Protracted CCR5 antagonists and uses thereof

Abstract

A CCR5 antagonist comprising a polypeptide comprising a Glutamic acid or an Aspartic Acid at position 45 and 46, and a Cysteine or a Lysine at position 68, optionally comprising a protraction moiety attached to the polypeptide at position 68 comprising a fatty acid and a linker with at least one negative charge. The CCR5 antagonist providing increased potency, stability, and / or pharmacokinetic properties. A formulation comprising the CCR5 antagonist may be suitable for parenteral administration. The compound and pharmaceutical formulation comprising such a compound may be used for medical treatment of patients with non-alcoholic steatohepatitis (NASH), more specifically F3 and / or F4 NASH.

Description

[0001] PROTRACTED CCR5 ANTAGONISTS AND USES THEREOF

[0002] TECHNICAL FIELD

[0003] This invention relates to a protracted C-C chemokine receptor type 5 (CCR5) antagonist compound. The invention also relates to a pharmaceutical formulation, suitable for but not limited to parenteral administration, which comprises such a compound. The compound and pharmaceutical formulation comprising such a compound can be used for the medical treatment of patients with non-alcoholic steatohepatitis (NASH), more specifically F3 and / or F4 NASH.

[0004] BACKGROUND

[0005] Non-alcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) which is marked by chronic necro-inflammation and fibrosis of the liver. It is estimated that 1.5-6.5% of people worldwide live with NASH, with numbers expected to rise (Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64:73-84.), yet people with NASH are often unaware that they are living with the condition due to difficulty in diagnosing it. As such, it often occurs that the condition advances to a stage of significant fibrosis (Araujo AR, Rosso N, Bedogni G, et al. Global epidemiology of non-alcoholic fatty liver disease / nonalcoholic steatohepatitis: What we need in the future. Liver I nt. 2018; 38:47-51). This is further compounded to the fact that there are currently no approved treatment options for NASH that address the underlying cause of disease and / or prevent progression to cirrhosis (Banini B and Sanyal A. Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options. Clin Med Insights Ther.2016; 8:75-83). Treatment of NASH is typically limited to incorporation of a healthier diet and lifestyle interventions to assist weight loss and facilitate reduction of fat in the liver.

[0006] Chronic inflammation and fibrosis of the liver can progress to cirrhosis, cancer and liver failure, highlighting the need for diagnosis and treatment options which are essential to prevent the progression of NASH, or regress it.

[0007] While some researchers are investigating pathways to generally reduce hepatic fibrosis via modulating metabolic contributors, others are investigating the effect of inhibiting C-C chemokine receptor type 5, commonly referred to as CCR5.

[0008] Activation of CCR5 is believed to be associated with the recruitment and polarisation of macrophages and T-cells which drive a pro-inflammatory response in the liver, while also believed to lead to collagen production and fibrogenesis. This activation of CCR5 may be by endogenous chemokine (C-C motif) ligand 5, commonly referred to as CCL5 and known as RANTES (regulated on activation, normal T cell expressed and secreted), alongside chemokine ligand 3 (CCL3) and chemokine ligand 4 (CCL4).

[0009] Whilst small molecule antagonists of CCR5, such as Maraviroc (CAS registry number: 376348-65-1) and Cenicriviroc (CAS registry number: 497223-25-3), are known for their antiretroviral applications, their liver toxicity and lack of efficacy have rendered them ineffective as therapeutic drugs. The monocolonal antibody (mAb) Leronlimab (CAS registry number: 674782-26-4) is also known for targeting the CCR5 receptor. However, a substantial dose would be required for the treatment of NASH, requiring undesirable doses quantities and administration frequencies resulting in undesirable complexities and challenges regarding patient compliance in NASH, among other issues.

[0010] Hubert et al. demonstrated that modification of the native RANTES sequence can result in potent CCR5 antagonists which attenuate CCR5 signalling and sequestration (Gaertner, Hubert, et al. "Highly potent, fully recombinant anti-H IV chemokines: reengineering a low-cost microbicide." Proceedings of the National Academy of Sciences 105.46 (2008): 17706-17711). WO 2008 / 012689 describes modifying an / V-terminal of native RANTES to provide an analogue that inhibits entry of R5-tropic Human Immunodeficiency Virus (HIV) into human cells while generally lowering the CCR5 agonist side effect, providing a capacity to elicit a generally low degree of pro-inflammatory signalling cascade. WO 2019 / 229616 further builds on these RANTES analogues, identifying a particular / V-terminally modified RANTES variant commonly called “5P12 RANTES” with high anti-H IV potency, for use in treating cancer. The analogue 5P12 RANTES is currently used as a microbicide for prevention of HIV transmission and is administered vaginally or rectally as an aqueous gel formulation which is unsuitable for subcutaneous administration by injection. Furthermore, this 5P12 RANTES analogue exhibits a short in vivo half-life, poor physical and chemical stability and undesirable glycosaminoglycans (GAGs) binding, to name a few drawbacks, leaving much to be desired for an anti-inflammatory treatment. There remains room for improvement.

[0011] SUMMARY

[0012] It is an objective of the present work to provide a RANTES analogue having CCR5 antagonist properties and increased potency, stability and / or pharmacokinetic properties, such as an increased circulating half-life, for use in the medical treatment of subjects with NASH. Another objective is to provide RANTES analogues which can be formulated into compositions for use as a medicament. In certain embodiments, such medicament is suitable for parenteral administration, and more specifically for use as a medicament suitable for subcutaneous injection.

[0013] As will be made evident below, the inventors have surprisingly found that providing certain combinations of modifications to the inhibitor known as 5P12 RANTES resulted in a RANTES analogue with superior CCR5 antagonist properties, such as increased potency, stability and / or pharmacokinetic properties. More specifically, the inventors have surprisingly found that replacing one or both of the residues in positions 45 and 46 of SEQ ID No. 2 amino acid sequence of 5P12 RANTES) with either a Glutamic acid residue or an Aspartic Acid residue at least led to a reduction in the GAG interactions and an increase in in vivo half-life. The inventors have further surprisingly found that replacing residue 68 of SEQ ID No. 2 with a Cysteine residue or a Lysine residue, and further providing a fatty acid protraction moiety having a negative charge therein, further contributed to superior in vivo half-life, while further providing solubility and stability enhancements.

[0014] One of skill in the art understands that the advantages provided by the enclosed invention is the combination of properties provided by the CCR5 antagonist of the application. For instance, while some combinations of modifications to the inhibitor known as 5P12 RANTES provide great improvement in potency, it is, in certain aspects, desirable to strike a balance such that superior or adequate improvements in stability and pharmacokinetic properties be also provided by the same compound. In some aspects, this results, for instance, in a CCR5 antagonist of the invention where moderate improvements are provided in the properties desired, but where the overall properties of the CCR5 antagonist are superior, such as to be of use for the prevention, treatment and / or alleviation of inflammation of the liver tissue associated with non-alcoholic steatohepatitis (NASH), such as F3 and / or F4 NASH.

[0015] The inventors have identified a number of combinations that, in certain embodiments, further provide improvements to the potency, stability and / or pharmacokinetic properties of the CCR5 antagonist.

[0016] The above stated objectives are achieved by the teaching of the subject claims.

[0017] Disclosed herein is a CCR5 antagonist comprising a polypeptide comprising a maximum of 9 amino acid modifications relative to SEQ ID No. 2 and comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45; a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 46; and a Cysteine (Cys, C) or a Lysine (Lys, K) at position 68.

[0018] Further disclosed herein is a CCR5 antagonist comprising a polypeptide comprising a maximum of 9 amino acid modifications relative to SEQ ID No. 2 and comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45; a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 46; a Cysteine (Cys, C) or a Lysine (Lys, K) at position 68; and a protraction moiety attached to the polypeptide at position 68 comprising a fatty acid and a linker with at least one negative charge.

[0019] Further disclosed herein is a CCR5 antagonist comprising a polypeptide according to Formula I (SEQ ID No. 60):

[0020] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala-Val- Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Xaa49-Val-Cys-Ala-Asn-Pro-Glu-Xaa56-Xaa57-Trp- Val-Xaa60-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0021] Xaa1 is Pyroglutamic Acid (Pyr),

[0022] Xaa6 is Met (M) or Gin (Q),

[0023] Xaa8 is Thr (T) or Ala (A),

[0024] Xaa45 is Asp (D) or Glu (E),

[0025] Xaa46 is Asp (D) or Glu (E),

[0026] Xaa49 is Glu (E) or Gin (Q),

[0027] Xaa56 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0028] Xaa57 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0029] Xaa60 is Arg (R) or Glu (E),

[0030] Xaa64 is Asn (N), Glu (E) or Asp (D),

[0031] Xaa65 is Ser (S) or Glu (E), and

[0032] Xaa68 is Lys (K) or Cys (C).

[0033] Further disclosed herein is a CCR5 antagonist comprising a polypeptide according to Formula I (SEQ ID No. 60):

[0034] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala-Val- Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Xaa49-Val-Cys-Ala-Asn-Pro-Glu-Xaa56-Xaa57-Trp- Val-Xaa60-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0035] Xaa1 is Pyroglutamic Acid (Pyr),

[0036] Xaa6 is Met (M) or Gin (Q),

[0037] Xaa8 is Thr (T) or Ala (A), Xaa45 is Asp (D) or Glu (E),

[0038] Xaa46 is Asp (D) or Glu (E),

[0039] Xaa49 is Glu (E) or Gin (Q),

[0040] Xaa56 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0041] Xaa57 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0042] Xaa60 is Arg (R) or Glu (E),

[0043] Xaa64 is Asn (N), Glu (E) or Asp (D),

[0044] Xaa65 is Ser (S) or Glu (E),

[0045] Xaa68 is Lys (K) or Cys (C) and comprising a protraction moiety attached to the polypeptide at position 68 comprising a fatty acid and a linker with a at least one negative charge.

[0046] In accordance with another aspect, there is provided a pharmaceutical composition comprising a CCR5 antagonist as defined herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is suitable for parenteral administration such as subcutaneous administration, for use in the prevention, treatment and / or alleviation of inflammation of the liver tissue associated with non-alcoholic steatohepatitis (NASH), such as F3 and / or F4 NASH.

[0047] SEQUENCE LISTING

[0048] SEQ ID No. 1 represents the amino acid sequence of Native Human CCL5 / RANTES;

[0049] SEQ ID No. 2 represents the amino acid sequence of 5P12 RANTES, also being referred to in the example section as the comparator compound;

[0050] SEQ ID Nos. 3-59 represent the amino acid sequences of exemplified CCR5 antagonist polypeptide backbones;

[0051] SEQ ID Nos. 60-63 represent the amino acid sequences according to Formulae l-l V respectively;

[0052] SEQ ID Nos. 64-67 represent the amino acid sequences of exemplified / V-terminal segment polypeptide backbones;

[0053] SEQ ID Nos. 68 represents the amino acid sequence according to Formula V;

[0054] SEQ ID Nos. 69-109 represent the amino acid sequence of exemplified C-terminal segment polypeptide backbones;

[0055] SEQ ID No. 110 represents the amino acid sequence according to Formula VI; and

[0056] SEQ ID No. 111 represents the amino acid sequence of a protracted 5P12 RANTES derivative polypeptide backbone, also being referred to in the example section as the protracted comparator compound. DESCRIPTION OF DRAWINGS

[0057] Fig. 1-76 depict the manufactured compounds according to the invention that are further described in the Example section.

[0058] Fig. 1 depicts compound 1 ;

[0059] Fig. 2 depicts compound 2;

[0060] Fig. 3 depicts compound 3;

[0061] Fig. 4 depicts compound 4;

[0062] Fig. 5 depicts compound 5;

[0063] Fig. 6 depicts compound 6;

[0064] Fig. 7 depicts compound 7;

[0065] Fig. 8 depicts compound 8;

[0066] Fig. 9 depicts compound 9;

[0067] Fig. 10 depicts compound 10;

[0068] Fig. 11 depicts compound 11;

[0069] Fig. 12 depicts compound 12;

[0070] Fig. 13 depicts compound 13;

[0071] Fig. 14 depicts compound 14;

[0072] Fig. 15 depicts compound 15;

[0073] Fig. 16 depicts compound 16;

[0074] Fig. 17 depicts compound 17;

[0075] Fig. 18 depicts compound 18;

[0076] Fig. 19 depicts compound 19;

[0077] Fig. 20 depicts compound 20;

[0078] Fig. 21 depicts compound 21;

[0079] Fig. 22 depicts compound 22;

[0080] Fig. 23 depicts compound 23;

[0081] Fig. 24 depicts compound 24;

[0082] Fig. 25 depicts compound 25;

[0083] Fig. 26 depicts compound 26;

[0084] Fig. 27 depicts compound 27;

[0085] Fig. 28 depicts compound 28;

[0086] Fig. 29 depicts compound 29;

[0087] Fig. 30 depicts compound 30;

[0088] Fig. 31 depicts compound 31;

[0089] Fig. 32 depicts compound 32; Fig. 33 depicts compound 33; Fig. 34 depicts compound 34; Fig. 35 depicts compound 35; Fig. 36 depicts compound 36; Fig. 37 depicts compound 37; Fig. 38 depicts compound 38; Fig. 39 depicts compound 39; Fig. 40 depicts compound 40; Fig. 41 depicts compound 41 ; Fig. 42 depicts compound 42; Fig. 43 depicts compound 43; Fig. 44 depicts compound 44; Fig. 45 depicts compound 45; Fig. 46 depicts compound 46; Fig. 47 depicts compound 47; Fig. 48 depicts compound 48; Fig. 49 depicts compound 49; Fig. 50 depicts compound 50; Fig. 51 depicts compound 51 ; Fig. 52 depicts compound 52; Fig. 53 depicts compound 53; Fig. 54 depicts compound 54; Fig. 55 depicts compound 55; Fig. 56 depicts compound 56; Fig. 57 depicts compound 57; Fig. 58 depicts compound 58; Fig. 59 depicts compound 59; Fig. 60 depicts compound 60; Fig. 61 depicts compound 61 ; Fig. 62 depicts compound 62; Fig. 63 depicts compound 63; Fig. 64 depicts compound 64; Fig. 65 depicts compound 65; Fig. 66 depicts compound 66; Fig. 67 depicts compound 67; Fig. 68 depicts compound 68;

[0090] Fig. 69 depicts compound 69;

[0091] Fig. 70 depicts compound 70;

[0092] Fig. 71 depicts compound 71 ;

[0093] Fig. 72 depicts compound 72;

[0094] Fig. 73 depicts compound 73;

[0095] Fig. 74 depicts compound 74;

[0096] Fig. 75 depicts compound 75; and

[0097] Fig. 76 depicts compound 76.

[0098] DESCRIPTION

[0099] The current invention relates to a C-C chemokine receptor type 5 (CCR5) antagonist compound. The compounds disclosed herein are capable of inhibiting CCR5 biological activity thus driving an anti-inflammatory effect in NASH patients, whilst having an increased potency, long biological half-life and / or increased chemical and physical stability in comparison to known inhibitors. In an aspect, the CCR5 antagonist disclosed herein prevent the binding of ligands, such as native human CCL5, by achieving partial or complete occupation of the site or sites on CCR5 that said ligands require for interaction, or by adopting a conformation that cannot be recognized by ligands. In the context of NASH, the CCR5 antagonist disclosed herein may further indirectly reduce the proportion of natural killer T (NKT) cells, CD8-positive T cells and / or macrophages in fibrotic or cirrhotic livers. The CCR5 antagonists disclosed herein may further modulate the liver macrophages to favour liver regeneration.

[0100] WO 2019 / 229616 describes a CCR5 inhibitor referred to as “5P12 RANTES” (SEQ ID No. 2) for the purposes of suppressing growth of cancer cells, while WO 2008 / 012689 describes the same inhibitor for its anti-HIV applications. However, 5P12 RANTES tends to interact with Glycosaminoglycans (GAGs), provides short in vivo half-life and lacks chemical and physical stability, while having a limited potency.

[0101] Herein, the “5P12 RANTES” (SEQ ID No. 2) CCR5 inhibitor is referred to as a “reference compound” and has formed part of the basis of comparison for the compounds of the invention and examples identified herein. For these purposes, and unless otherwise described reference to “5P12-RANTES”, “5P12 RANTES”, “5P12 Rantes”, “5P12” and / or “comparator compound” are used interchangeably and refer to this 5P12 RANTES CCR5 inhibitor.

[0102] 5P12 RANTES (SEQ ID No. 2) is a RANTES derivative with a C-terminal portion corresponding to that of residues 10 to 68 of native human RANTES (SEQ ID No. 1) and an N-terminal portion having a 10 amino acid residue “signature sequence”. 5P12 RANTES (SEQ ID No. 2) comprises an additional amino acid residue, found within the / V-terminal portion, in comparison to the residues of native human RANTES (SEQ ID No. 1) and is generally referred to in the art as being in position 0 in the amino acid sequence of 5P12 RANTES (SEQ ID No. 2). Written otherwise, one of skill in the art may refer to the amino acid residues of 5P12 RANTES (SEQ ID No. 2) as starting at position 0, such that alignment with the native human CCL5 / RANTES (SEQ ID No. 1) may be easily accomplished.

[0103] However, the numbering herein, of the amino acid residues of the CCR5 antagonists, of the invention, and in the sequence listings always starts with no. 1. As such, unless otherwise clearly stated, any reference herein to a position number of an amino acid residue of a CCR5 antagonist is to a residue numbered based on a sequence starting at position no. 1. For the purposes of clarity, the formulas provided herein, having their respective amino acid residue sequences starting with no. 1 , further include a cross-reference to their numbering in accordance with the native 68 residue human RANTES (SEQ ID No. 1).

[0104] CCR5 antagonists

[0105] The current invention relates to a protracted CCR5 antagonist satisfying the objective of providing a compound having fewer undesirable interactions with GAGs, a superior inhibitory potency, a superior chemical and physical stability and / or a long biological half-life. Said objectives are achieved by the present invention, such as by the subject matter of the appended claims. In the below examples, when referring to a CCR5 inhibitor or a CCR5 antagonist with given features, it is understood to refer to features provided in comparison to the 5P12 RANTES (SEQ ID No. 2) compound.

