "21" VARIOUS FEATURES "320" (29)429) "da" High Red

"au" "2213 VARIOUS FEATURES "la" (3131) "RAD" Mav x Red "00 what

Nikchslu Spr schu TVh RBe TV: be Ar Te bek Su Sp Me Siv STI 1 5 1 15

Siv Aa Ma Ate Tem Riye Pe Styr Geb i uye Abo Hwa Gu Hai TU 2 zo

Su Ter ben Ahr Rieh "21" 83 "211 "12" RET "iy" TShituchna "P" "23" Synthetic peptide sequence "TO 83

No SPpu SYA SLU TVi Re Twe bZeg Ar Teny ve buh ia Messi Oh

And 5 Well! 15

Ow Ow Ma! Ate Gey Re Ne Str bech Sya Aza But STU Ttrogvy 2 Z Zo

Azr Re "102 Va "11" 34 "2122 RKT "3" Pituchna. "ХА" "23" The sequence of the synthetic peptide x4005 Ya

No SIK On Ou Tv Re TvVE bek Ako ev Bek Gu Sv Me they and 5 19 И5

Sv A MN Atge Ge Re Pe bib Ttr Ge Gu Av Tut STU Tr Re 2a 5 B.) kr Re "A 85 "y" 3 "212" RET "2132" Artificial "21" "da" Consistency of synthetic chceptide "2" "ah DIFFERENT FEATURES of the code" (313,3) "203" Ha: 1Mvi "kyu" B

Niv biu Si Su Te Re TVi 5eg Ar ep beg Guz Sing biv Siy

She is 5 and 15

Sm Aa Ua Ago Ge Rlde Pe and Tr be Buk Ava TuyeSpu Zhav Gen za

Acre Re "105 b. "2115 34 "212" RET "VI" Artificial "o" "23" Sequence of synthetic centide "20 "2212. VARIOUS FEATURES OF "VA" 321,32) "203" Jean Me

"AND". Be

Nis SchYai SPU Tag Re TE 5et AvroGen Zeg Hm Siv Gev Oi OT and 5 her IV

Siv Aa Mag At Gen Re PE SV Who Sen Buk Ava Tut SYA» Ttr Hai 20 25 BIV

Avr RNe "ZM" 57 "LI" 35 "222 REK "213" Artificial "a "da" Sequence of synthetic petsutide "TO "221" DIFFERENT FEATURES "a" (MEDIA "U" Henna ZAZAPRIDYLULANIL "A" 87

B STU Siv Su Tik Re Te Zet Ahr en et Bu o Geo Sto Su

Sk Aga Ma Ate Se Rtse Ne Si tr ber uv Ahy Tut SU Tv vi di 25 HE

Avr.Hva "310" 8 "51" 35 "a" RET "135 Artificial "Shchi" "223" Sequence of synthetic peptide

"o" ka" VIZNI. FEATURES "o" (25).(29) "2235 Hai x Reri "AP" 58

Niv Su Siv slu GWt Re Tk Zeg Si Ge beg uk Tut ev bin So 1 5 yuyu 15

Oli Aiva Mag Ate em Re Pe bij Rvbe Tez Bu Hwa Hai Tug TU To 2 30 14y Ar re 35. "vii" 89 "11" 35 "2" RET "213" Artificial "Y" "AH" Synonym of synthetic peptyl "DM » «212. MISCELLANEOUS CHARACTERISTICS of kdd (08) (29) "2" Zhaay - Reb3 "AP" 89

Ni bu Siv Su Tit Re Tit beg Ahri ev Beh Duh Tug Gen Ov Ov i 5 yuyu z

SYA Ada Uvi Ah be Ve Ne b R ev Guk Ha Haa Tut Siu pe: 20 25 3)

Iva l5r Re "2" 90 "211" 35 "212 RET "3" Pigechna

"DM "y" Sipistic peptide sequence "vah "21" DIFFERENT FEATURES "j (25).429) "223" Khvaa xx Red "from 90

Ni su Spi st TVg RBe Tv be Sv Ben eh Bu Tut ev ST STO 1 5 Y 15

Si Aa Ma Ate Gay Rv Pe ish RBE beo uh Hav Hav Tu Oh Riye 23 zo

Gen Azr Re 33 "TO" 9 "1" 34 "1" RK "213" Artificial "2005 "223" Synthesis of synthetic peptyl "M" "221" DIFFERENT FEATURES jayo (28 (28) "203" Kha x Rev3 "400 » 91