[0106] As will be described in detail below and in accordance with an aspect, the CCR5 antagonist of the present invention comprises a polypeptide with no more than 9 amino acid modifications, such as 9, 8, 7, 6, 5, 4 or 3 amino acid modifications, relative to the sequence of SEQ ID No. 2, where a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) residue(s) are provided at both positions 45 and 46 and a Cysteine (Cys, C) or a Lysine (Lys, K) residue is provided at position 68. In some embodiments, the CCR5 antagonist is comprises a protraction moiety with a fatty acid attached to the polypeptide at position 68. In some embodiments, the protraction moiety further comprises a linker.

[0107] In some embodiment, the CCR5 antagonist comprises a polypeptide with no more than 9 amino acid modifications relative to the sequence of SEQ ID No. 2, comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45 and / or 46, and a Cysteine (Cys, C) or a Lysine (Lys, K) residue at position 68; optionally, further comprising a protraction moiety attached to the residue at position 68. The protraction moiety may further comprise a fatty acid and a linker.

[0108] In certain embodiments, the CCR5 antagonist polypeptide is provided with an additional negative charge. Preferably, the CCR5 antagonist polypeptide is provided with a Glutamic acid (Glu, E) at position 56.

[0109] In some embodiments, the CCR5 antagonist has the following structure

[0110] X1-X2 (Chem. 1) where X1 is the polypeptide backbone with no more than 9 amino acid modifications relative to the amino acid sequence of SEQ ID No. 2, comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45 and / or 46, and a Cysteine (Cys, C) or a Lysine (Lys, K) residue at position 68, and where X2 is a protraction moiety attached to the polypeptide X1 at position 68.

[0111] In some embodiments, X1 has the following structure

[0112] Y1-Y2-* (Chem. 1a) where Y1 is a first polypeptide and Y2 is a second polypeptide, Y1 and Y2 being chemically ligated to one another and Y2 coupled to the protraction moiety X2 (Chem 1). The * denotes the chemical ligation, in this case with X2 (Chem 1) or as will be described below Z1 (Chem 1a).

[0113] In some embodiments X2 has the following structure

[0114] *-Z1-Z2 (Chem. 1b) where Z2 is a fatty acid coupled to polypeptide X1 , or more specifically polypeptide Y2, via linker Z1. The * denotes the chemical ligation with X1 (Chem 1) or Y2 (Chem 1a).

[0115] In an aspect, the CCR5 antagonist inhibit CCR5 biological activity.

[0116] In an aspect, he CCR5 antagonist prevent at least partial binding of ligands to CCR5.

[0117] The CCR5 antagonist may promote a CCR5 conformation that is unrecognizable to ligands.

[0118] The CCR5 antagonist may reduce the recruitment of immune cells in the liver.

[0119] The CCR5 antagonist may modulate liver macrophages to favour liver regeneration.

[0120] The CCR5 antagonist may produce an anti-inflammatory therapeutic effect.

[0121] It is understood that the embodiments provided herein are non-limitative. Modifications, substitutions, changes, and equivalents will occur to those of ordinary skill in the art in view of the present disclosure without departing from the present invention. Peptide Backbone

[0122] The CCR5 antagonist disclosed herein comprises a polypeptide with at least 3 amino acid modifications, such as 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid modifications, relative to the amino acid sequence of SEQ ID No. 2.

[0123] In some embodiments, he CCR5 antagonist comprises a polypeptide with no more than 12 amino acid modifications relative to the sequence of SEQ ID No. 2. In some embodiments, the CCR5 antagonist comprises a polypeptide with no more than no more than 9 amino acid modifications, such as 8, 7, 6, 5, 4 or 3 amino acid modifications, relative to the sequence of SEQ ID No. 2.

[0124] In some embodiments, the CCR5 antagonist comprises a polypeptide with 9 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0125] In some embodiments, the CCR5 antagonist comprises a polypeptide with 8 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0126] In some embodiments, the CCR5 antagonist comprises a polypeptide with 7 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0127] In some embodiments, the CCR5 antagonist comprises a polypeptide with 6 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0128] In some embodiments, the CCR5 antagonist comprises a polypeptide with 5 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0129] In some embodiments, the CCR5 antagonist comprises a polypeptide with 4 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0130] In some embodiments, the CCR5 antagonist comprises a polypeptide with 3 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0131] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide of Formula I, depicted in the sequence listing SEQ ID No. 60 as follows:

[0132] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn- Pro-Ala-Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Xaa49-Val-Cys-Ala-Asn-Pro- Glu-Xaa56-Xaa57-Trp-Val-Xaa60-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0133] Xaa1 is Pyroglutamic Acid (Pyr),

[0134] Xaa6 is Met (M) or Gin (Q),

[0135] Xaa8 is Thr (T) or Ala (A),

[0136] Xaa45 is Asp (D) or Glu (E), Xaa46 is Asp (D) or Glu (E),

[0137] Xaa49 is Glu (E) or Gin (Q),

[0138] Xaa56 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0139] Xaa57 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0140] Xaa60 is Arg (R) or Glu (E),

[0141] Xaa64 is Asn (N), Glu (E) or Asp (D),

[0142] Xaa65 is Ser (S) or Glu (E),

[0143] Xaa68 is Lys (K) or Cys (C).

[0144] In certain embodiments, the CCR5 antagonist polypeptide is preferably provided with an additional negative charge. More preferably, the CCR5 antagonist polypeptide is provided with a Glutamic acid (Glu, E) at position 56.

[0145] In certain embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide of Formula II, depicted in the sequence listing SEQ ID No. 61 as follows:

[0146] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn- Pro-Ala-Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu- Xaa56-Xaa57-Trp-Val-Arg-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0147] Xaa1 is Pyroglutamic Acid (Pyr),

[0148] Xaa6 is Met (M) or Gin (Q),

[0149] Xaa8 is Thr (T) or Ala (A),

[0150] Xaa45 is Asp (D) or Glu (E),

[0151] Xaa46 is Asp (D) or Glu (E),

[0152] Xaa56 is Glu (E) or Lys (K),

[0153] Xaa57 is Glu (E) or Lys (K),

[0154] Xaa64 is Asn (N) or Glu (E),

[0155] Xaa65 is Ser (S) or Glu (E),

[0156] Xaa68 is Lys (K) or Cys (C).

[0157] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide of Formula III, depicted in the sequence listing SEQ ID No. 62 as follows:

[0158] Xaa1-Gly-Pro-Pro-Leu-Gln-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-Pro- Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala- Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu-Glu-

[0159] Xaa57-Trp-Val-Arg-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0160] Xaa1 is Pyroglutamic Acid (Pyr),

[0161] Xaa8 is Thr (T) or Ala (A),

[0162] Xaa45 is Asp (D) or Glu (E),

[0163] Xaa46 is Asp (D) or Glu (E),

[0164] Xaa57 is Glu (E) or Lys (K),

[0165] Xaa64 is Asn (N) or Glu (E),

[0166] Xaa65 is Ser (S) or Glu (E),

[0167] Xaa68 is Lys (K) or Cys (C).

[0168] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide of Formula IV, depicted in the sequence listing SEQ ID No. 63 as follows:

[0169] Xaa1-Gly-Pro-Pro-Leu-Gln-Ala-Thr-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-Pro- Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala- Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu-Glu-Lys- Trp-Val-Arg-Glu-Tyr-lle-Asn-Ser-Leu-Glu-Xaa68-Ser, wherein

[0170] Xaa1 is Pyroglutamic Acid (Pyr),

[0171] Xaa45 is Asp (D) or Glu (E),

[0172] Xaa46 is Asp (D) or Glu (E),

[0173] Xaa68 is Lys (K) or Cys (C).

[0174] In some embodiments, the CCR5 antagonist may have a polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID No. 3-59. The CCR5 antagonist may have a polypeptide consisting of an amino acid sequence as set forth in any one of SEQ ID No. 3-59.

[0175] In some embodiments, the CCR5 antagonist comprises a polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID No. 4, 6, 8, 13, 15, 27, 31 , 32, 34, 46, 47.

[0176] In some embodiments, the CCR5 antagonist comprises a polypeptide consisting of an amino acid sequence as set forth in any one of SEQ ID No. 4, 6, 8, 13, 15, 27, 31 , 32, 34, 46, 47. In some embodiments, the CCR5 antagonist comprises a polypeptide comprising an amino acid sequence as set forth in SEQ ID No. 27.

[0177] In some embodiments, the CCR5 antagonist comprises a polypeptide comprising an amino acid sequence as set forth in SEQ ID No. 31 .

[0178] In some embodiments, the CCR5 antagonist comprises a polypeptide comprising an amino acid sequence as set forth in SEQ ID No. 32.

[0179] In some embodiments, the CCR5 antagonist comprises a polypeptide comprising an amino acid sequence as set forth in SEQ ID No. 46.

[0180] The peptide backbone of the CCR5 antagonist having a amino acid sequence of any one of Formulas l-l V or comprising an amino acid sequence as set forth in any one of SEQ ID No. 3-59 further has a disulfide bond between the Cysteine (Cys, C) residues found in positions 11 and 35, as well as a disulfide bond between the Cysteine (Cys, C) residues found in positions 12 and 51. One of skill in the art understands that the disulfides provided between the Cysteine (Cys, C) residues found in positions 11 and 35, as well as a disulfide between the Cysteine (Cys, C) residues found in positions 12 and 51 which are found in 5P12 RANTES are also provided in the compounds of the invention unless otherwise specified.

[0181] Protraction moiety

[0182] In an aspect of the invention, the CCR5 antagonist disclosed herein comprises a protraction moiety attached to the peptide backbone described above. In some embodiments, the protraction moiety is attached to the residue found in position 68 of the peptide backbone of the CCR5 antagonist described above.

[0183] In one aspect, the protraction moiety has the effect of extending and protracting the time of action of the CCR5 antagonist. The protraction moiety prolongs the circulation of the CCR5 antagonist in the blood stream, this having the effect of protracting plasma exposure and extending circulating half-life of the CCR5 antagonist.

[0184] Examples of protraction moiety include but are not limited to: fatty acids and derivatives thereof, Hydroxy Alkyl Starch (HAS) e.g. Hydroxy Ethyl Starch (HES), Poly Ethylen Glycol (PEG), Poly (Glyx-Sery)n (HAP), Hyaluronic acid (HA), Heparosan polymers (HEP), Phosphorylcholine-based polymers (PC polymer), Fleximers, Dextran, Poly-sialic acids (PSA), an Fc domain, Transferrin, Albumin, Elastin like peptides, unstructured and repeated amino sequences (e.g. XTEN polymers), Albumin binding peptides, a CTP peptide, and any combination thereof.

[0185] In some embodiments, the protraction moiety is attached to the residue found in position 68 of the peptide backbone as set forth in any one of Formula l-l V. In some embodiments, the protraction moiety is attached to the residue found in position 68 of amino acid sequence set forth in any one of SEQ ID No. 3-59.

[0186] In some embodiments, the protraction moiety is attached to a Lysine residue in position 68 of a peptide backbone as described above, such as is set forth in any one of Formula l-l V. In such a case, the epsilon-amino group of the Lysine residue may be acylated to receive a protraction as described in detail below.

[0187] In some embodiments, the protraction moiety is attached to a Cysteine residue in position 68 of a peptide backbone as described above, such as is set forth in in any one of formula l-IV. In such a case, the beta-thiol group of the Cysteine residue is alkylated to receive a protraction as described in detail below.

[0188] In some embodiments, the protraction moiety comprises a fatty acid therein and may generally be referred to as a fatty acid protraction moiety.

[0189] In some embodiments, theCCR5 antagonist have the following structure

[0190] X1-X2 (Chem. 1) where X1 is the polypeptide backbone as described above and X2 is the protraction moiety attached to the polypeptide X1.

[0191] In some embodiments, the protraction moiety comprises a linker, the linker chemically ligated to the peptide backbone, attaching the fatty acid to the peptide backbone.

[0192] In some embodiments, theCCR5 antagonist have the following structure X1-X2 (Chem. 1) where X1 is the polypeptide backbone as described above and X2 is the protraction moiety having the following structure

[0193] *-Z1-Z2 (Chem. 1b) where Z2 is the fatty acid and Z1 is the linker attached to the peptide backbone.

[0194] In some embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one negative charge, which may be selected from Glutamate (Glu) or y- Glutamate (gGlu).

[0195] Fatty acid

[0196] In some embodiments, the fatty acid is referred to as Z2 of the protraction moiety *- Z1-Z2 (Chem. 1b) of the CCR5 antagonist disclosed herein. In some embodiments, the fatty acid of CCR5 antagonist protraction moiety is a long-chain fatty acid. In some embodiments, the fatty acid of CCR5 antagonist protraction moiety comprises a dicarboxylic acid. In some embodiments, the fatty acid of CCR5 antagonist protraction moiety comprises a long-chain dicarboxylic acid. In one aspect of the invention, the protraction moiety is a fatty acid capable of forming non-covalent associations with albumin and thereby lower renal clearance, thus having the effect of protracting plasma exposure and extending plasma half-life of the CCR5 antagonist.

[0197] In some embodiments, the fatty acid of the CCR5 antagonist protraction moiety comprises a fatty acid of the following structure

[0198] HO2C-(CH2)n-CO-*

[0199] (Chem. 2) where n may be any integer value between 14-20. In some embodiments, the fatty acid of the CCR5 antagonist protraction moiety comprises a C(n+2) diacid, such as a C16, C17, C18, C19, C20, C21 or C22 diacid.

[0200] In certain embodiments, the fatty acid Z2 of the CCR5 antagonist protraction moiety is octadecanedioic acid. In certain embodiments, the fatty acid Z2 of the CCR5 antagonist protraction moiety is a C18 diacid shown as Chem 2a.

[0201] In certain embodiments, the fatty acid Z2 of the CCR5 antagonist protraction moiety is eicosanedioic acid. In some embodiments, the fatty acid Z2 of the CCR5 antagonist protraction moiety is a C20 diacid shown as Chem 2b.

[0202] Linker

[0203] In some embodiments, the linker is referred to as Z1 of the protraction moiety *-Z1- Z2 (Chem. 1 b) of the CCR5 antagonist disclosed herein. The linker may effectively couple the fatty acid Z2 to the CCR5 antagonist peptide backbone described above, which may generally be referred to as X1 in structure X1-X2 (Chem. 1) or Y2 when referring to X1 of Chem. 1 as structure Y1-Y2-* (Chem. 1a). Written otherwise, and as will become clear in view of the examples provided herein, the linker may be chemically ligated the CCR5 antagonist peptide backbone at a first end and the fatty acid and a second end, opposite the first end.

[0204] The linker of the CCR5 antagonist protraction moiety may be composed of one or a plurality of constituents, as will be described in further detail below. In some embodiments, the linker is composed of between 1 and 10 constituents. In some embodiments, the linker is composed of 1-10 constituents. In some embodiments, the linker is composed of no more than 8 constituents. In some embodiments, the linker is composed of between 1 and 8 constituents. In some embodiments, the linker is composed of 1-8 constituents. In some embodiments, the linker is composed of between 2 and 8 constituents. In some embodiments, the linker is composed of 2-8 constituents. In some embodiments, the linker is composed of between 3 and 8 constituents. In some embodiments, the linker is composed of 3-8 constituents. In some embodiments, the linker is composed of between 4 and 8 constituents. In some embodiments, the linker is composed of 4-8 constituents. In some embodiments, the linker is composed of 1 , 2, 3, 4, 5, 6, 7 or 8 constituents. In some embodiments, the linker is composed of 3, 4, 5, 6 or 8 constituents.

[0205] In some embodiments, the linker of the CCR5 antagonist protraction moiety comprises one or a plurality of constituents selected from a group consisting of a Glutamate (Glu), a y-Glutamate (gGlu - may also be referred to as gamma-Glutamate), an 8-amino-3,6- dioxaoctanoic acid (Ado) group, an ethylenediamine (C2DA) group and an acetamide (Ac) group. A constituent is understood to mean a single repetition of any one of the above structures. For instance, should the linker be composed of two (2) y-Glutamate (gGlu) said linker may be referred to as being composed of two (2) constituents although only a one (1) type of constituent may be provided.

[0206] In certain embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one negative charge. The linker of the CCR5 antagonist protraction moiety preferably comprises at least one negative charge. In certain embodiments, the linker of the CCR5 antagonist protraction moiety comprise a plurality of negative charges. In certian embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one Glutamate (Glu) or y-Glutamate (gGlu). In some embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one negative charge selected from Glutamate (Glu) or y-Glutamate (gGlu). In some embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one ethylenediamine (C2DA) group and an acetamide (Ac) group when the residue at position 68 of the CCR5 antagonist peptide backbone is a Cysteine (Cys, C). In some embodiments, the linker of the CCR5 antagonist protraction moiety comprises at least one ethylenediamine (C2DA) group and an acetamide (Ac) group when the residue at position 68 of any one of Formulas l-l V is a Cysteine (Cys, C).

[0207] In some embodiments, the linker of the CCR5 antagonist protraction moiety have the following structure of Chem 3a:

[0208] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(gGlu)n3-R2 (Chem. 3a) where R1 represents the location of the ligation to the CCR5 peptide backbone, as described above, R2 represents the location of the ligation to the fatty acid, and ni, n2 and ns represent the repetition of each one of the substituents. In some embodiments, the linker of Chem. 3a have a m of 0-1 , a n2 of 0-4, and a ns of 1-4. In some embodiments, the linker of Chem. 3a have a m of 0 or 1 , a n2 of 0, 2 or 4, and an ns of 1 or 4.

[0209] In some embodiments, the linker of the CCR5 antagonist protraction moiety have a structure of Chem 3b:

[0210] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(Glu)n3-R2 (Chem. 3b) where R1 represents the location of the ligation to the CCR5 peptide backbone, as described above, R2 represents the location of the ligation to the fatty acid, and m , n2 and ns represent the repetition of each one of the substituents. In some embodiments, the linker of Chem. 3b have a m of 0-1 , a n2 of 0-4, and a ns of 1-4. In some embodiments, the linker of Chem. 3a have a m of 0 or 1 , a n2 of 0, and an ns of 4.

[0211] In some embodiments, the linker of the CCR5 antagonist protraction moiety is selected from any one of the linkers identified in Table. 1 below.

[0212] Table 1. Linker examples of the CCR5 antagonist protraction moiety of the present application.

[0213] R1 represents the location of the ligation to the CCR5 peptide backbone, as describee above, R2 represents the location of the ligation to the fatty acid. These ligations are shown via the symbol in the corresponding structure. One of skill in the art will understand that in the CCR5 antagonist structure X1-X2 (Chem. 1), R1 may correspond to X1 , while R2 forms part of X2. Alternatively, one of skill in the art further understands that R1 may correspond to Y2 when referring to the backbone polypeptide as structure Y1-Y2-* (Chem. 1a) while R2 may correspond to Z2 when referring to the protraction moiety as having structure *-Z1-Z2 (Chem. 1b).

[0214] It is understood that the linkers identified above are examples and not be to be construed as limitative in any way. One of skill in the understands that various combinations and alternatives may be possible using the same constituents listed above, such as by providing them in a different order and / or with different quantity of repetitions, without parting from the present disclosure. Likewise, one of skill in the art understand that other, equivalent, constituents may be provided without departing from the present disclosure.

[0215] Preparation of CCR5 antagonists

[0216] Further disclosed herein are methods of making a CCR5 antagonist according to the invention.

[0217] The backbone of the CCR5 antagonists according to the invention may for instance be produced by classical peptide synthesis, e.g. solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well established techniques, see e.g. Greene and Wuts, “Protective Groups in Organic Synthesis", John Wiley & Sons, 1999', Florencio Zaragoza Dbrwald, “Organic Synthesis on Solid Phase", Wiley-VCH Verlag GmbH, 2000', and “Fmoc Solid Phase Peptide Synthesis", Edited by W.C. Chan and P.D. White, Oxford University Press, 2000.

[0218] The backbone of the CCR5 antagonists according to the present disclosure may also be produced by recombinant methods, e.g. by culturing a host cell containing a DNA sequence encoding the peptide sequence and capable of expressing the peptide, in a suitable nutrient medium under conditions permitting the expression of the peptide. Non-limiting examples of host cells suitable for expression of these peptides are Escherichia coli, Saccharomyces cerevisiae and mammalian BHK or CHO cell lines.

[0219] Alternatively, the backbone of the CCR5 antagonists is advantageously suited for a semi-recombinant process as is established in the art.

[0220] The CCR5 antagonists of the instant application may be prepared via native chemical ligation of two separate segments, which may be referred to as an / V-terminal segment that will ultimately contain residues that may be referred to as the / V-terminal residues in the ligated peptide, and a C-terminal segment that will ultimately contain residues that may be referred to as the C-terminal residues in the ligated peptide. These peptides segments may be synthesized by any of the means listed above and known in the art, and may then be subject to native chemical ligation via established techniques, see eg. P. E. Dawson, T. W. Muir, I. Clark-Lewis, S.B. Kent; Science 1994, 266, 776-779., to yield the full-length peptide. The necessary disulfides may be formed via folding thereafter.

[0221] In the context of the CCR5 antagonist of the present application, the CCR5 antagonist may be of structure

[0222] X1-X2 (Chem. 1) where X1 is the polypeptide backbone and a X2 is a protraction moiety attached to the polypeptide. X1 may further be of structure

[0223] Y1-Y2-* (Chem. 1a) where Y1 is a first polypeptide that may correspond to a / V-terminal segment for the purposes of preparation and Y2 is a second polypeptide that may correspond to a C-terminal segment for the purposes of preparation. Y1 and Y2 may be chemically ligated through the native chemical ligation known in the art and described above.

[0224] X2, the protraction moiety, may be chemically ligated to the C-terminal segment Y2 prior to the native chemical ligation with the / V-terminal segment Y1 . Written otherwise, the C- terminal segment and the protraction moiety may form the following structure:

[0225] *-Y2-X2 (Chem. 1c) where * denotes the chemical ligation. In this particular case Chem. 1c is to be ligated with the / V-terminal segment Y1.

[0226] Specific examples of methods of preparing the CCR5 antagonists of the instant application are included in the examples section herein. / V-terminal segment

[0227] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment of Formula V, depicted in the sequence listing SEQ ID No. 68 as follows:

[0228] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys wherein

[0229] Xaa1 is Pyroglutamic Acid (Pyr),

[0230] Xaa6 is Met (M) or Gin (Q), and

[0231] Xaa8 is Thr (T) or Ala (A).

[0232] The CCR5 antagonist disclosed herein may be formed by native chemical ligation of an / V-terminal segment of Formula V to a C-terminal segment of Formula VI, described in detail below.

[0233] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of SEQ ID No. 64, such as 3, 2, 1 or 0 amino acid modifications.

[0234] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of SEQ ID No. 64.

[0235] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of 65, such as 3, 2, 1 or 0 amino acid modifications.

[0236] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of 65.

[0237] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of 66, such as 3, 2, 1 or 0 amino acid modifications.

[0238] In some embodiments, theCCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of 66.

[0239] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of 67, such as 3, 2, 1 or 0 amino acid modifications. In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of 67.

[0240] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of any one of SEQ ID No. 64, 65, 66 or 67. The CCR5 antagonist disclosed herein may have a polypeptide with an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of any one of SEQ ID No. 64, 65, 66 or 67.

[0241] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment comprising an amino acid sequence as set forth in any one of SEQ ID No. 64-67.

[0242] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment comprising an amino acid sequence as set forth in any one of SEQ ID No. 64, 65, 66, 67.

[0243] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment comprising an amino acid sequence selected from a group of sequences consisting of SEQ ID No. 64, 65, 66 and 67.

[0244] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment consisting of an amino acid sequence as set forth in any one of SEQ ID No. 64, 65, 66, 67.

[0245] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with an / V-terminal segment consisting of an amino acid sequence selected from a group of sequences consisting of SEQ ID No. 64, 65, 66 and 67.

[0246] C-terminal segment

[0247] In some embodiments, theCCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment of Formula VI, depicted in the sequence listing SEQ ID No. 110, as follows:

[0248] Cys-Ser-Asn-Pro-Ala-Val-Val-Phe-Val-Thr-Xaa11-Xaa12-Asn-Arg-Xaa15-Val-Cys- Ala-Asn-Pro-Glu-Xaa22-Xaa23-Trp-Val-Xaa26-Glu-Tyr-lle-Xaa30-Xaa31-Leu-Glu-Xaa34-Ser wherein

[0249] Xaa11 is Asp (D) or Glu (E),

[0250] Xaa12 is Asp (D) or Glu (E),

[0251] Xaa15 is Glu (E) or Gin (Q),

[0252] Xaa22 is Asp (D), Glu (E), Lys (K) or Gin (Q), Xaa23 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0253] Xaa26 is Arg (R) or Glu (E),

[0254] Xaa30 is Asn (N), Glu (E) or Asp (D),

[0255] Xaa31 is Ser (S) or Glu (E),

[0256] Xaa34 is Lys (K) or Cys (C).

[0257] As is described above, a C-terminal peptide segment of Formula VI may be chemically ligated with an / V-terminal peptide segment of Formula V to provide for a full peptide backbone, such as those set forth in any one of SEQ ID No. 3-59, for a CCR5 antagonist as described above. In this manner, the skilled person will understand that residue no. 11 (Xaa11) of Formula VI may be considered to correspond to residue no. 45 (Xaa45) in any one for Formulas I- IV above in the full peptide form.

[0258] In some embodiments, the CCR5 antagonist disclosed herein is formed by native chemical ligation of an / V-terminal segment of Formula V to a C-terminal segment of Formula VI.

[0259] In some embodiments, the protraction moiety is chemically ligated to the C-terminal segment of Formula VI prior to native chemical ligation with an / V-terminal segment.

[0260] In some embodiments, the protraction moiety is ligated to the C-terminal segment of Formula VI at the residue in position 34 prior to native chemical ligation with an / V-terminal segment. In some embodiments, the protraction moiety is ligated to the C-terminal segment of Formula VI at the Cysteine (Cys, C) residue found in position 34 prior to native chemical ligation with an / V-terminal segment. In some embodiments, the protraction moiety is ligated to the C- terminal segment of Formula VI at the Lysine (Lys, K) residue found in position 34 prior to native chemical ligation with an / V-terminal segment.

[0261] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment with no more than 11 amino acid modifications relative to the sequence of any one of SEQ ID No. 69-109, such as 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 amino acid modifications.

[0262] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment with no more than 9 amino acid modifications relative to the sequence of any one of SEQ ID No. 69-109.

[0263] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment comprising an amino acid sequence as set forth in any one of 69-109. In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment comprising an amino acid sequence selected from a group of sequences consisting of SEQ ID No. 69-109.

[0264] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment consisting of an amino acid sequence as set forth in any one of 69-109.

[0265] In some embodiments, the CCR5 antagonist disclosed herein comprises a polypeptide with a C-terminal segment comprising an amino acid sequence selected from a group of sequences consisting of SEQ ID No. 69-109.

[0266] Pharmaceutical Compositions

[0267] The invention further relates to pharmaceutical compositions comprising a CCR5 antagonist as disclosed in the present application and according to the embodiments of the invention disclosed herein, and at least one pharmaceutical excipient. Such pharmaceutical compositions may be prepared as is known in the art. The excipient may serve various purposes, e.g. as a carrier, vehicle, diluent, and / or to improve administration, and / or absorption of the active substance.

[0268] The formulation of pharmaceutically active ingredients with various excipients is known in the art, see e.g. Remington: The Science and Practice of Pharmacy, 19th edition (1995), and any later editions.

[0269] Non-limiting examples of excipients are solvents, diluents, buffers, preservatives, tonicity regulating agents, chelating agents, and stabilisers.

[0270] Liquid Pharmaceutical Formulations

[0271] Examples of a liquid formulation are aqueous formulations, i.e. formulations that comprise water. A liquid formulation may be a solution. An aqueous formulation typically comprises at least 50% (w / w) water, or at least 60%, 70%, 80% or even at least 90% (w / w) water.

[0272] A liquid pharmaceutical composition may comprise a buffer. A liquid pharmaceutical composition may comprise a preservative. A liquid pharmaceutical composition may comprise a chelating agent. The chelating agent may e.g. be selected from salts of ethylenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof. A liquid pharmaceutical composition may comprise a stabiliser. The stabiliser may e.g. be one or more oxidation inhibitors, aggregation inhibitors, surfactants, and / or one or more protease inhibitors. Route of Administration

[0273] In an aspect, theCCR5 antagonist of the present invention is administered in the form of a pharmaceutical composition. Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection.

[0274] Methods of treatment

[0275] Further disclosed herein is a CCR5 antagonist and a CCR5 antagonist pharmaceutical composition for use as a medicament.

[0276] The term “treatment”, as used herein, refers to the medical treatment of any human subject in need thereof. The treatment may be preventive, prophylactic, palliative, symptomatic and / or curative. The timing and purpose of said treatment may vary from one individual to another, according to the status of the subject’s health.

[0277] The invention relates to a CCR5 antagonist or a CCR5 antagonist pharmaceutical composition for use in the treatment of a disease, disorder or condition associated with, including but not limited to, non-alcoholic steatohepatitis (NASH), metabolic dysfunction- associated steatohepatitis (MASH), alcohol-related fatty liver disease (ALD) and MetALD. MASH is proposed as the replacement term for NASH describing the same diagnostic entity (M.E. Rinella, et al, j.aohep.2023.101133). As used herein the terms “NASH” and “MASH” means the same thing and are used interchangeably. The invention further relates to a CCR5 antagonist or a CCR5 antagonist pharmaceutical composition for use in the treatment of hepatitis.

[0278] The invention further relates to a CCR5 antagonist or a CCR5 antagonist pharmaceutical composition for use in the prevention, treatment and / or alleviation of hepatitis associated with non-alcoholic steatohepatitis (NASH) and associated with metabolic dysfunction-associated steatohepatitis (MASH), including but not limited to advanced fibrosis F3 and / or cirrhosis F4 NASH.

[0279] In some embodiments, the methods comprise administering the CCR5 antagonist or the pharmaceutical composition as described herein to a patient with NASH. The patient may be an F3 or F4 NASH patient. In some embodiments, the patient is at risk of developing F3 and / or F4 NASH. The patient may be an F2 NASH patient.

[0280] Definitions

[0281] As used herein, the terms "subject", "individual," and "patient" are used interchangeably to refer to a vertebrate, for example, a mammal. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed. None of the terms entail supervision of a medical professional.

[0282] Unless otherwise specified, “CCR5 inhibitor”, “protracted CCR5 inhibitor”, “CCR5 antagonist”, “protracted CCR5 antagonist” are synonymous and refer to the CCR5 antagonist of the invention.

[0283] "Amino acid" refers to both canonical and non-canonical amino acids. Non-canonical amino acids, or non-natural amino acid include, but are not limited to, 2-aminoisobutyric acid (Aib) and pyroglutamate.

[0284] A "conservative” amino acid substitution refers to the substitution of an amino acid in a peptide or polypeptide with another amino acid having similar chemical properties, such as size or charge. For purposes of the present disclosure, each of the following eight groups contains amino acids that are conservative substitutions for one another:

[0285] 1) Alanine (A) and Glycine (G);

[0286] 2) Aspartic acid (D) and Glutamic acid (E);

[0287] 3) Asparagine (N) and Glutamine (Q);

[0288] 4) Arginine (R) and Lysine (K);

[0289] 5) Isoleucine (I), Leucine (L), Methionine (M), and Valine (V);

[0290] 6) Phenylalanine (F), Tyrosine (Y), and Tryptophan (W);

[0291] 7) Serine (S) and Threonine (T); and

[0292] 8) Cysteine (C) and Methionine (M).

[0293] Naturally occurring residues can be divided into classes based on common side group properties, for example: polar positive (histidine (H), lysine (K), and arginine (R)); polar negative (aspartic acid (D), glutamic acid (E)); polar neutral (serine (S), threonine (T), asparagine (N), glutamine (Q)), non-polar aliphatic (alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M)); non-polar aromatic (phenylalanine (F), tyrosine (Y), tryptophan (W)), proline (P) and glycine (G); and cysteine (C). A "semi-conservative" amino acid substitution refers to the substitution of an amino acid in a peptide or polypeptide with another amino acid within the same class.

[0294] “Pharmaceutically acceptable” indicates that the substance or composition must be chemically and / or toxicologically suitable for the treatment of mammals.

[0295] "Pharmaceutical composition” refers to the combination of an active agent (e.g., the CCR5 antagonist) with a carrier, inert or active, making the composition especially suitable for therapeutic or diagnostic use. "Pharmaceutically acceptable salt" of a molecule refers to the salt form of the molecule. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion. If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art.

[0296] Unless otherwise specified, “modification” refers to amino acid modifications selected from elongations, truncations, substitutions (e.g. substitution of one amino acid for another), and chemical modifications, or a combination thereof. When referring to a polypeptide, the term “modification” of such a polypeptide is to exclude protractions thereof. As such, when referring to a given number of “modifications” relative to the sequence of SEQ ID No. 2, for instance, the Glu or y-Glu in the protraction at position 68 provided in the compounds of the invention are not to be considered. However, elongations at the / V- or C-terminal, truncations, substitutions, chemical modifications, or a combination thereof of the polypeptide of SEQ ID No. 2 shall be considered. In certain embodiments of the invention, the one or more amino acid modifications referred to are amino acid substitutions.

[0297] The term “negative charge”, as used herein, refers to a negative charge on the CCR5 antagonist compound at a given pH, where the charge is defined solely by the acid dissociation constant of each ionizable group in the CCR5 antagonist compound. In an embodiment, negative charges on the CCR5 antagonist compound are determined at physiological pH. For example, the charge of an ionizable group in a peptide at a given pH can be calculated using the Henderson-Hasselbalch equation using empirically determined acid dissociation constants (pKa) for each amino acid residue as is well known in the art, for example as by the method described by B. Skoog and A. Wichman (Trends in Analytical Chemistry, 1986, vol. 5, pp. 82- 83.) and L. Kozlowski (Biology Direct, 2016, 11 :55).

[0298] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For illustration purposes, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1- 3, from 2-4, and from 3-5, etc., as well as 1 , 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.

[0299] LIST OF FURTHER EMBODIMENTS OF THE INVENTION

[0300] 1. A CCR5 antagonist comprising a polypeptide with a maximum of 9 amino acid modifications relative to the sequence of SEQ ID No. 2 and comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45; and a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 46.

[0301] 2. A CCR5 antagonist comprising a polypeptide comprising a maximum of 9 amino acid modifications relative to the sequence of SEQ ID No. 2 and comprising a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45; a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 46; and a Cysteine (Cys, C) or a Lysine (Lys, K) at position 68.

[0302] 3. A CCR5 antagonist comprising a polypeptide according to Formula I (SEQ ID No. 60):

[0303] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn- Pro-Ala-Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Xaa49-Val-Cys-Ala-Asn-Pro- Glu-Xaa56-Xaa57-Trp-Val-Xaa60-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0304] Xaa1 is Pyroglutamic Acid (Pyr),

[0305] Xaa6 is Met (M) or Gin (Q),

[0306] Xaa8 is Thr (T) or Ala (A),

[0307] Xaa45 is Asp (D) or Glu (E),

[0308] Xaa46 is Asp (D) or Glu (E),

[0309] Xaa49 is Glu (E) or Gin (Q),

[0310] Xaa56 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0311] Xaa57 is Asp (D), Glu (E), Lys (K) or Gin (Q), Xaa60 is Arg (R) or Glu (E),

[0312] Xaa64 is Asn (N), Glu (E) or Asp (D),

[0313] Xaa65 is Ser (S) or Glu (E), and

[0314] Xaa68 is Lys (K) or Cys (C). A CCR5 antagonist comprising a polypeptide according to Formula II (SEQ ID No.