Ni SH Siv Siu TB RE Te ke Avr gen boi Gu Tu Gei Siv OV i 5 10 I5

Si Liv Ua! ev Geo RBe De Sat Re Bey Ag Hai Tug Su tri ho 25 30

Avr tears "10" 55

"Mi" 34 "2 with RET "213". Artificial "im" "DU" Sequence of synthetic peptide ke" "2212" VARIOUS FEATURES "oda" (283428) "dO" Haa is Reva "800 92

Ni Spu Sv Su TP Rve Ti et Ar T.ei Zeg At Tut Ge SK Buv: 1 KI Jv 15

ST Aiz Ua Ate Sen Re She Oh Rpe Gay Age Hwa Tu SPU Ter Beiler RN "105 93 "pis Z "212" RET "13" Artificial "2" "oh" Synthetic Peptide Sequence "2205 "two" MISCELLANEOUS FEATURES "Rol " (28).428) "223" Hai: Reoi "VSHYuh 95.

EB5 TU Sv Spu re Re nu Zet Avroiev Beh Ago Tut Tem Siv biv i 5 I 15

Si Azh Uvi was Ben Rne Le Si Re Gen te Hwa Tug Siu Tr Bay 20 25 30

Azr RBe

"NO" 94 "No" "lyz" RCT "2152 Artificial "yo" -yy3" Sequence of synthetic peptide "220" "rZ1" DIFFERENT FEATURES "ha" (2828) kraZ" Live x RerZ "8005 94

No STU Siv Siu Tik RNe Gvg bet Avr Tech bet Aga Tugiei OI Ov

And from 10 to 15

Sy Aza Ua Ag sy Re Pe buye Ro yed Ate Haa Tug SiuU Ter ey zo der Re "210" 95 "LI" 34 "2125 RET "213" Artificial "OO "fah" MGlareness of synthetic peltte "ol "315 VARIOUS FEATURES "to " (253.48) "Oo3" Zhan t RevZ "Oy" 95

Nih Ou Siv Su Te Rbe Tvg bek Ahriyu et Atr Tut Ge biv Sa 3 To 15

Sn Aa Uzi Ago bej Rne Pe Siv Re Hep Guz Haa Tug S1u Ter Geo

28 30

Avr not "2" 96 "from M "212" RCT "3" Artificial "DO" "Give" Sequence of synthetic peptide "HO 96:

No Dreams SNU Tv Ri Te beg OTO s bei Guv tuye beo Ob STI

And with IR. their

Siv Aa Uvi Ate Ge Rpie Ne so Re Geo Guk r ema Avr Re 20 23 0 "y" 97 "2115" 33 "212" RK "213" Artificial "2" "23" Sequence of synthetic peptide "ah "2212. DIFFERENT FEATURES of zayy" (351.8 "203" High x Reard "40" 97

Nick Su Siv STU TV Rve. Trsbeg Om Ge bet uv Tut Te Sat S v ! 5 NV IV

Siv Az Ma! Ate Ge Re Tse Siv ve Se Gu Hav To Ben olar RN in; 2 ZI "OO" 98 "211 35 "sh125" CT

"213" Artificial "MM "y" Synthetic peptide sequence "FO" "221" MISCELLANEOUS FEATURES "vah (28328) "2O3" Haah Ogl "A" "o" MISCELLANEOUS FEATURES "ai (2929 "MOZ" Hwa t Ray "NK » 98

No STU Si slu Tv RNe Tvt Zeh Sp vy beg Hek Tubivy Siv We 1 5 10 15 sly Aa MagAte ey Re Ne Sy Re ev uh Hna Hai Ter vy hr 23 B te "DM 99 "711 33 "212" RET "213" Artificial "PO" "23" Sequence of synthetic peptide "2 "di" MISCELLANEOUS FEATURES "23 (281.18) "23" Haa eri "20" "212 MISCELLANEOUS FEATURES "di" (29) "ia" Hai Ogv "WHAT" 99

No SU OpeOTU Tv Riye Tv beg So ev et bu Tut Sem OB Ov

! 5 10 I5

Siv Ai Ma At et rve Pe Sta Re G by b u5 Hva Hvya Tv oo Achor 20 a 30

Re "Oh WHAT "2115 33 "213" RAT "2132 Shtechna "2" "223" Sequence of synthetic peptide "their "221" DIFFERENT FEATURES "iod (25). (29) "ZL" Khav k STV "Ai CYU

No SLU ssh Ou Tvg RVE Te Beg Siv beo be Sl Bug ev OY Si sie Aa UagAte ev Re Pe biv Rbe Be Guz Ha Hva Ttr Geo Der

Rie "1 Y1 "F1ikh 33 "12" RET "13" Artificial "oh "ya3zh Tsosequence of the synthetic peptide "Yur" LO

Ni slu Spo Sim Tit Re Tk et Siv Sechobet Geh Tut Ben Siyu Om 1 5 t ih

Sich Aia Ul Ak Set Rwe Pe Ti Re Ge bu Tug Su Ter Geo Der

RO 75 for

Re "Ov 102 "ii x Za "212" RT "1Uz NNKuchna sa "Water" The sequence of the synthetic peptide "2" "2231" VARIOUS FEATURES "Kei (28).28) "Yo" Hai x ECZ "4005 105

NiESTU Sleep Sp u Tv Re TNB STU Tem ches buye Hug vi Siv Sat 1 V 160 5

Si Aa Mais Ag Bez Riye Pe Styny Rv Sei uh Haa Tus Su Ter ev ta 25 Z der Rke. "2105 3 "Ii" 35 "M" RKK "213" Artificial "am" "aha" Synthetic pentide sequence "2 "221" VARIOUS FEATURES "vo" (95M(OX) "823" Haah Ogp "kah

"2212 VARIOUS FEATURES "222" (29429) "Pa" Hai RevZ "43002 103.

No SPU STOLU Tvt Rve Te beebij you beg Was TU Pe SO OIII and Z 10 15 ssh Aiv Uvi Ago Gea Rne Ne sly Rie Ge uh Haz Ha Tuk O1uU Tr

National National Academy of Sciences; And ZO

Gev Abr RNe 35 "2102". 104 "211" 35 "212" RT "2135 Artificial "a" "3" Sequence of synthetic peptide "Ox "231" DIFFERENT FEATURES "oi" (28128) "Ba3" Hai eh RevZ "EM" "2215. VARIOUS FEATURES "ai (293.29) "paZ" Kha x Ot "Yukh 104

Z slu pastu Te Re Tve Zee STI Gevobet buh Tukh Bem ST 1 OF 10 IZ siv Aa MagAte ep RYE Tse Oh Rie bez uv Hav Zhai gug Su tr

Teny A5r RI «li izh 105

"Mi" 35 "212" RE "213" Artificial "ah "to" Nosequence of synthetic peptide "2" "221" DIFFERENT FEATURES "Ha" (28,429) "va" Hai (In "Shyu" 105.

Niv Siu Siv SLU Tv Re Tv beh Siv I si beg Tl Gug bi bib 1 5 yuyu 15

Sich Aa Mag At Bechm Re Ne Sim RNe Pec Gu Haz Haz Tut STU Ter za

Sem Avr Vpe 25 "oh 6 "l1i" 39 "keid2 RKK "2135 Artificial "poh "rea" Sequence of synthetic peptide ko" "221" DIFFERENT FEATURES "j (28)428) "VAZ" Khva x K(Hexadecanoit-isostv " roof "22Y" MISCELLANEOUS FEATURES "222" (32).(33) "Zh Haareri "Y" 6

Ni Aa Ov Oiu Ti Re TV beats Ar Ma! bek et Tut Sey Si SNU and 5 10 IZ

Siv Av Aa uh Sleep Re Che Abe Ter Gen Mar Ha Su Av Ou Hav. by

Hai Tut SNU Tri der Re "I" TSI "21-2 39 "2122 RVT "213 Artificial "A" "Z2a" Sequence of synthetic peptide "A" "221" DIFFERENT FEATURES "222" (2010203. "323z Hva k KI exalekanot-isosy ) "M" "2212 VARIOUS FEATURES "bai" 1233 "she" Hai Roda "sniff 107