[0315] 61):

[0316] Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-

[0317] Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-

[0318] Pro-Ala-Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu-

[0319] Xaa56-Xaa57-Trp-Val-Arg-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0320] Xaa1 is Pyroglutamic Acid (Pyr),

[0321] Xaa6 is Met (M) or Gin (Q),

[0322] Xaa8 is Thr (T) or Ala (A),

[0323] Xaa45 is Asp (D) or Glu (E),

[0324] Xaa46 is Asp (D) or Glu (E),

[0325] Xaa56 is Glu (E) or Lys (K),

[0326] Xaa57 is Glu (E) or Lys (K),

[0327] Xaa64 is Asn (N) or Glu (E),

[0328] Xaa65 is Ser (S) or Glu (E), and

[0329] Xaa68 is Lys (K) or Cys (C). A CCR5 antagonist comprising a polypeptide according to Formula III (SEQ ID No.

[0330] 62):

[0331] Xaa1-Gly-Pro-Pro-Leu-Gln-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-Pro-

[0332] Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala-

[0333] Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu-Glu-

[0334] Xaa57-Trp-Val-Arg-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, wherein

[0335] Xaa1 is Pyroglutamic Acid (Pyr),

[0336] Xaa8 is Thr (T) or Ala (A),

[0337] Xaa45 is Asp (D) or Glu (E),

[0338] Xaa46 is Asp (D) or Glu (E),

[0339] Xaa57 is Glu (E) or Lys (K), Xaa64 is Asn (N) or Glu (E),

[0340] Xaa65 is Ser (S) or Glu (E), Xaa68 is Lys (K) or Cys (C);

[0341] 6. A CCR5 antagonist comprising a polypeptide according to Formula IV (SEQ ID No.

[0342] 63):

[0343] Xaa1-Gly-Pro-Pro-Leu-Gln-Ala-Thr-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-Pro- Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn-Pro-Ala- Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Gln-Val-Cys-Ala-Asn-Pro-Glu-Glu-Lys- Trp-Val-Arg-Glu-Tyr-lle-Asn-Ser-Leu-Glu-Xaa68-Ser, wherein

[0344] Xaa1 is Pyroglutamic Acid (Pyr),

[0345] Xaa45 is Asp (D) or Glu (E),

[0346] Xaa46 is Asp (D) or Glu (E), and Xaa68 is Lys (K) or Cys (C).

[0347] 7. The CCR5 antagonist of any one of the preceding embodiments, further comprising a protraction moiety ligated to the polypeptide at position 68.

[0348] 8. The CCR5 antagonist of any one of the preceding embodiments, further comprising a protraction moiety ligated to the polypeptide at position 68 comprising a fatty acid.

[0349] 9. The CCR5 antagonist of any one of the preceding embodiments, further comprising a protraction moiety ligated to the polypeptide at position 68 comprising a fatty acid and a linker with a negative charge.

[0350] 10. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises at least 3 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0351] 11 . The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises at least 4 amino acid modifications relative to the sequence of SEQ ID No. 2. 12. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises at least 5 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0352] 13. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 9 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0353] 14. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 8 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0354] 15. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 7 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0355] 16. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 6 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0356] 17. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 5 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0357] 18. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 4 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0358] 19. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a maximum of 3 amino acid modifications relative to the sequence of SEQ ID No. 2.

[0359] 20. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises 3 amino acid modifications relative to the sequence of SEQ ID No. 2. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises 5 amino acid modifications relative to the sequence of SEQ ID No. 2. The CCR5 antagonist of any one of the preceding embodiments, wherein the CCR5 antagonist has a structure of

[0360] X1-X2 (Chem. 1) wherein X1 is the polypeptide and X2 is a protraction moiety attached to the polypeptide X1. The CCR5 antagonist of any one of the preceding embodiments, wherein the CCR5 antagonist has a structure of

[0361] X1-X2 (Chem. 1) wherein X1 is the polypeptide and X2 is a protraction moiety attached to the polypeptide X1 at position 68. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID No. 3-59. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide consists of an amino acid sequence as set forth in any one of SEQ ID No. 3-59. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID No.

[0362] 4, 6, 8, 13, 15, 27, 31 , 32, 34, 46, 47. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide consists of an amino acid sequence as set forth in any one of SEQ ID No. 4, 6, 8, 13, 15, 27, 31, 32, 34, 46, 47. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in SEQ ID No. 27. 29. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in SEQ ID No. 31.

[0363] 30. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in SEQ ID No. 32.

[0364] 31. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an amino acid sequence as set forth in SEQ ID No. 46.

[0365] 32. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a Glutamic acid (Glu, E) at position 56.

[0366] 33. The CCR5 antagonist of any one of the preceding embodiments, further comprising a disulfide between the Cysteine (Cys, C) residues found in positions 11 and 35, as well as a disulfide between the Cysteines (Cys, C) residues found in positions 12 and 51.

[0367] 34. The CCR5 antagonist of any one of the preceding embodiments, wherein the residue in position 68 is a Lysine (K) with an acylated epsilon-amino group or a Cysteine (C) with an alkylated beta-thiol group.

[0368] 35. The CCR5 antagonist of any one of the preceding embodiments, wherein the residue in position 68 is a Lysine (K) with an acylated epsilon-amino group or a Cysteine (C) with an alkylated beta-thiol group, such as to receive the protraction moiety.

[0369] 36. The CCR5 antagonist of any one of the preceding embodiments, wherein the residue in position 68 is a Lysine (K) with an acylated epsilon-amino group.

[0370] 37. The CCR5 antagonist of any one of the preceding embodiments, wherein the residue in position 68 is a Cysteine (C) with an alkylated beta-thiol group.

[0371] 38. The CCR5 antagonist of any one of the preceding embodiments, wherein the protraction moiety has the structure of

[0372] *-Z1-Z2 (Chem. 1b) where Z2 is the fatty acid and Z1 is the linker ligated to the polypeptide. The CCR5 antagonist of any one of the preceding embodiments, wherein the protraction moiety has the structure of

[0373] *-Z1-Z2 (Chem. 1b) where Z2 is the fatty acid and Z1 is the linker ligated to the polypeptide, the linker Z1 comprising a at least one negative charge. The CCR5 antagonist of any one of the preceding embodiments, wherein the protraction moiety has the structure of

[0374] *-Z1-Z2 (Chem. 1b) where Z2 is the fatty acid and Z1 is the linker ligated to the polypeptide, the linker Z1 comprising a at least one negative charge selected from Glutamate (Glu) or y- Glutamate (gGlu). The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a dicarboxylic acid. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a long-chain dicarboxylic acid. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is of structure

[0375] (Chem. 2) where n is any integer value between 14-20. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a C16, C17, C18, C19, C20, C21 or C22 diacid. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a C18 diacid or C20 diacid. 46. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is octadecanedioic acid.

[0376] 47. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a C18 diacid.

[0377] 48. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is of structure

[0378] (Chem 2a)

[0379] 49. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is eicosanedioic acid.

[0380] 50. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is a C20 diacid.

[0381] 51. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is of structure

[0382] (Chem 2b)

[0383] 52. The CCR5 antagonist of any one of the preceding embodiments, wherein the fatty acid is selected from a group consisting of

[0384] (Chem 2a); and The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises 1-10 constituents. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises no more than 8 constituents. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises between 2 and 8 constituents. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises between 3 and 8 constituents. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises between 3 and 8 constituents. The CCR5 antagonist of any one of the preceding embodiments, wherein at least one of the constituents of the linker is the negative charge. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises at least one Glutamate (Glu) or y-Glutamate (gGlu). The CCR5 antagonist of any one of the preceding embodiments, wherein at least one of the constituents of the linker is a Glutamate (Glu) or a y-Glutamate (gGlu). The CCR5 antagonist of any one of the preceding embodiments, wherein the negative charge is selected from Glutamate (Glu) or y-Glutamate (gGlu). The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises no more than 8 constituents selected from a group consisting of a Glutamate (Glu), a y-Glutamate (gGlu), an Ado group, an ethylenediamine (C2DA) group and an acetamide (Ac) group.

[0385] 63. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises between 2 and 8 constituents selected from a group consisting of a Glutamate (Glu), a y-Glutamate (gGlu), an Ado group, an ethylenediamine (C2DA) group and an acetamide (Ac) group.

[0386] 64. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker comprises constituents selected from a group consisting of a Glutamate (Glu), a y- Glutamate (gGlu), an Ado group, an ethylenediamine (C2DA) group and an acetamide (Ac) group.

[0387] 65. The CCR5 antagonist of any one of the preceding embodiments, wherein the residue at position 68 is a Cysteine (Cys, C) and wherein the linker comprises an ethylenediamine (C2DA) group and an acetamide (Ac) group.

[0388] 66. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker has the structure of

[0389] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(gGlu)n3-R2 (Chem. 3a) wherein R1 is the location of the ligation to the polypeptide, R2 is the location of the ligation to the fatty acid, m is 0-1 , n2 is 0-4, and ns is 1-4.

[0390] 67. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker has the structure of

[0391] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(gGlu)n3-R2 (Chem. 3a) wherein R1 is the location of the ligation to the polypeptide, R2 is the location of the ligation to the fatty acid, m is 0 or 1 , n2 is 0, 2 or 4, and ns is 1 or 4.

[0392] 68. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker has the structure of

[0393] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(Glu)n3-R2 (Chem. 3b) wherein R1 is the location of the ligation to the polypeptide, R2 is the location of the ligation to the fatty acid, m is 0-1 , n2 is 0-4, and ns is 1-4. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker has the structure of

[0394] R1-(Ac)ni-(C2DA)ni-(Ado)n2-(Glu)n3-R2 (Chem. 3b) wherein R1 is the location of the ligation to the polypeptide, R2 is the location of the ligation to the fatty acid, m is 0 or 1 , n2 is 0, and ns is 4. The CCR5 antagonist of any one of the preceding embodiments, wherein the linker is selected from a group consisting of

[0395] (Chem. 4d);

[0396] (Chem. 4f); and

[0397] (Chem 4g). The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide is of structure

[0398] Y1-Y2-* (Chem. 1a) wherein Y1 is an N-terminal segment and Y2 is a C-terminal segment of the polypeptide, Y1 being chemically ligated to Y2, Y2 further ligated to the protraction moiety. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an / V-terminal segment according to Formula V (SEQ ID No. 68): Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg-Pro- Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys wherein

[0399] Xaa1 is Pyroglutamic Acid (Pyr),

[0400] Xaa6 is Met (M) or Gin (Q),

[0401] Xaa8 is Thr (T) or Ala (A).

[0402] 73. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an / V-terminal segment with no more than 4 amino acid modifications relative to the sequence of any one of SEQ ID No. 64, 65, 66 or 67.

[0403] 74. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an / V-terminal segment with no more than 2 amino acid modifications relative to the sequence of any one of SEQ ID No. 64, 65, 66 or 67.

[0404] 75. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an / V-terminal segment comprising an amino acid sequence as set forth in any one of SEQ ID No. 64, 65, 66 or 67.

[0405] 76. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises an / V-terminal segment consisting of an amino acid sequence selected from a group consisting of SEQ ID No. 64, 65, 66 and 67.

[0406] 77. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a C-terminal segment according to Formula VI (SEQ ID No. 110):

[0407] Cys-Ser-Asn-Pro-Ala-Val-Val-Phe-Val-Thr-Xaa11-Xaa12-Asn-Arg-Xaa15-Val-Cys- Ala-Asn-Pro-Glu-Xaa22-Xaa23-Trp-Val-Xaa26-Glu-Tyr-lle-Xaa30-Xaa31-Leu-Glu- Xaa34-Ser wherein

[0408] Xaa11 is Asp (D) or Glu (E),

[0409] Xaa12 is Asp (D) or Glu (E),

[0410] Xaa15 is Glu (E) or Gin (Q),

[0411] Xaa22 is Asp (D), Glu (E), Lys (K) or Gin (Q),

[0412] Xaa23 is Asp (D), Glu (E), Lys (K) or Gin (Q), Xaa26 is Arg (R) or Glu (E),

[0413] Xaa30 is Asn (N), Glu (E) or Asp (D), Xaa31 is Ser (S) or Glu (E), and Xaa34 is Lys (K) or Cys (C).

[0414] 78. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a C-terminal segment with no more than 11 amino acid modifications relative to the sequence of any one of SEQ ID Nos. 69-109.

[0415] 79. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a C-terminal segment with no more than 9 amino acid modifications relative to the sequence of any one of SEQ ID Nos. 69-109.

[0416] 80. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a C-terminal segment comprising an amino acid sequence as set forth in any one of SEQ ID Nos. 69-109.

[0417] 81. The CCR5 antagonist of any one of the preceding embodiments, wherein the polypeptide comprises a C-terminal segment consisting of an amino acid sequence as set forth in any one of SEQ ID Nos. 69-109.

[0418] 82. A pharmaceutical composition comprising a CCR5 antagonist according to any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0419] 83. A pharmaceutical composition comprising a CCR5 antagonist according to any one of the preceding embodiments and a pharmaceutically acceptable excipient, such as a solvent, diluent, buffer, preservative, tonicity regulating agent, chelating agent, and stabiliser.

[0420] 84. A pharmaceutical composition comprising a CCR5 antagonist according to any one of the preceding embodiments and a pharmaceutically acceptable carrier.

[0421] 85. A pharmaceutical composition comprising a CCR5 antagonist according to any one of the preceding embodiments and a pharmaceutically acceptable buffer. A pharmaceutical composition comprising a CCR5 antagonist according to any one of embodiments 82-85, wherein the pharmaceutical composition is suitable for parenteral administration such as subcutaneous, intramuscular, intraperitoneal, or intravenous administration. A pharmaceutical composition comprising a CCR5 antagonist according to any one of embodiments 82-86, wherein the pharmaceutical composition is a liquid pharmaceutical formulation. A pharmaceutical composition comprising a CCR5 antagonist according to any one of embodiments 82-87, wherein the pharmaceutical composition is an aqueous liquid pharmaceutical formulation. The CCR5 antagonist according to any one of the embodiments 1-81 or the pharmaceutical composition according to any one of embodiments 82-88 for use as a medicament. The CCR5 antagonist according to any one of the embodiments 1-81 or the pharmaceutical composition according to any one of embodiment 82-89 for use as a therapeutic drug. The CCR5 antagonist according to any one of the embodiments 1-81 or the pharmaceutical composition according to any one of embodiments 82-90 for use in the prevention, treatment and / or alleviation of hepatitis. The CCR5 antagonist according to any one of the embodiments 1-81 or the pharmaceutical composition according to any one of the embodiments 82-91 for use in the prevention, treatment and / or alleviation of hepatitis associated with nonalcoholic steatohepatitis (NASH), such as F3 and / or F4 NASH. The CCR5 antagonist according to any one of the embodiments 1-81 or the pharmaceutical composition according to any one of the embodiments 82-91 for use in the prevention, treatment and / or alleviation of NASH or MASH. EXAMPLES

[0422] This experimental section starts with a list of abbreviations and is followed by a section on the general methods for compound preparation and a section on the methods for measuring properties relevant for the exposure profile. A number of specific examples have been included in each of the sections to illustrate the invention. All example compounds were prepared according to the general methods described herein.

[0423] The Fmoc-protected amino acid derivatives used were the standard recommended: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OfBu)-OH, Fmoc-Cys(Trt)- OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OfBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-lle- OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc- Ser(fBu)-OH, Fmoc-Thr(fBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(fBu)-OH and Fmoc-Val-OH unless mentioned otherwise and were procured from Gyros Protein Technologies AB. Fmoc- Cys(SfBu)-OH, Fmoc-Glu-OfBu, and resins for solid phase peptide synthesis were obtained from Novabiochem (Merck Millipore). Fmoc-Ado-OH was purchased from Bachem. Pseudoproline dipeptides Fmoc-Ala-Thr(Psi(Me,Me)pro)-OH, Fmoc-Val(fBu)- Thr(Psi(Me,Me)pro)-OH and Fmoc-Tyr(fBu)-Thr(Psi(Me,Me)pro)-OH were obtained from Gorden Pharma, Technocomm Ltd. or Bachem. Sodium nitrite, methyl thioglycolate, tris(2- carboxyethyl)phosphine, cystamine dihydrochloride, cysteamine hydrochloride, triisopropylsilane and / V, / V-diisopropylethylamine were purchased from Sigma. Oxyma was purchased from Gyros Protein Technologies. / V, / V-dimethylformamide, piperidine, / V, / V- diisopropylcarbodiimide, trifluoroacetic acid, acetic anhydride and 1 ,1 , 1 ,3,3, 3-hexafluoro-2- propanol were obtained from Biosolve. HPLC grade acetonitrile was procured from Merck.