Nih Aa Siv Ou tni RVE VU Bek Avr Ua) Beszeg Tut Sov So SOU ! 5 30 I5

Sil Av AT Hvaloi Re Pe ATa Tgr be Uvi Atgo SLU Atv Spu Hva 2 2x Z

Hwa Guk Siu TgrGeo er RNe 35 "ah 108 "ih shcha "ia" RET "213" Artificial "o "23" Sequence of synthetic peptide "B" "0215 VARIOUS FEATURES kla (30.30) "225" Hai - K(Hexalekanoyl-zosne ) "A" "21" VARIOUS FEATURES "222" (321433) "303" KhZhai x Rera "00" SHE

Nv Aza Ot Ou Tv Re Tv et Avr Uvi 5et beg Tug ev S OTU

And 5 July I"

Sp Aa Aa Ago Sta Rpe Pe Aza Ttriev Ma At S1u Haa SPU Haa 2 25 ZO

Khan Tut Syau Tr Ge Ar vve "2105 109 "VR" 39 "12" RET "213" Tsreuchna "DYA "223" Sequence of synthetic peptide "ra" 2215 DIFFERENT FEATURES "dalo" (201.20) "23" Khaya g K(Hexalekanoiyazoyuta ) "by" "231" VARIOUS FEATURES "302" (323.33 "roof" Zhai eh Reri "MO 109:

Ni Aza Sv biu Te Re Tv Zet Avr Ma! Zeg et Guh Sen S. Ou 1 Z 16 15

Steve Az Az Hna Sv Re Tse Aa Tgr Gay at u s At Siu Hai 2 25 Zo zhva Gug SPU Terez Ar Re

"10" TSO "1" 39 "12" RET "213" Artificial "220" "LoZh Sequence of synthetic peptide "ee "2" DIFFERENT FEATURES "202" (30343) "ba" Zhaa sh K(Hexadecanoyl-zostv "ah. "2212 VARIOUS FEATURES "da" (372).433) "23" Haa - Rer3 "Me" Po

Niv OIU Siv SPu Te Be: Tv bet Avr Uvi beg beg Tug Hep Sn SPU i 5 io 15

Siv Az Aa: ato Sto Rve Pe Aza to Geo Ua Ate SPu hna Su Zhva. 2U 30

Hav ut SU tr De A hr re 3 "Moss 111 "112 39 "aa" RT "142 Artificial "902 "lada" Cosistency of syutetic peptyl "g" "22" DIFFERENT FEATURES "pa" (2 "293" Hai x DIV " M" "i" RI FEATURES

"223" (20)-(2)) "DOSE" Hai x KO exadekanomnisosiy) "OD" "rai DIFFERENT FEATURES "pov (3235033)

OZ" Hva e Rer3 "MK

Viv Khan beat SIu Te Re Te beg Ar Uvi Beg god Tugivy Si O1u sat down Aza Aa Hai Sleep Re Ne Aa Tr Gay Uvi Ave Siu Ago Spu Kaya 2 25 for

Haz Tut STU Ter Tsev Akr Re 35 "y PZ "1" 39 "12 RET "215" Artificial code" "poz Synietic peptide sequence "Z" "291" DIFFERENT. CHARACTERISTICS OF "Od z (22) "va" Let AV "VE" "z21" are DIFFERENT. FEATURES "Za" (323-433) "823" High Revs "00 2

NE Haz Spa bih Te Re Tv Zeg Ar Uvi Bet Zag Bug Te biv S1u 1 5 o B

Sp Aa Aiv uv Siv Re PeoAda Tur ev Mai Age Spu Age Ou Hwa 28 0

Haz TUg O1uU Ter Ge Ar rve

"2" 115 "21" 39 "12" RCT "213" Artificial "arch "223" MPosylability of synthetic peptide "YO "t" DIFFERENT FEATURES. "2225 (323 "d23" High - Red "AP" 13

Niv Aiv Siv SIu Tg Rpe Te Zeg Ahr Ua be bet Tut Geo S1V Oh! From 16 I:

STI AtaAva ru Siv ve Tse liz TerTev UarAte Su Ate Syau Hva zo

Haa Tu Ou Etriev Ar Re "No" 114 "A" ZI "212" CANCER "13" Artificial cochlear "yes" Sequence of synthetic peptide "00" 114