[0424] Abbreviations

[0425] Ado: 8-amino-3,6-dioxaoctanoic acid

[0426] Boc: f-butyloxycarbonyl

[0427] CAD: Charged Aerosol Detector

[0428] Collidine: 2,4,6-trimethylpyridine

[0429] DCM: Dichloromethane

[0430] DIG: / V, / V'-diisopropylcarbodiimide

[0431] DMF: / V, / V-dimethylformamide

[0432] D-PBS: Dulbecco's phosphate-buffered saline

[0433] DTT: 1 ,4-dithiothreitol

[0434] Fmoc: 9-fluorenylmethyloxycarbonyl Gu HCI: Guanidine hydrochloride

[0435] HFIP: 1,1 ,1 ,3,3,3-hexafluoro-2-propanol or hexafluoroisopropanol

[0436] HPLC: High Performance Liquid Chromatography

[0437] / Pr3SiH: Triisopropylsilane

[0438] / Pr2EtN: / V, / V-diisopropylethylamine

[0439] LC: Liquid Chromatography

[0440] LCMS: Liquid Chromatography Mass Spectroscopy

[0441] MeCN: Acetonitrile

[0442] MTG: Methyl thioglycolate

[0443] MQ: Milli-Q

[0444] MS: Mass Spectroscopy

[0445] Mtt: 4-methyltrityl

[0446] NMP: / V-methyl-2-pyrrolidone

[0447] OtBu: tert-butoxy

[0448] Oxyma Pure®: Ethyl cyano / hydroxyamino)acetate

[0449] OVA: Ovalbumin

[0450] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0451] PBS: Phosphate Buffered Saline

[0452] RP: Reverse Phase

[0453] RP-HPLC: Reverse Phase High Performance Liquid Chromatography

[0454] RT: Room Temperature

[0455] SEC: Size-Exclusion Chromatography

[0456] SPPS: Solid Phase Peptide Synthesis tBu: tert-butyl

[0457] TCEP: tris(2-carboxyethyl)phosphine

[0458] TFA: trifluoroacetic acid

[0459] TIPS: triisopropylsilane

[0460] Trt: triphenylmethyl (trityl)

[0461] UPLC: Ultra Performance Liquid Chromatography

[0462] UV: Ultraviolet Synthesis

[0463] Synthesis of building block Fmoc-Cvs(Ac-C2DA-Alloc)-OH

[0464] The below section refers to the synthesis of building block Fmoc-Cys(Ac-C2DA-

[0465] Alloc)-OH, which will form part of the compound synthesis provided here below.

[0466] (F?)-14-((((9 / 7-Fluoren-9-yl)methoxy)carbonyl)amino)-5,10-dioxo-4-oxa-12-thia-6,9- diazapentadec-1-en-15-oic acid

[0467] The general reaction scheme is as follows:

[0468] Step 1 to 2

[0469] Allyl chloroformate (10.1 mL, 95.1 mmol) was added dropwise to a solution of terf-butyl (2- aminoethyl)carbamate (1 , 15.2 g, 95.1 mmol) and triethylamine (26.5 mL, 190 mmol) in dry dichloromethane (285 mL) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 1 hour, then the cooling bath was removed, and the mixture was stirred at room temperature for additional 3 hours. The resulting mixture was washed with 0.5 M aqueous solution of hydrochloric acid (3 x 200 mL) and water (1 x 200 mL); dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1 to 98:2) to afford allyl terf-butyl ethane-1 ,2-diyldicarbamate (2) as a white solid. Step 2 to 3

[0470] Allyl tert-butyl ethane-1 ,2-diyldicarbamate (2, 19.2 g, 78.5 mmol) was dissolved in trifluoroacetic acid (70 mL), and the resulting solution was stirred at room temperature for 1.5 hours. The solution was evaporated in vacuo. The residue was evaporated from dichloromethane / toluene mixture (1 :4, 250 mL), toluene (200 mL), acetonitrile (2 x 100 mL) and dichloromethane (2 x 100 mL) to give 2-(((allyloxy)carbonyl)amino)ethan-1-aminium trifluoroacetate (3) as a pale brown oil containing excess of trifluoroacetic acid.

[0471] Step 3 to 4

[0472] A solution of 2-(((allyloxy)carbonyl)amino)ethan-1-aminium trifluoroacetate (3, 74.3%, 25.2 g, 72.6 mmol) in dichloromethane (200 mL) was extracted with a solution of potassium carbonate (200 g) in water (1 x 200 mL). The phases were separated, and the aqueous one was reextracted with dichloromethane (100 mL) and dichloromethane / diethyl ether mixture (1 :1 , 4 x 200 mL). All organic fractions were combined, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to yield allyl (2-aminoethyl)carbamate (4) as a pale yellow oil.

[0473] Step 4 to 5

[0474] Bromoacetyl bromide (6.02 mL, 69.1 mmol) was added dropwise to a solution of allyl (2- aminoethyl)carbamate (4, 9.49 g, 65.8 mmol) and 2,4,6-collidine (17.5 mL, 132 mmol) in dry dichloromethane (660 mL) at -30 °C under argon. The resulting mixture was stirred for 30 minutes at -30 °C, and then for 30 minutes at 0 °C prior to quenching with cold 5% aqueous solution of potassium hydrogen sulfate (1 L). The phases were separated, and the organic one was washed with 5% aqueous solution of potassium hydrogen sulfate (1 x 1 L). The aqueous phases were combined and re-extracted with dichloromethane (10 x 100 mL). All organic fractions were combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash column chromatography (Silicagel 60, 0.040-0.063 mm; eluent: dichloromethane / methanol 99:1 to 95:5) to afford allyl (2-(2- bromoacetamido)ethyl)carbamate (5) as a white solid.

[0475] Step 5 to 6

[0476] L-Cysteine hydrochloride monohydrate (5.27 g, 30.0 mmol) was added to argon-sparged solution of potassium hydrogen carbonate (18.0 g, 180 mmol) in water (150 mL), and the resulting solution was evacuated and backfilled with argon. An argon-sparged solution of allyl (2-(2-bromoacetamido)ethyl)carbamate (5, 8.11 g, 30.6 mmol) in acetonitrile (150 mL) was added to the above solution via cannula. The mixture was evacuated and backfilled with argon; and then it was vigorously stirred at room temperature overnight. / \ / -(9- Fluorenylmethoxycarbonyloxy)succinimide (FmocOSu, 10.3 g, 30.6 mmol) was added; and the mixture was stirred for additional 3 hours. The resulting mixture was washed with hexanes (2 x 450 mL). The aqueous phase was acidified with 1 M aqueous solution of hydrochloric acid (200 mL) and extracted with ethyl acetate (3 x 250 mL). The ethyl acetate extracts were combined, washed with 0.5 M aqueous solution of hydrochloric acid (3 x 300 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting oily residue was immediately dissolved in dichloromethane (150 mL), and the solution was placed in a fridge over weekend. The precipitated solid was filtered; washed with dichloromethane (2 x 60 mL) and dichloromethane / hexanes mixture (1 :1 , 3 x 90 mL); and dried in vacuo to afford the title compound of step 6 as a white powder.

[0477] Fmoc SPPS Procedures

[0478] Derivatization of 2-Chlorotrityl chloride Resin with Hydrazine

[0479] 2-Chlorotrityl chloride (2-CTC) resin (24.5 g) was swollen in NMP (100 mL) for 1 h and then washed with NMP (3 x 100 mL). Fmoc-hydrazine (16.9 g, 2 eq) was dissolved in NMP (160 mL) followed by the addition of triethylamine (18.5 mL, 4 eq) and the resulting mixture was added to the resin and shaken for 1 h. The resin was drained and washed with NMP (6 x 100 mL), incubated with 5 vol.% MeOH in NMP (150 mL) for 10 min and washed with NMP (6 x 100 mL) and DCM (6 x 100 mL) and dried in vacuo overnight before use.

[0480] Automated Fmoc SPPS

[0481] Automated Fmoc SPPS was performed on a Symphony™ X (Gyros Protein Technologies AB). Fmoc-deprotection was achieved with 2 x 10 min treatments of 20 vol.% piperidine in 0.1 M Oxyma in DMF. Peptide couplings were performed using DIC / collidine. Amino acid / Oxyma solutions (0.3 M / 0.3 M in DMF at a molar excess of 5 fold) were added to the resin followed by the same molar equivalent of DIG (1.5 M in DMF) and the same molar equivalent of collidine (1.5 M in DMF). The coupling procedure was allowed to proceed for 60 min unless specified otherwise. Upon completion of the coupling reaction, residual free amino groups were capped by the addition of 24 equivalents of collidine (1.5 M in DMF) and 16 equivalents of acetic anhydride (1.0 M in DMF) for 20 min. Global deprotection of resin bound peptides

[0482] After synthesis the resin was washed with DCM, and the peptidyl resin subject to a 2- 3 h treatment with TFA / TIPS / DTT / water (95:2.5:2.5:2.5, v / v / v / v). In case of presence of methionine, water was exchanged with 1.0 M ammonium iodide(aq). The treatment was followed by precipitation in ice cold diethylether and collection by centrifugation. The pellet was resuspended in diethylether before being centrifuged once more. The washed pellet was dissolved in a suitable mixture of water, MeCN and acetic acid or Gu HCI, before purification by reversed-phase preparative HPLC.

[0483] Installation of side chain modifications on resin

[0484] Side chain modifications were selectively installed on resin via orthogonally protected amino acids such as Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Alloc)-OH or Fmoc-Cys(Ac-C2DA-Alloc)- OH. The Mtt group was removed by treatment with HFIP / DCM / TIPS (75:22.5:2.5) (3 x 15 min). Following this, the resin was subjected to treatment with 20 vol.% piperidine in 0.1 M Oxyma in DMF (1x 5 min). In the case of Alloc based strategies, the resin was initially washed with DMF (2 x 3 min) and then washed with degassed inert DMF for 2 mins. BH3-NHMe2 (~ 15 eq) was dissolved in degassed DMF and added to the reaction vessel followed by Pd(PPha)4 (-0.01 eq) dissolved in degassed DMF. Additions were performed manually as quick as possible followed by capping of the reaction vessel to prevent prolonged air exposure. The reaction vessel was subsequently mixed for 2 mins followed by nitrogen bubbling for 2 mins. The reaction vessel was then mixed for 3 hours before being washed with methanol (6 x 5 min). The procedure was optionally repeated once more to ensure complete deprotection. Following deprotection, the resin was subsequently washed with DCM and DMF before the substituent was introduced using standard SPPS procedures described above.

[0485] Ligation and folding of peptides

[0486] The compounds of the invention were typically prepared through Native Chemical Ligation (Chemistry & Biology Volume 6, Issue 1, January 1999, Pages 43-51). Typically, the / V-terminal region of the peptide functionalised with a C-terminal hydrazide motif was used in slight molar excess (1.2-1.5 eq.) and activated under conditions adopted from (Angewandte Chemie Int Ed Volume 50, Issue 33 August 8, 2011 Pages 7645-7649). Peptide hydrazides were dissolved in 6 M Gu.HCI, 200 mM phosphate pH 3.0 at a concentration of 2-5 mM, adjusted to pH 3.0 and cooled in a salt ice bath to -10 °C before the dropwise addition of 1 M aq sodium nitrite solution (10 eq) followed by stirring of the resulting mixture for 10-20 minutes. A solution of MTG was prepared at a concentration of 200 mM in 6 M Gu.HCI, 200 mM phosphate pH 7.0 which was subsequently sparged with nitrogen bubbling. The C-terminal region of the peptide functionalised with an / V-terminal cysteine was subsequently dissolved in MTG containing buffer at a concentration of 2-5 mM and added to the activation mixture which was subsequently adjusted to pH 7.0 and allowed to warm to room temperature. Optionally, TCEP was added to the ligation mixture to a final concentration of 20 mM after 1 hour. Progress of the reaction could be assessed by LC-MS analysis and was typically complete within 5-18 h. Following confirmation of completion of the reaction, the crude ligation mixture was added to folding buffer comprised of 2 M Gu HCI, 50 mM Tris, 5 mM cysteamine, 0.5 mM cystamine pH 8 (sparged with nitrogen before use). Progress of the folding reaction was followed by LC- MS analysis and upon completion, the mixture was acidified to pH 2 prior to purification. In the event that precipitation occurred, MeCN was added to the mixture to aid dissolution prior to loading onto the HPLC column.

[0487] Purification of peptides and final analogues

[0488] Preparative purification was performed on a Waters™ Deltaprep 4000 Preparative Chromatography System using a reversed phase HPLC column. Elution was performed using a mobile phase composed of 0.1 vol.% TFA in Milli-Q® water (Solvent A) and 0.1 vol.% TFA in HPLC grade acetonitrile (Solvent B) utilizing a linear gradient.

[0489] Elution was performed using a mobile phase composed of 0.1 vol.% TFA, 10 vol.% acetonitrile in Milli-Q water (Solvent A) and 0.1 vol.% TFA in HPLC grade acetonitrile (Solvent B) utilizing a linear gradient. Relevant fractions were assessed by LC-MS and purity of pooled fractions was assessed by analytical HPLC or UPLC. Fractions containing the pure target peptide were pooled and freeze dried.

[0490] Analytical procedures

[0491] LC-MS conditions:

[0492] Table 2. LC-MS Conditions

[0493] Compounds

[0494] For the below compounds, the expression “pGlu”, “PyroGlu”, “Pyr” or “pG” may interchangeably used to refer to Pyroglutamic Acid.

[0495] Intermediates N-terminal segments

[0496] N-terminal segment 1 pGlu-GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGK-hydrazide

[0497] Molecular weight calculated for C175 H265 N47 O45 S3: 3843.46 g / mol (average), 3840.91 g / mol (monoisotopic)

[0498] LCMS34: found [M+3H]3+: 1282.30; [M+4H]4+: 962.00; [M+5H]5+: 769.40 (average)

[0499] Sequence (Y1): XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGK (SEQ ID No. 64) where X is PyroGlu.

[0500] N-terminal segment 2 pGlu-GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGK-hydrazide

[0501] Molecular weight calculated for C175 H264 N48 O46 S2: 3840.39 g / mol (average), 3837.92 g / mol (monoisotopic)

[0502] LCMS36: found [M+3H]3+: 1280.26; [M+4H]4+: 960.47; [M+5H]5+: 768.58 (monoisotopic)

[0503] Sequence (Y1): XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGK (SEQ ID No. 65) where X is PyroGlu.

[0504] N-terminal segment 3 pGlu-GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGK-hydrazide

[0505] Molecular weight calculated for C174 H262 N48 O45 S2: 3810.37 g / mol (average), 3807.91 g / mol (monoisotopic) LCMS36: found [M+2H]2+: 1904.97; [M+3H]3+: 1270.31 ; [M+4H]4+: 952.99; [M+5H]5+: 762.59 (monoisotopic)

[0506] Sequence (Y1): XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGK (SEQ ID No. 66) where X is PyroGlu.

[0507] N-terminal segment 4 pGlu-GPPLMAAQSCCFAYIARPLPRAHIKEYFYTSGK-hydrazide

[0508] Molecular weight calculated for C174 H263 N47 O44 S3: 3813.43 g / mol (average), 3810.89 g / mol (monoisotopic)

[0509] LCMS34: found [M+2H]2+: 1906.40; [M+3H]3+: 1271.28; [M+4H]4+: 953.72; [M+5H]5+: 763.18 (monoisotopic)

[0510] Sequence (Y1): XGPPLMAAQSCCFAYIARPLPRAHIKEYFYTSGK (SEQ ID No. 67) where X is PyroGlu.

[0511] C-terminal segments

[0512] C-terminal segment 1

[0513] CSNPAVVFVTEENRQVCANPEKKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0514] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0515] Molecular weight calculated for C215 H340 N54 O71 S2: 4881.45 g / mol (average), 4878.41 g / mol (monoisotopic) LCMS36: found [M+3H]3+: 1627.15; [M+4H]4+: 1220.61 ; [M+5H]5+: 976.70 (monoisotopic)

[0516] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYINSLEKS (SEQ ID No. 69) Z1 : Chem 4a; Z2: C18 diacid

[0517] C-terminal segment 2

[0518] CSNPAVVFVTEENRQVCANPEKKWVREYINSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0519] ]ethylamino]-2-oxoethyl]-S-acid

[0520] Molecular weight calculated for C216 H341 N55 O72 S3: 4956.54 g / mol (average), 4953.39 g / mol (monoisotopic)

[0521] LCMS36: found [M+3H]3+: 1652.10; [M+4H]4+: 1239.34; [M+5H]5+: 991.67 (monoisotopic)

[0522] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYINSLECS (SEQ ID No. 70) Z1 : Chem 4c; Z2: C18 diacid

[0523] C-terminal segment 3

[0524] CSNPAWFVTEDNRQVCANPEKKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0525] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0526] Molecular weight calculated for C214 H338 N54 O71 S2: 4867.42 g / mol (average), 4864.39 g / mol (monoisotopic)

[0527] LCMS34: found [M+3H]3+: 1623.20; [M+4H]4+: 1217.90; [M+5H]5+: 974.30 (average)

[0528] Seguence (Y2): CSNPAVVFVTEDNRQVCANPEKKWVREYINSLEKS (SEQ ID No. 71)

[0529] Z1 : Chem 4a; Z2: C18 diacid

[0530] C-terminal segment 4

[0531] CSNPAVVFVTDENRQVCANPEKKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0532] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0533] Molecular weight calculated for C214 H338 N54 O71 S2: 4867.42 g / mol (average), 4864.39 g / mol (monoisotopic)

[0534] LCMS34: found [M+3H]3+: 1623.51 ; [M+4H]4+: 1217.61 ; [M+5H]5+: 974.49 (average)

[0535] Seguence (Y2): CSNPAVVFVTDENRQVCANPEKKWVREYINSLEKS (SEQ ID No. 72)

[0536] Z1 : Chem 4a; Z2: C18 diacid

[0537] C-terminal segment 5 CSNPAWFVTEENRQVCANPEKKWVREYINSLE-K[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-

[0538] 4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino ]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]e thoxy]acetyl]-S-acid

[0539] Molecular weight calculated for C239 H384 N58 O83 S2: 5462.08 g / mol (average), 5458.71 g / mol (monoisotopic)

[0540] LCMS34: found [M+5H]5+: 1092.76; [M+6H]6+: 910.79; [M+7H]7+: 780.82 (monoisotopic)

[0541] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYINSLEKS (SEQ ID No. 69) Z1 : Chem 4b; Z2: C18 diacid

[0542] C-terminal segment 6

[0543] CSNPAVVFVTEENRQVCANPEEKWVREYINSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0544] Molecular weight calculated for C211 H336 N52 O70 S2: 4785.36 g / mol (average), 4782.38 g / mol (monoisotopic)

[0545] LCMS34: found [M+3H]3+: 1596.10; [M+4H]4+: 1197.30; [M+5H]5+: 957.90 (average) Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 73)

[0546] Z1 : Chem 4d; Z2: C18 diacid

[0547] C-terminal segment 7

[0548] CSNPAVVFVTEENRQVCANPEKEWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0549] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0550] Molecular weight calculated for C214 H335 N53 O73 S2: 4882.39 g / mol (average), 4879.36 g / mol (monoisotopic)

[0551] LCMS34: found [M+3H]3+: 1628.50; [M+4H]4+: 1221.40; [M+5H]5+: 977.30 (average) Sequence (Y2): CSNPAVVFVTEENRQVCANPEKEWVREYINSLEKS (SEQ ID No. 78) Z1 : Chem 4a; Z2: C18 diacid

[0552] C-terminal segment 8

[0553] CSNPAWFVTEENRQVCANPEEEWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0554] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0555] Molecular weight calculated for C213 H330 N52 O75 S2: 4883.33 g / mol (average), 4880.3 g / mol (monoisotopic)

[0556] LCMS34: found [M+3H]3+: 1628.80; [M+4H]4+: 1221.80; [M+5H]5+: 977.70 (average)

[0557] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYINSLEKS (SEQ ID No. 79)

[0558] Z1 : Chem 4a; Z2: C18 diacid

[0559] C-terminal segment 9

[0560] CSNPAVVFVTEENRQVCANPEKKWVREYINELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0561] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0562] Molecular weight calculated for C217 H342 N54 O72 S2: 4923.49 g / mol (average), 4920.42 g / mol (monoisotopic)

[0563] LCMS34: found [M+3H]3+: 1641.80; [M+4H]4+: 1231.90; [M+5H]5+: 985.70 (average)

[0564] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYIN ELEKS (SEQ ID No. 75)

[0565] Z1 : Chem 4a; Z2: C18 diacid

[0566] C-terminal segment 10 CSNPAWFVTEENRQVCANPEEKWVREYIESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0567] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0568] Molecular weight calculated for C215 H336 N52 O74 S2: 4897.4 g / mol (average), 4894.36 g / mol (monoisotopic)

[0569] LCMS34: found [M+3H]3+: 1633.50; [M+4H]4+: 1225.40; [M+5H]5+: 980.30 (average)

[0570] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIESLEKS (SEQ ID No. 76)

[0571] Z1 : Chem 4a; Z2: C18 diacid

[0572] C-terminal segment 11

[0573] CSNPAVVFVTEENRQVCANPEEKWVREYINELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0574] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0575] Molecular weight calculated for C216 H33? N53 O74 S2: 4924.43 g / mol (average), 4921.37 g / mol (monoisotopic)

[0576] LCMS34: found [M+3H]3+: 1642.10; [M+4H]4+: 1231.90; [M+5H]5+: 985.70 (average)

[0577] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIN ELEKS (SEQ ID No. 77) Z1 : Chem 4a; Z2: C18 diacid

[0578] C-terminal segment 12

[0579] CSNPAWFVTEENRQVCANPEEKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0580] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0581] Molecular weight calculated for C214 H335 N53 O73 S2: 4882.39 g / mol (average), 4879.36 g / mol (monoisotopic)

[0582] LCMS36: found [M+3H]3+: 1627.47; [M+4H]4+: 1220.85; [M+5H]5+: 976.89 (monoisotopic)

[0583] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 73)

[0584] Z1 : Chem 4a; Z2: C18 diacid

[0585] C-terminal segment 13

[0586] CSNPAVVFVTEENRQVCANPEKKWVREYIESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0587] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid Molecular weight calculated for C216 H341 N53 O72 S2: 4896.46 g / mol (average), 4893.41 g / mol (monoisotopic)

[0588] LCMS34: found [M+3H]3+: 1633.20; [M+4H]4+: 1225.10; [M+5H]5+: 980.30 (average)

[0589] Seguence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYIESLEKS (SEQ ID No. 74)

[0590] Z1 : Chem 4a; Z2: C18 diacid

[0591] C-terminal segment 14

[0592] CSNPAVVFVTEENRQVCANPEKKWVREYINSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino] ethylamino]-2-oxoethyl]-S-acid

[0593] Molecular weight calculated for C218 H345 N55 O72 S3: 4984.59 g / mol (average), 4981.42 g / mol (monoisotopic)

[0594] LCMS34: found [M+3H]3+: 1661.44; [M+4H]4+: 1246.34; [M+5H]5+: 997.28; [M+6H]6+: 831.24 (monoisotopic)

[0595] Seguence: CSNPAVVFVTEENRQVCANPEKKWVREYINSLECS (SEQ ID No. 70)

[0596] Z1 : Chem 4c; Z2: C20 diacid

[0597] C-terminal segment 15

[0598] CSNPAWFVTEENREVCANPEKKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0599] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0600] Molecular weight calculated for C215 H339 N53 O72 S2: 4882.43 g / mol (average), 4879.39 g / mol (monoisotopic)

[0601] LCMS34: found [M+3H]3+: 1627.44; [M+4H]4+: 1220.82; [M+5H]5+: 976.87 (monoisotopic)

[0602] Sequence (Y2): CSNPAVVFVTEENREVCANPEKKWVREYINSLEKS (SEQ ID No. 80) Z1 : Chem 4a; Z2: C18 diacid

[0603] C-terminal segment 16

[0604] CSNPAWFVTEENRQVCANPEKKWVREYIEELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0605] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0606] Molecular weight calculated for C218 H343 N53 O73 S2: 4938.5 g / mol (average), 4935.42 g / mol (monoisotopic)

[0607] LCMS34: found [M+3H]3+: 1646.70; [M+4H]4+: 1235.06; [M+5H]5+: 988.47 (average)

[0608] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKKWVREYIEELEKS (SEQ ID No. 83)

[0609] Z1 : Chem 4a; Z2: C18 diacid

[0610] C-terminal segment 17 CSNPAVVFVTEENRQVCANPEQKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0611] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0612] Molecular weight calculated for C214 H336 N54 O72 S2: 4881.41 g / mol (average), 4878.37 g / mol (monoisotopic)

[0613] LCMS34: found [M+2H]2+: 2441.48; [M+3H]3+: 1627.69; [M+4H]4+: 1220.80; [M+5H]5+: 977.25

[0614] (average)

[0615] Sequence (Y2): CSNPAVVFVTEENRQVCANPEQKWVREYINSLEKS (SEQ ID No. 81)

[0616] Z1 : Chem 4a; Z2: C18 diacid

[0617] C-terminal segment 18

[0618] CSNPAWFVTEENRQVCANPEKQWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0619] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0620] Molecular weight calculated for C214 H336 N54 O72 S2: 4881.41 g / mol (average), 4878.37 g / mol (monoisotopic)

[0621] LCMS34: found [M+3H]3+: 1628.16; [M+4H]4+: 1221.12; [M+5H]5+: 977.09 (average) Sequence (Y2): CSNPAWFVTEENRQVCANPEKQWVREYINSLEKS (SEQ ID No. 82) Z1 : Chem 4a; Z2: C18 diacid

[0622] C-terminal segment 19

[0623] CSNPAWFVTEENRQVCANPEEEWVREYIESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0624] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0625] Molecular weight calculated for C214 H331 N51 076 S2: 4898.34 g / mol (average), 4895.3 g / mol (monoisotopic)

[0626] LCMS34: found [M+2H]2+: 2450.21 ; [M+3H]3+: 1633.47; [M+4H]4+: 1225.60; [M+5H]5+: 980.68 (average)

[0627] Sequence: CSNPAVVFVTEENRQVCANPEEEWVREYIESLEKS (SEQ ID No. 84)

[0628] Z1 : Chem 4a; Z2: C18 diacid

[0629] C-terminal segment 20

[0630] CSNPAVVFVTEENRQVCANPEEEWVREYINELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0631] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0632] Molecular weight calculated for C215 H332 N52 O76 S2: 4925.37 g / mol (average), 4922.32 g / mol (monoisotopic)

[0633] LCMS34: found [M+3H]3+: 1642.80; [M+4H]4+: 1232.40; [M+5H]5+: 985.90 (average)

[0634] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYIN ELEKS (SEQ ID No. 85)

[0635] Z1 : Chem 4a; Z2: C18 diacid

[0636] C-terminal segment 21

[0637] CSNPAVVFVTEENRQVCANPEQEWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0638] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0639] Molecular weight calculated for C213 H331 N53 O74 S2: 4882.35 g / mol (average), 4879.32 g / mol (monoisotopic)

[0640] LCMS36: found [M+3H]3+: 1627.45; [M+4H]4+: 1220.94; [M+5H]5+: 976.86 (monoisotopic)

[0641] Sequence (Y2): CSNPAVVFVTEENRQVCANPEQEWVREYINSLEKS (SEQ ID No. 86) Z1 : Chem 4a; Z2: C18 diacid

[0642] C-terminal segment 22 CSNPAVVFVTEENRQVCANPEEQWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0643] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0644] Molecular weight calculated for C213 H331 N53 O74 S2: 4882.35 g / mol (average), 4879.32 g / mol (monoisotopic)

[0645] LCMS34: found [M+2H]2+: 2442.17; [M+3H]3+: 1628.46; [M+4H]4+: 1221.61 ; [M+5H]5+: 977.48

[0646] (average)

[0647] Sequence (Y2): CSNPAWFVTEENRQVCANPEEQWVREYINSLEKS (SEQ ID No. 87)

[0648] Z1 : Chem 4a; Z2: C18 diacid

[0649] C-terminal segment 23

[0650] CSNPAWFVTEENRQVCANPEKEWVREYIESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0651] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0652] Molecular weight calculated for C215 H336 N52 O74 S2: 4897.4 g / mol (average), 4894.36 g / mol (monoisotopic)

[0653] LCMS36: found [M+3H]3+: 1632.46; [M+4H]4+: 1224.60; [M+5H]5+: 979.87 (monoisotopic) Sequence (Y2): CSNPAVVFVTEENRQVCANPEKEWVREYIESLEKS (SEQ ID No. 88)

[0654] Z1 : Chem 4a; Z2: C18 diacid

[0655] C-terminal segment 24

[0656] CSNPAVVFVTEENRQVCANPEKEWVREYINELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0657] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0658] Molecular weight calculated for C216 H337 N53 O74 S2: 4924.43 g / mol (average), 4921.37 g / mol (monoisotopic)

[0659] LCMS34: found [M+3H]3+: 1642.50; [M+4H]4+: 1231.90; [M+5H]5+: 985.70 (average)

[0660] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKEWVREYIN ELEKS (SEQ ID No. 89)

[0661] Z1 : Chem 4a; Z2: C18 diacid

[0662] C-terminal segment 25

[0663] CSNPAWFVTEENRQVCANPEEKWVREYIEELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0664] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid Molecular weight calculated for C217 H338 N52 O75 S2: 4939.44 g / mol (average), 4936.37 g / mol (monoisotopic)

[0665] LCMS34: found [M+3H]3+: 1647.50; [M+4H]4+: 1235.60; [M+5H]5+: 988.90 (average) Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIEELEKS (SEQ ID No. 94) Z1: Chem 4a; Z2: C18 diacid

[0666] C-terminal segment 26

[0667] CSNPAWFVTEENRQVCANPEKEWVREYIEELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0668] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0669] Molecular weight calculated for C217 H338 N52 O75 S2: 4939.44 g / mol (average), 4936.37 g / mol (monoisotopic)

[0670] LCMS34: found [M+3H]3+: 1647.50; [M+4H]4+: 1235.60; [M+5H]5+: 988.90 (average)

[0671] Sequence (Y2): CSNPAVVFVTEENRQVCANPEKEWVREYIEELEKS (SEQ ID No. 95)

[0672] Z1: Chem 4a; Z2: C18 diacid

[0673] C-terminal segment 27

[0674] CSNPAVVFVTEENRQVCANPEEEWVREYIEELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0675] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0676] Molecular weight calculated for C216 H333 N51 077 S2: 4940.38 g / mol (average), 4937.32 g / mol (monoisotopic)

[0677] LCMS34: found [M+3H]3+: 1647.80; [M+4H]4+: 1236.10; [M+5H]5+: 989.10 (average)

[0678] Seguence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYIEELEKS (SEQ ID No. 96)

[0679] Z1 : Chem 4a; Z2: C18 diacid

[0680] C-terminal segment 28

[0681] CSNPAVVFVTEENRQVCANPEQKWVREYIESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0682] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0683] Molecular weight calculated for C215 H337 N53 O73 S2: 4896.42 g / mol (average), 4893.37 g / mol (monoisotopic)

[0684] LCMS36: found [M+3H]3+: 1632.13; [M+4H]4+: 1224.34; [M+5H]5+: 979.68 (monoisotopic)

[0685] Seguence (Y2): CSNPAVVFVTEENRQVCANPEQKWVREYIESLEKS (SEQ ID No. 91) Z1 : Chem 4a; Z2: C18 diacid

[0686] C-terminal segment 29 CSNPAVVFVTEENRQVCANPEQKWVREYIEELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0687] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0688] Molecular weight calculated for C217 H339 N53 O74 S2: 4938.45 g / mol (average), 4935.38 g / mol (monoisotopic)

[0689] LCMS36: found [M+3H]3+: 1646.15; [M+4H]4+: 1234.85; [M+5H]5+: 988.09 (monoisotopic)

[0690] Sequence (Y2): CSNPAVVFVTEENRQVCANPEQKWVREYIEELEKS (SEQ ID No. 92) Z1 : Chem 4a; Z2: C18 diacid

[0691] C-terminal segment 30

[0692] CSNPAWFVTEENRQVCANPEEKWVREYINSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0693] ]ethylamino]-2-oxoethyl]-S-acid

[0694] Molecular weight calculated for C215 H336 N54 O74 S3: 4957.48 g / mol (average), 4954.34 g / mol (monoisotopic)

[0695] LCMS36: found [M+3H]3+: 1652.45; [M+4H]4+: 1239.59; [M+5H]5+: 991.88 (monoisotopic)

[0696] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLECS (SEQ ID No. 90) Z1 : Chem 4c; Z2: C18 diacid C-terminal segment 31

[0697] CSNPAVVFVTEENRQVCANPEQQWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0698] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0699] Molecular weight calculated for C213 H332 N54 O73 S2: 4881.36 g / mol (average), 4878.34 g / mol (monoisotopic)

[0700] LCMS36: found [M+3H]3+: 1627.12; [M+4H]4+: 1220.60; [M+5H]5+: 976.67 (monoisotopic)

[0701] Sequence (Y2): CSNPAVVFVTEENRQVCANPEQQWVREYINSLEKS (SEQ ID No. 93) Z1 : Chem 4a; Z2: C18 diacid

[0702] C-terminal segment 32

[0703] CSNPAWFVTEENRQVCANPEEEWVREYINSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0704] Molecular weight calculated for C210 H331 N51 072 S2: 4786.3 g / mol (average), 4783.32 g / mol (monoisotopic)

[0705] LCMS34: found [M+2H]2+: 2392.59; [M+3H]3+: 1595.40; [M+4H]4+: 1196.82; [M+5H]5+: 957.66;

[0706] [M+6H]6+: 798.23 (monoisotopic)

[0707] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYINSLEKS (SEQ ID No. 79) Z1: Chem 4d; Z2: C18 diacid

[0708] C-terminal segment 33

[0709] CSNPAVVFVTEENREVCANPEEEWVREYINSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0710] Molecular weight calculated for C210 H330 N50 O73 S2: 4787.29 g / mol (average), 4784.31 g / mol (monoisotopic)

[0711] LCMS34: found [M+3H]3+: 1596.46; [M+4H]4+: 1197.60 (average)

[0712] Sequence (Y2): CSNPAVVFVTEENREVCANPEEEWVREYINSLEKS (SEQ ID No. 97)

[0713] Z1: Chem 4d; Z2: C18 diacid

[0714] C-terminal segment 34

[0715] CSNPAVVFVTEENREVCANPEEKWVREYIESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0716] Molecular weight calculated for C212 H336 N50O72 S2: 4801.36 g / mol (average), 4798.36 g / mol (monoisotopic)

[0717] LCMS34: found [M+3H]3+: 1601.47; [M+4H]4+: 1201.35; [M+5H]5+: 961.28 (average)

[0718] Sequence (Y2): CSNPAWFVTEENREVCANPEEKWVREYIESLEKS (SEQ ID No. 98)

[0719] Z1: Chem 4d; Z2: C18 diacid

[0720] C-terminal segment 35 CSNPAWFVTEENRQVCANPEEEWVREYIESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0721] Molecular weight calculated for C211 H332 N50 O73 S2: 4801.32 g / mol (average), 4798.32 g / mol (monoisotopic)

[0722] LCMS34: found [M+3H]3+: 1601.47; [M+4H]4+: 1201.10; [M+5H]5+: 961.08 (average)

[0723] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYIESLEKS (SEQ ID No. 84)

[0724] Z1 : Chem 4d; Z2: C18 diacid

[0725] C-terminal segment 36

[0726] CSNPAVVFVTEENRQVCANPEEEWVREYINELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0727] Molecular weight calculated for C212 H333 N51 073 S2: 4828.34 g / mol (average), 4825.34 g / mol

[0728] (monoisotopic)

[0729] LCMS34: found [M+3H]3+: 1610.46; [M+4H]4+: 1207.84; [M+5H]5+: 966.48 (average)

[0730] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYIN ELEKS (SEQ ID No. 85)

[0731] Z1 : Chem 4d; Z2: C18 diacid

[0732] C-terminal segment 37

[0733] CSNPAWFVTEENRQVCANPEEKWVREYIEELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0734] Molecular weight calculated for C214 H339 N51 072 S2: 4842.41 g / mol (average), 4839.39 g / mol (monoisotopic)