No AY Si STU Tu pe tv bet Ar Ua! be vek Tu Pev So STU 1 of 10 15

Si At Aza Gu Sv Re Pe Lida Ttrbev Magtid su Ah Ou 20 25 30 "0" 115 "2115 38 "2" RET

"213" Artificial "ah "DO3" Sequence of synthetic peptide "002 115

STU Si STU Tvu RBe Pi 5et Ahr Gei Gu biv Meboish Ev St 1 Z 10 I5 dia Ua Ate Bey Re Pe Sy Tur Ge GT uv Ako Siu Ou Ro bek bei i 25 za

Spu Aa Rgo Rio Rto be "22 116 "I" 17 "212" RVT "13" Artificial "Mu" "223" Cosylology of svitetic peptide "A" "2212. VARIOUS FEATURES "ro" (1515) "po3" May selected Sem, Mie, Rbe ii Gn "a I

Siv Su Rgo bor without Sa biz Snu Se Sleep Aa Tut SNU Ter Hva Ar 1 c) 10 15

Re ko tse ke i; zi" CHI ih, ON tn; in Yi eh y ko ne - b ne

F Shy

E and Z intravenously

F! - TyuMMIilKka of intravenous sh: I'm a cold-skinned woman! - hypodermic error

TK!

B and; a 5 cho BI Ko oyu

Nominal time (min)

Fig. Ta t vie ey (U y kv - IN with them Sho "d- "intravenous d te e chik poOMMILK of intravenous rya "V y I subcutaneous v o | Sha sh-e-- Tyuomylka subcutaneous 8. : : o E

U a 5 che cho x o

Nominal time (min)

Fig. 16, that is the life of geo iv Ya. s | She and I have a drink" I am full

F | eta t

That's what they said at 05 o'clock at 15 p.5

Time (hours)

Fig. 2 g. same re ; M Carrier in WHAT Combination (1 nmol/kg each)

E E EV SHY Combination (10 nmol/kg each) I women KU Combination (50 nmol/kg each)

EOZ: | SHO Sloluka 1 (1 nmol/kg) yav and 44 p NYA r and more

With | and: SHY! Mo. Compound 1 (10 nmol/kg) was administered to the patient | Y - SHY Compound 1 (50-nmol/kg) i ! I am NINE renn and - MU | tech:

Statistics: "r. 0.05 by the method of one-factor analysis

Gaia - Y - - a AMOKHA with multiple comparison of the tested substance against the carrier using Dunn's criterion

Fig. WITH

From what Z I N Y

And you are the Bearer

NI ie i SHE Hksendin-y

OO Eksendin-I I Gastrin-17

In Compound 33

In her Z v she peeatzhzhtya 5 B she zvytyanivh evidences

E MON BO 0 uomnnynane i sweat DN SCHE Ann,

That! NN o beomm I zh shi t m sh - B ke BO Z zh sh t p ha hmm zh sh sh what

Fig. 4th with Y Y tk gray I syst.

And: YOU carry a wife

Oh 0 she SCHI pen SCHA Yeksendin-y - ZE JAK I - E sechi y 4 more Ge u 17 rea 4 po SHE ehotkeyuk, VE vh ze KeENDyINEYa t I STI - s Bo z drytnnsllyny - rony 33

E NN B Poluka

FAO yr pin VV v t Kk i .

In and:

With | y y "g e- su h- more; her: - Kk

Z Vya x shk 5 ih- ih g ih- o 2 o schi Her-he.

J

- 5 in - her about

Wh-

Fig. 5 sh

ОЖ бою чик Eh I - ! Yi duankinn W Nosyy

With two complete En SHY skosndyniya

NE nn POS SHO sksendinyai in I astrin-ia7 not r: 5; TIRES nn vktut and p sh Yilen porosek V Compound 33

WASH the eco key rheostat

IS ! Sho oh V te y o SHVY ee ey p Shi se o ssh: nyu Or

In the same I of i-y EE ke . i i t- ee 1 - o sh M i 5 i dir: z dh

Z zv v E kh g ze - Gen ra sh Ekh. -

KE) 5. t o - I in o

WITH

M

IS

F

S mya ke ki

Fig. 6 and ke SHY ChPosii a zhk STILL Exendin-4 I and Without Exendin-I Gastrin-17

S zioiei ! shi tre 0 DN Z Compound 33 - ny Boeotes SHE mak

I eat Bosch and ki

In p pini pd Om ven y de. I saved Oh paleleetiechtt, 4 a) n MORE essays in ; ; while we are OO i. E VEN tek ky x PEK TO voru shih I y te che m

AND; g z KE Z s shcha Glas shch ke A

Ky

Bysk and and.