[0735] LCMS34: found [M+3H]3+: 1614.81 ; [M+4H]4+: 1211.36; [M+5H]5+: 969.29 (average)

[0736] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIEELEKS (SEQ ID No. 94)

[0737] Z1 : Chem 4d; Z2: C18 diacid

[0738] C-terminal segment 38

[0739] CSNPAVVFVTEENRQVCANPEQKWVREYIEELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0740] Molecular weight calculated for C214 H340 N52 O71 S2: 4841.43 g / mol (average), 4838.4 g / mol (monoisotopic)

[0741] LCMS34: found [M+3H]3+: 1614.50; [M+4H]4+: 1211.10; [M+5H]5+: 969.30 (average)

[0742] Sequence (Y2): CSNPAVVFVTEENRQVCANPEQKWVREYIEELEKS (SEQ ID No. 92)

[0743] Z1 : Chem 4d; Z2: C18 diacid

[0744] C-terminal segment 39

[0745] Cys(StBu)-SNPAWFVTEENRQV-Cys(StBu)-ANPEEEWVREYINSLE-C[2-[2-[[2-[2-[2-[[2-[2-

[0746] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0747] Molecular weight calculated for C219 H348 N52 O73 S5: 5037.74 g / mol (average), 5034.37 g / mol (monoisotopic)

[0748] LCMS34: found [M+3H]3+: 1679.12; [M+4H]4+: 1259.60; [M+5H]5+: 1007.89 (monoisotopic)

[0749] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYINSLECS (SEQ ID No. 99) Z1 : Chem 4e; Z2: C18 diacid

[0750] C-terminal segment 40

[0751] Cys(StBu)-SNPAVVFVTEENREV-Cys(StBu)-ANPEEKWVREYIESLE-C[2-[2-[[2-[2-[2-[[2-[2-

[0752] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0753] Molecular weight calculated for C221 H353 N51 073 S5: 5052.79 g / mol (average), 5049.41 g / mol (monoisotopic)

[0754] LCMS34: found [M+4H]4+: 1264.12; [M+5H]5+: 1011.49 (average)

[0755] Sequence (Y2): CSNPAVVFVTEENREVCANPEEKWVREYIESLECS (SEQ ID No. 101)

[0756] Z1 : Chem 4e; Z2: C18 diacid

[0757] C-terminal segment 41 Cys(StBu)-SNPAWFVTEENRQV-Cys(StBu)-ANPEEKWVEEYINSLE-C[2-[2-[[2-[2-[2-[[2-[2-

[0758] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0759] Molecular weight calculated for C219 H348 N50 O73 S5: 5009.72 g / mol (average), 5006.37 g / mol (monoisotopic)

[0760] LCMS34: found [M+3H]3+: 1669.80; [M+4H]4+: 1252.60; [M+5H]5+: 1002.28 (monoisotopic)

[0761] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVEEYINSLECS (SEQ ID No. 102) Z1 : Chem 4e; Z2: C18 diacid

[0762] C-terminal segment 42

[0763] Cys(StBu)-SNPAVVFVTEENRQV-Cys(StBu)-ANPEEKWVREYIESLE-C[2-[2-[[2-[2-[2-[[2-[2-

[0764] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0765] Molecular weight calculated for C221 H354 N52 O72 S5: 5051.81 g / mol (average), 5048.42 g / mol (monoisotopic)

[0766] LCMS34: found [M+3H]3+: 1684.80; [M+4H]4+: 1263.90; [M+5H]5+: 1011.30 (average)

[0767] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIESLECS (SEQ ID No. 100) Z1 : Chem 4e; Z2: C18 diacid

[0768] C-terminal segment 43

[0769] Cys(StBu)-SNPAVVFVTEENRQV-Cys(StBu)-ANPEEKWVREYIEELE-C[2-[2-[[2-[2-[2-[[2-[2-

[0770] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0771] Molecular weight calculated for C223 H356 N52 O73 S5: 5093.84 g / mol (average), 5090.43 g / mol (monoisotopic)

[0772] LCMS34: found [M+3H]3+: 1697.81 ; [M+4H]4+: 1273.61 ; [M+5H]5+: 1019.09 (monoisotopic)

[0773] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIEELECS (SEQ ID No. 103) Z1 : Chem 4e; Z2: C18 diacid

[0774] C-terminal segment 44

[0775] CSNPAVVFVTEENRQVCANPEEKWVREYIESLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy- 4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0776] Molecular weight calculated for C213 H338 N52 O72 S3: 4875.46 g / mol (average), 4872.35 g / mol (monoisotopic) LCMS36: found [M+3H]3+: 1625.08; [M+4H]4+: 1219.06; [M+5H]5+: 975.46 (monoisotopic) Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIESLECS (SEQ ID No. 100) Z1 : Chem 4e; Z2: C18 diacid

[0777] C-terminal segment 45

[0778] CSNPAWFVTEENRQVCANPEEKWVREYIESLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0779] ]ethylamino]-2-oxoethyl]-S-acid

[0780] Molecular weight calculated for C216 H337 N53 O75 S3: 4972.49 g / mol (average), 4969.33 g / mol (monoisotopic)

[0781] LCMS36: found [M+3H]3+: 1657.44; [M+4H]4+: 1243.34; [M+5H]5+: 994.87 (monoisotopic)

[0782] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIESLECS (SEQ ID No. 100) Z1 : Chem 4c; Z2: C18 diacid

[0783] C-terminal segment 46

[0784] CSNPAWFVTEDNRQVCANPEEKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0785] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid Molecular weight calculated for C213 H333 N53 O73 S2: 4868.36 g / mol (average), 4865.34 g / mol (monoisotopic)

[0786] LCMS34: found [M+3H]3+: 1622.75; [M+4H]4+: 1217.31 ; [M+5H]5+: 974.06 (monoisotopic)

[0787] Sequence (Y2): CSNPAVVFVTEDNRQVCANPEEKWVREYINSLEKS (SEQ ID No. 105)

[0788] Z1 : Chem 4a; Z2: C18 diacid

[0789] C-terminal segment 47

[0790] CSNPAVVFVTDDNRQVCANPEEKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0791] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0792] Molecular weight calculated for C212 H331 N53 O73 S2: 4854.34 g / mol (average), 4851.33 g / mol (monoisotopic)

[0793] LCMS34: found [M+3H]3+: 1618.08; [M+4H]4+: 1213.82; [M+5H]5+: 971.26; [M+6H]6+: 809.56 (monoisotopic)

[0794] Sequence (Y2): CSNPAVVFVTDDNRQVCANPEEKWVREYINSLEKS (SEQ ID No. 106)

[0795] Z1 : Chem 4a; Z2: C18 diacid

[0796] C-terminal seqment 48

[0797] CSNPAWFVTEENRQVCANPEEKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0798] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-acid

[0799] Molecular weight calculated for C216 H339 N53 O73 S2: 4910.44 g / mol (average), 4907.39 g / mol (monoisotopic)

[0800] LCMS34: found [M+3H]3+: 1636.77; [M+4H]4+: 1227.84; [M+5H]5+: 982.48; [M+6H]6+: 818.91 (monoisotopic)

[0801] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 73)

[0802] Z1 : Chem 4a; Z2: C20 diacid

[0803] C-terminal segment 49

[0804] CSNPAVVFVTEENRQVCANPEEKWVREYINSLE-K[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-

[0805] [[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0806] Molecular weight calculated for C214 H335 N53 O73 S2: 4882.39 g / mol (average), 4879.36 g / mol (monoisotopic)

[0807] LCMS34: found [M+3H]3+: 1627.42; [M+4H]4+: 1220.82; [M+5H]5+: 976.87; [M+6H]6+: 814.23 (monoisotopic)

[0808] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 73)

[0809] Z1 : Chem 4f; Z2: C18 diacid C-terminal segment 50

[0810] CSNPAVVFVTEENRQVCANPEEKWVREYINSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acety l]-S-acid

[0811] Molecular weight calculated for C213 H340 N52 O70 S2: 4813.42 g / mol (average), 4810.41 g / mol (monoisotopic)

[0812] LCMS34: found [M+3H]3+: 1604.43; [M+4H]4+: 1203.59; [M+5H]5+: 963.08; [M+6H]6+: 802.74;

[0813] [M+7H]7+: 688.21 (monoisotopic)

[0814] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 73)

[0815] Z1 : Chem 4d; Z2: C20 diacid

[0816] C-terminal segment 51

[0817] CSNPAWFVTEENRQVCANPEDKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0818] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0819] Molecular weight calculated for C213 H333 N53 O73 S2: 4868.36 g / mol (average), 4865.34 g / mol (monoisotopic)

[0820] LCMS34: found [M+3H]3+: 1622.75; [M+4H]4+: 1217.31 ; [M+5H]5+: 974.06 (monoisotopic)

[0821] Sequence (Y2): CSNPAVVFVTEENRQVCANPEDKWVREYINSLEKS (SEQ ID No. 107) Z1 : Chem 4a; Z2: C18 diacid C-terminal segment 52

[0822] CSNPAWFVTEENRQVCANPEEDWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0823] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0824] Molecular weight calculated for C212 H328 N52 O75 S2: 4869.31 g / mol (average), 4866.29 g / mol (monoisotopic)

[0825] LCMS34: found [M+2H]2+: 2434.06; [M+3H]3+: 1623.07; [M+4H]4+: 1217.55; [M+5H]5+: 974.25;

[0826] [M+6H]6+: 812.05 (monoisotopic)

[0827] Sequence (Y2): CSNPAWFVTEENRQVCANPEEDWVREYINSLEKS (SEQ ID No. 108)

[0828] Z1 : Chem 4a; Z2: C18 diacid

[0829] C-terminal segment 53

[0830] CSNPAVVFVTEENRQVCANPEEKWVREYIDSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0831] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid Molecular weight calculated for C214 H334 N52 O74 S2: 4883.38 g / mol (average), 4880.34 g / mol (monoisotopic)

[0832] LCMS34: found [M+3H]3+: 1627.75; [M+4H]4+: 1221.07; [M+5H]5+: 977.06; [M+6H]6+: 814.39 (monoisotopic)

[0833] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIDSLEKS (SEQ ID No. 109)

[0834] Z1 : Chem 4a; Z2: C18 diacid

[0835] C-terminal segment 54

[0836] CSNPAWFVTEENRQVCANPEEKWVREYIESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[0837] Molecular weight calculated for C212 H337 N51 071 S2: 4800.37 g / mol (average), 4797.38 g / mol (monoisotopic)

[0838] LCMS34: found [M+3H]3+: 1600.09; [M+4H]4+: 1200.33; [M+5H]5+: 960.46; [M+6H]6+: 800.56

[0839] (monoisotopic)

[0840] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYIESLEKS (SEQ ID No. 76)

[0841] Z1 : Chem 4d; Z2: C18 diacid

[0842] C-terminal segment 55

[0843] CSNPAWFVTEENRQVCANPEEKWVREYINSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino] ethylamino]-2-oxoethyl]-S-acid

[0844] Molecular weight calculated for C217 H340 N54 O74 S3: 4985.53 g / mol (average), 4982.37 g / mol (monoisotopic)

[0845] LCMS34: found [M+3H]3+: 1661.75; [M+4H]4+: 1246.58; [M+5H]5+: 997.47; [M+6H]6+: 831.40 (monoisotopic)

[0846] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLECS (SEQ ID No. 90)

[0847] Z1 : Chem 4c; Z2: C20 diacid

[0848] C-terminal segment 56

[0849] CSNPAVVFVTEENRQVCANPEEKWVREYINSLE-C[2-[2-[[(2S)-4-carboxy-2-[[(2S)-4- carboxy-2-[[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0850] ]ethylamino]-2-oxoethyl]-S-acid

[0851] Molecular weight calculated for C215 H336 N54 O74 S3: 4957.48 g / mol (average), 4954.34 g / mol (monoisotopic)

[0852] LCMS34: found [M+3H]3+: 1652.41 ; [M+4H]4+: 1239.57; [M+5H]5+: 991.86; [M+6H]6+: 826.72 (monoisotopic)

[0853] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLECS (SEQ ID No. 90)

[0854] Z1 : Chem 4g; Z2: C18 diacid

[0855] C-terminal segment 57 CSNPAVVFVTEENRQVCANPEEKWVREYINSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy- 4-(19- carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acety l]amino]ethylamino]-2-oxoethyl]-S-acid

[0856] Molecular weight calculated for C214 H341 N53 O71 S3: 4888.5 g / mol (average), 4885.39 g / mol (monoisotopic)

[0857] LCMS34: found [M+3H]3+: 1629.43; [M+4H]4+: 1222.32; [M+5H]5+: 978.07; [M+6H]6+: 815.23;

[0858] [M+7H]7+: 698.92 (monoisotopic)

[0859] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLECS (SEQ ID No. 90)

[0860] Z1 : Chem 4e; Z2: C20 diacid

[0861] C-terminal segment 58

[0862] Cys(StBu)-SNPAWFVTEENRQV-Cys(StBu)-ANPEEKVWREYINSLE-C[2-[2-[[2-[2-[2-[[2-[2-

[0863] [2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[0864] Molecular weight calculated for C220 H353 N53 O71 S5: 5036.79 g / mol (average), 5033.42 g / mol (monoisotopic)

[0865] LCMS34: found [M+3H]3+: 1678.82; [M+4H]4+: 1259.38; [M+5H]5+: 1007.70; [M+6H]6+: 839.91 (monoisotopic) Sequence (Y2): CSNPAVVFVTEENRQVCANPEEKWVREYINSLECS (SEQ ID No. 90)

[0866] Z1 : Chem 4e; Z2: C18 diacid

[0867] C-terminal segment 59

[0868] Cys(StBu)-SNPAVVFVTEENRQV-Cys(StBu)-ANPEEEWVREYINSLE-C[2-[2-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0869] ]ethylamino]-2-oxoethyl]-S-acid

[0870] Molecular weight calculated for C222 H347 N53 O76 S5: 5134.77 g / mol (average), 5131.35 g / mol (monoisotopic)

[0871] LCMS34: found [M+3H]3+: 1711.46; [M+4H]4+: 1283.85; [M+5H]5+: 1027.29 (monoisotopic)

[0872] Sequence (Y2): CSNPAVVFVTEENRQVCANPEEEWVREYINSLECS (SEQ ID No. 99)

[0873] Z1 : Chem 4c; Z2: C18 diacid

[0874] C-terminal segment 60

[0875] CSNPAWFVTDENRQVCANPEEKWVREYINSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0876] [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0877] Molecular weight calculated for C213 H333 N53 O73 S2: 4868.36 g / mol (average), 4865.34 g / mol (monoisotopic)

[0878] LCMS34: found [M+3H]3+: 1622.75; [M+4H]4+: 1217.32; [M+5H]5+: 974.06; [M+6H]6+: 811.90 (monoisotopic)

[0879] Sequence (Y2): CSNPAVVFVTDENRQVCANPEEKWVREYINSLEKS (SEQ ID No. 104)

[0880] Z1 : Chem 4a; Z2: C18 diacid

[0881] Molecular weight calculated for C353 H544 Ngs Ogy Se: 7905.08 g / mol (average), 7899.9 g / mol (monoisotopic)

[0882] LCMS34: found [M+5H]5+: 1581.00; [M+6H]6+: 1317.68; [M+7H]7+: 1129.58 (average)

[0883] Sequence:

[0884] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVRE YINSLEMS (SEQ ID No. 2) where X is PyroGlu. Protracted Reference compound (protracted 5P12 RANTES) pGlu-

[0885] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTRKNRQVCANPEKKWVREYI

[0886] NSLEMS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-acid

[0887] Molecular weight calculated for C394 H617 N a Ono Se: 8749.13 g / mol (average), 8743.42 g / mol (monoisotopic)

[0888] LCMS36: found [M+4H]4+: 2188.32; [M+5H]5+: 1750.64; [M+6H]6+: 1458.95; [M+7H]7+:

[0889] 1250.88; [M+8H]8+: 1094.66 (average)

[0890] Sequence:

[0891] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVRE YINSLEMSK (SEQ ID No. 111) where X is PyroGlu.

[0892] Compounds of the invention

[0893] Compound 1 pGlu-

[0894] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[0895] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0896] Molecular weight calculated for C390 H597 N99 O116 S5: 8688.83 g / mol (average), 8683.25 g / mol (monoisotopic)

[0897] LCMS34: found [M+5H]5+: 1737.64; [M+6H]6+: 1448.23 (monoisotopic)

[0898] Sequence:

[0899] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0900] YINSLEKS (SEQ ID No. 3) where X is PyroGlu.

[0901] Segment composition: N-terminal segment 1 - C-terminal segment 1

[0902] Compound 2 pGlu-

[0903] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[0904] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0905] (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[0906] ]ethylamino]-2-oxoethyl]-S-acid

[0907] Molecular weight calculated for C391 H598 N o Ony Se: 8763.92 g / mol (average), 8758.22 g / mol (monoisotopic)

[0908] LCMS36: found [M+5H]5+: 1752.66; [M+6H]6+: 1460.71 ; [M+7H]7+: 1252.19 (monoisotopic) Sequence:

[0909] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0910] YINSLECS (SEQ ID No. 4) where X is PyroGlu.

[0911] Segment composition: N-terminal segment 1 - C-terminal segment 2

[0912] Compound 3 pGlu-

[0913] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEDNRQVCANPEKKWVREYI

[0914] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0915] Molecular weight calculated for C389 H595 N99 O116 S5: 8674.81 g / mol (average), 8669.23 g / mol (monoisotopic)

[0916] LCMS34: found [M+4H]4+: 2168.38; [M+5H]5+: 1734.84; [M+6H]6+: 1445.90; [M+7H]7+: 1239.63 (monoisotopic) Sequence:

[0917] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEDNRQVCANPEKKWVRE

[0918] YINSLEKS (SEQ ID No. 5) where X is PyroGlu.