UK

I am

IS

Eyana

Fig. 7

WITH! What SHE Carrier

S. - SHE Exendin-4 o y sezhny ShZHZh Eksendin-4- 5 Gastrin-17 g poly shi ED. Compound 33

NN I and ee m. |. the sadness of biting and Mr. Essay EE

E I and S o V EE with I Y 7 zhi zhi ee is i 0025 MORE Eh

Жх Ne la ancient times

Ов и От МИ se В

Where: a. iz E sh B in 8 ge a e shchi o o

AND

5 sh p h isevy sh

Also see

Fig. 8 che Carrier-carrier ek Exendin-i- Exendin-y i ' ko Liraglutide-niraglutide x , y i t roko Compound 33-Snoluka 33 o oyu ti cy i shk sany oyayu. and | I'm still too late

FOR t, ; zikhanyanykh schu zha and we sk en v z a "e tvty

Days of treatment in zara Carrier-carrier "and Exendin-4- Exendin-4 for Liraglutide-liraglutide give! | "yo Compound 33-Compound 33 stack, TOWER "and backgrounds and kA.

E ikh and A - -Yu - I; y y z y z t h, N Y y y same A and Ya

Mak burned me with 3 barks

With other | N y uk zhi " zav z and z

WITH

3 more with reni still vi n ned, m i z a mm Kk in xx am

Days of treatment with carrier-carrier seagull Exendin-4-Exendin-I

What ; Livaglutide-liraglutide

I, as Compound 33-Snoluka 33 to her ra t; 5 re Y Y g Z as i zale 1 EN and 2 ul y i Zhe -- and I and M, and se r that I -I and no I re ov and zh « I jin re

Kk and ACTION with Ya a a ay "is in p"

Days of treatment

Fig. 9 ee Carrier-carrier «eh Exendyn-4- Bksendyn-y

I' sao Liraglutideliraglutide and how Compound 33-Compound 33 is the same: SCHE Si and. also ! yai" ay and yaka With I I ssh WE a es NN: sy

Fo od ber Uvk r

OM fakes I lay down

Days of treatment o Carrier-carrier zakh Exendin-4- Exendin-i zv" . KO Liraglukid-liraelutide - about I and Snoluka 33-Compound 33 in the spirit of EI K M

NO | ay Zh jhe "re or Klen v y i I ik zhye that fozhke zhazh same sho Z i shchi i 2 zv same "kh a pi

Days of treatment with eco Carrier-carrier cha: Eksendivn-Ya» Ecoendnyi-Ya v. i zako Liratlutvd-liraklutyh y : che EUpopuka 33-Spoluka 35 х и ze ih B y : a Е и я и Е з Kene "sh ; е. zu, En

What is the background of VV?

Mo Shi 5 and a ku 6 mouse" and

Melon forging

Fig. 10 would be

I am B

M.: rovih Zhk vm sziiev yny shi ze M. dek Shkr ak shi KE z KO V rev VE V V zh tya yak sho - in SHYH. what - SHE Zhe che B i ish: B sao K y NN y Yak 5 "SHE eV until - VE: Vo yo KU K M she 5 SCHE VNI - Z y" vk Ba a oko shi s ШЙ Carrier-axis

KO Bexendin-4- Exendin-I with ShK raglutyl-liraelutide ee WHAT Compound 33-Compound 33 ze MORE Carrier- ExendinoY

WHAT |; ! - SCHO Nosiy- liragluty o, 33 Her: ". : avia "Zheche E tyh kh N se tk v V zha ey same v shi Carrier- Compound ZA 2 ZSH with za zhim v No oi roiv x ! t EV o 000 M Exendin-4-carrier in SHE... 5 I B Liraglutide-carrier to IN ZOBU 5 Compound 33-carrier 3 Ex: SCHI veSchya Bo I SHE I Zychu a ke V Lesya,

Fig. 11