[0919] Segment composition: N-terminal segment 1 - C-terminal segment 3

[0920] Compound 4 pGlu-

[0921] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVREYI

[0922] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0923] Molecular weight calculated for C390 H596 N o On? S4: 8685.77 g / mol (average), 8680.26 g / mol (monoisotopic)

[0924] LCMS36: found [M+4H]4+: 2172.40; [M+5H]5+: 1738.10 (average)

[0925] Sequence:

[0926] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0927] YINSLEKS (SEQ ID No. 6) where X is PyroGlu.

[0928] Segment composition: N-terminal segment 2 - C-terminal segment 1

[0929] Compound 5 pGlu-

[0930] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTDENRQVCANPEKKWVREYI

[0931] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0932] Molecular weight calculated for C389 H595 N99 O116 S5: 8674.81 g / mol (average), 8669.23 g / mol (monoisotopic)

[0933] LCMS36: found [M+4H]4+: 2169.70; [M+5H]5+: 1735.90 (average)

[0934] Sequence:

[0935] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTDENRQVCANPEKKWVRE

[0936] YINSLEKS (SEQ ID No. 7) where X is PyroGlu. Segment composition: N-terminal segment 1 - C-terminal segment 4 pGlu-

[0937] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[0938] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[0939] (19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino] ethylamino]-2-oxoethyl]-S-acid

[0940] Molecular weight calculated for C393 H602 N100 On? Se: 8791.97 g / mol (average), 8786.26 g / mol (monoisotopic)

[0941] LCMS34: found [M+5H]5+: 1758.44; [M+6H]6+: 1465.41; [M+7H]7+: 1256.36 (monoisotopic)

[0942] Sequence:

[0943] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0944] YINSLECS (SEQ ID No. 4) where X is PyroGlu.

[0945] Segment composition: N-terminal segment 1 - C-terminal segment 14

[0946] Compound 7 pGlu-

[0947] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[0948] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0949] Molecular weight calculated for C389 H592 Ngs Ons Ss: 8689.77 g / mol (average), 8684.19 g / mol (monoisotopic)

[0950] LCMS36: found [M+4H]4+: 2172.07; [M+5H]5+: 1737.86; [M+6H]6+: 1448.38; [M+7H]7+:

[0951] 1241.60 (monoisotopic)

[0952] Sequence:

[0953] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[0954] YINSLEKS (SEQ ID No. 8) where X is PyroGlu.

[0955] Segment composition: N-terminal segment 1 - C-terminal segment 12

[0956] Compound 8 pGlu-

[0957] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[0958] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0959] Molecular weight calculated for C391 H598 N98 O117 S5: 8703.84 g / mol (average), 8698.25 g / mol (monoisotopic)

[0960] LCMS36: found [M+5H]5+: 1740.57; [M+6H]6+: 1450.64; [M+7H]7+: 1243.66 (monoisotopic) Sequence:

[0961] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0962] YIESLEKS (SEQ ID No. 9) where X is PyroGlu.

[0963] Segment composition: N-terminal segment 1 - C-terminal segment 13

[0964] Compound 9 pGlu-

[0965] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[0966] NELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0967] Molecular weight calculated for C392 H599 N99 O117 S5: 8730.87 g / mol (average), 8725.26 g / mol (monoisotopic)

[0968] LCMS34: found [M+4H]4+: 2182.37; [M+5H]5+: 1746.04; [M+6H]6+: 1455.23; [M+7H]7+:

[0969] 1247.64 (monoisotopic)

[0970] Sequence:

[0971] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[0972] YINELEKS (SEQ ID No. 10) where X is PyroGlu.

[0973] Segment composition: N-terminal segment 1 - C-terminal segment 9 pGlu- GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0974] Molecular weight calculated for C390 H593 N97 O119 S5: 8704.78 g / mol (average), 8699.19 g / mol (monoisotopic)

[0975] LCMS34: found [M+4H]4+: 2175.86; [M+5H]5+: 1740.83; [M+6H]6+: 1450.90; [M+7H]7+:

[0976] 1243.91 (monoisotopic)

[0977] Sequence:

[0978] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[0979] YIESLEKS (SEQ ID No. 11) where X is PyroGlu.

[0980] Segment composition: N-terminal segment 1 - C-terminal segment 10

[0981] Compound 11 pGlu-

[0982] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[0983] NELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0984] Molecular weight calculated for C391 H594 N98 O119 S5: 8731.81 g / mol (average), 8726.2 g / mol (monoisotopic)

[0985] LCMS34: found [M+5H]5+: 1746.43; [M+6H]6+: 1455.40; [M+7H]7+: 1247.77 (monoisotopic) Backbone sequence:

[0986] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[0987] YINELEKS (SEQ ID No. 12) where X is PyroGlu.

[0988] Segment composition: N-terminal segment 1 - C-terminal segment 11

[0989] Compound 12 pGlu-

[0990] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKEWVREYI

[0991] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[0992] Molecular weight calculated for C389 H592 Ngs Ons Ss: 8689.77 g / mol (average), 8684.19 g / mol (monoisotopic)

[0993] LCMS36: found [M+4H]4+: 2172.09; [M+5H]5+: 1737.87 (monoisotopic)

[0994] Backbone sequence:

[0995] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVRE

[0996] YINSLEKS (SEQ ID No. 13) where X is PyroGlu.

[0997] Segment composition: N-terminal segment 1 - C-terminal segment 7 pGlu- GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEEWVREYI NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[0998] Molecular weight calculated for C388 H587 N97 O120 S5: 8690.72 g / mol (average), 8685.14 g / mol (monoisotopic)

[0999] LCMS34: found [M+4H]4+: 2173.60; [M+5H]5+: 1739.10 (average)

[1000] Sequence:

[1001] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1002] YINSLEKS (SEQ ID No. 14) where X is PyroGlu.

[1003] Segment composition: N-terminal segment 1 - C-terminal segment 8

[1004] Compound 14 pGlu-

[1005] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1006] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1007] Molecular weight calculated for C388 H586 N98 O121 S4: 8687.65 g / mol (average), 8682.16 g / mol (monoisotopic)

[1008] LCMS34: found [M+4H]4+: 2171.60; [M+5H]5+: 1737.43; [M+6H]6+: 1448.06 (monoisotopic)

[1009] Sequence:

[1010] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE YINSLEKS (SEQ ID No. 15) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 8

[1011] Compound 15 pGlu-

[1012] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVREYI

[1013] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1014] Molecular weight calculated for C391 H597 N99 O118 S4: 8700.78 g / mol (average), 8695.26 g / mol (monoisotopic)

[1015] LCMS34: found [M+4H]4+: 2174.88; [M+5H]5+: 1740.04; [M+6H]6+: 1450.24 (monoisotopic)

[1016] Sequence:

[1017] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1018] YIESLEKS (SEQ ID No. 16) where X is PyroGlu.

[1019] Segment composition: N-terminal segment 2 - C-terminal segment 13 pGlu- GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENREVCANPEKKWVREYI NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1020] Molecular weight calculated for C390 H596 N98 O117 S5: 8689.82 g / mol (average), 8684.23 g / mol (monoisotopic)

[1021] LCMS34: found [M+4H]4+: 2172.14; [M+5H]5+: 1737.84; [M+6H]6+: 1448.40 (monoisotopic)

[1022] Sequence:

[1023] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEKKWVRE

[1024] YINSLEKS (SEQ ID No. 17) where X is PyroGlu.

[1025] Segment composition: N-terminal segment 1 - C-terminal segment 15

[1026] Compound 17 pGlu-

[1027] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEQKWVREY

[1028] INSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1029] Molecular weight calculated for C389 H593 N99 O117 S5: 8688.79 g / mol (average), 8683.21 g / mol (monoisotopic)

[1030] LCMS34: found [M+4H]4+: 2171.87; [M+5H]5+: 1737.64; [M+6H]6+: 1448.23 (monoisotopic)

[1031] Sequence:

[1032] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVRE YINSLEKS (SEQ ID No. 18) where X is PyroGlu. Segment composition: N-terminal segment 1 - C-terminal segment 17

[1033] Compound 18 pGlu-

[1034] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKQWVREY

[1035] INSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1036] Molecular weight calculated for C389 H593 N99 O117 S5: 8688.79 g / mol (average), 8683.21 g / mol (monoisotopic)

[1037] LCMS34: found [M+4H]4+: 2171.87; [M+5H]5+: 1737.64; [M+6H]6+: 1448.23 (monoisotopic)

[1038] Backbone sequence:

[1039] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKQWVRE

[1040] YINSLEKS (SEQ ID No. 19) where X is PyroGlu.

[1041] Segment composition: N-terminal segment 1 - C-terminal segment 18 pGlu- GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1042] Molecular weight calculated for C393 H6oo Ngs Ons Ss: 8745.88 g / mol (average), 8740.26 g / mol (monoisotopic)

[1043] LCMS34: found [M+4H]4+: 2186.12; [M+5H]5+: 1749.05; [M+6H]6+: 1457.73 (monoisotopic)

[1044] Backbone sequence:

[1045] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1046] YIEELEKS (SEQ ID No. 20) where X is PyroGlu.

[1047] Segment composition: N-terminal segment 1 - C-terminal segment 16

[1048] Compound 20 pGlu-

[1049] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[1050] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1051] Molecular weight calculated for C389 H594 N100 One S4: 8655.74 g / mol (average), 8650.25 g / mol (monoisotopic)

[1052] LCMS36: found [M+4H]4+: 2163.59; [M+5H]5+: 1731.06; [M+6H]6+: 1442.72; [M+7H]7+:

[1053] 1236.76 (monoisotopic) Backbone sequence:

[1054] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1055] YINSLEKS (SEQ ID No. 21) where X is PyroGlu.

[1056] Segment composition: N-terminal segment 3 - C-terminal segment 1

[1057] Compound 21 pGlu-

[1058] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVREYI

[1059] EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1060] Molecular weight calculated for C393 H599 N99 O119 S4: 8742.81 g / mol (average), 8737.27 g / mol (monoisotopic)

[1061] LCMS34: found [M+4H]4+: 2185.53; [M+5H]5+: 1748.63; [M+6H]6+: 1457.37 (monoisotopic)

[1062] Sequence:

[1063] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1064] YIEELEKS (SEQ ID No. 22) where X is PyroGlu.

[1065] Segment composition: N-terminal segment 2 - C-terminal segment 16 pGlu-

[1066] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1067] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1068] Molecular weight calculated for C389 H587 N97 O122 S4: 8702.66 g / mol (average), 8697.16 g / mol (monoisotopic)

[1069] LCMS34: found [M+4H]4+: 2175.50; [M+5H]5+: 1740.61 ; [M+6H]6+: 1460.68 (monoisotopic)

[1070] Sequence:

[1071] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1072] YIESLEKS (SEQ ID No. 23) where X is PyroGlu.

[1073] Segment composition: N-terminal segment 2 - C-terminal segment 19

[1074] Compound 23 pGlu-

[1075] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1076] NELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1077] Molecular weight calculated for C390 Hsss N98 O122 S4: 8729.69 g / mol (average), 8724.17 g / mol (monoisotopic)

[1078] LCMS34: found [M+4H]4+: 2182.26; [M+5H]5+: 1746.01 ; [M+6H]6+: 1455.01 (monoisotopic)

[1079] Backbone sequence:

[1080] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE YINELEKS (SEQ ID No. 24) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 20

[1081] Compound 24 pGlu-

[1082] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQEWVREYI

[1083] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1084] Molecular weight calculated for C388 Hss? N99 O120 S4: 8686.66 g / mol (average), 8681.18 g / mol (monoisotopic)

[1085] LCMS34: found [M+4H]4+: 2172.51 ; [M+5H]5+: 1737.42; [M+6H]6+: 1448.02 (monoisotopic)

[1086] Backbone sequence:

[1087] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQEWVRE

[1088] YINSLEKS (SEQ ID No. 25) where X is PyroGlu.

[1089] Segment composition: N-terminal segment 2 - C-terminal segment 21 pGlu-

[1090] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEQWVREYI

[1091] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1092] Molecular weight calculated for C388 H587 N99 O120 S4: 8686.66 g / mol (average), 8681.18 g / mol (monoisotopic)

[1093] LCMS34: found [M+4H]4+: 2171.52; [M+5H]5+: 1737.42; [M+6H]6+: 1448.02 (monoisotopic)

[1094] Sequence:

[1095] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEQWVRE

[1096] YINSLEKS (SEQ ID No. 26) where X is PyroGlu.

[1097] Segment composition: N-terminal segment 2 - C-terminal segment 22

[1098] Compound 26 pGlu-

[1099] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1100] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1101] Molecular weight calculated for C389 H591 N99 O119 S4: 8686.71 g / mol (average), 8681.21 g / mol (monoisotopic)

[1102] LCMS36: found [M+4H]4+: 2171.48; [M+5H]5+: 1737.21 ; [M+6H]6+: 1447.84 (monoisotopic)

[1103] Backbone sequence:

[1104] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YINSLEKS (SEQ ID No. 27) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 12

[1105] Compound 27 pGlu-

[1106] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVREYI

[1107] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1108] Molecular weight calculated for C389 H591 N99 O119 S4: 8686.71 g / mol (average), 8681.21 g / mol (monoisotopic)

[1109] LCMS36: found [M+4H]4+: 2171.52; [M+5H]5+: 1737.42; [M+6H]6+: 1448.02 (monoisotopic)

[1110] Sequence:

[1111] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVRE

[1112] YINSLEKS (SEQ ID No. 28) where X is PyroGlu.

[1113] Segment composition: N-terminal segment 2 - C-terminal segment 7 pGlu-

[1114] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVREYI

[1115] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1116] Molecular weight calculated for C390 H592 N98 O120 S4: 8701.72 g / mol (average), 8696.21 g / mol (monoisotopic)

[1117] LCMS36: found [M+4H]4+: 2175.27; [M+5H]5+: 1740.43; [M+6H]6+: 1450.35 (monoisotopic)

[1118] Sequence:

[1119] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVRE

[1120] YIESLEKS (SEQ ID No. 29) where X is PyroGlu.

[1121] Segment composition: N-terminal segment 2 - C-terminal segment 23

[1122] Compound 29 pGlu-

[1123] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVREYI

[1124] NELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1125] Molecular weight calculated for C391 H593 N99 O120 S4: 8728.74 g / mol (average), 8723.22 g / mol (monoisotopic)

[1126] LCMS36: found [M+4H]4+: 2182.01 ; [M+5H]5+: 1745.82; [M+6H]6+: 1454.86 (monoisotopic)

[1127] Sequence:

[1128] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVRE YINELEKS (SEQ ID No. 30) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 24

[1129] Compound 30 pGlu-

[1130] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1131] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[1132] (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1133] ]ethylamino]-2-oxoethyl]-S-acid

[1134] Molecular weight calculated for C390 H593 N99 O119 S6: 8764.86 g / mol (average), 8759.17 g / mol (monoisotopic)

[1135] LCMS36: found [M+4H]4+: 2191.00; [M+5H]5+: 1753.01 ; [M+6H]6+: 1461.01 ; [M+7H]7+:

[1136] 1252.29 (monoisotopic)

[1137] Sequence:

[1138] XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1139] YINSLECS (SEQ ID No. 31) where X is PyroGlu.

[1140] Segment composition: N-terminal segment 1 - C-terminal segment 30

[1141] Compound 31 pGlu-

[1142] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1143] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4- (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1144] ]ethylamino]-2-oxoethyl]-S-acid

[1145] Molecular weight calculated for C390 H592 N100 O120 S5: 8761.8 g / mol (average), 8756.19 g / mol (monoisotopic)

[1146] LCMS36: found [M+4H]4+: 2190.01 ; [M+5H]5+: 1752.22; [M+6H]6+: 1460.36 (monoisotopic)

[1147] Sequence:

[1148] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1149] YINSLECS (SEQ ID No. 32) where X is PyroGlu.

[1150] Segment composition: N-terminal segment 2 - C-terminal segment 30

[1151] Compound 32 pGlu-

[1152] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVREYI

[1153] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[1154] (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1155] ]ethylamino]-2-oxoethyl]-S-acid

[1156] Molecular weight calculated for C391 H597 N101 Ons Ss: 8760.85 g / mol (average), 8755.24 g / mol (monoisotopic)

[1157] LCMS36: found [M+5H]5+: 1752.02; [M+6H]6+: 1460.18; [M+7H]7+: 1251.87 (monoisotopic) Sequence:

[1158] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1159] YINSLECS (SEQ ID No. 33) where X is PyroGlu.

[1160] Segment composition: N-terminal segment 2 - C-terminal segment 2

[1161] Compound 33 pGlu-

[1162] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEKKWVREYI

[1163] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4- (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1164] ]ethylamino]-2-oxoethyl]-S-acid

[1165] Molecular weight calculated for C390 H595 N101 O117 S5: 8730.83 g / mol (average), 8725.23 g / mol (monoisotopic)

[1166] LCMS36: found [M+4H]4+: 2182.53; [M+5H]5+: 1746.23; [M+6H]6+: 1455.36; [M+7H]7+: 1247.59 (monoisotopic) Sequence:

[1167] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE YINSLECS (SEQ ID No. 34) where X is PyroGlu.

[1168] Segment composition: N-terminal segment 3 - C-terminal segment 2

[1169] Compound 34 pGlu-

[1170] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVREYI

[1171] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1172] Molecular weight calculated for C390 H593 N99 O119 S4: 8700.73 g / mol (average), 8695.23 g / mol (monoisotopic)

[1173] LCMS36: found [M+4H]4+: 2175.03; [M+5H]5+: 1740.22; [M+6H]6+: 1450.37; [M+7H]7+:

[1174] 1243.31 (monoisotopic)

[1175] Sequence:

[1176] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVRE

[1177] YIESLEKS (SEQ ID No. 35) where X is PyroGlu.

[1178] Segment composition: N-terminal segment 2 - C-terminal segment 28

[1179] Compound 35 pGlu-

[1180] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVREYI

[1181] EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1182] Molecular weight calculated for C392 H595 N99 O120 S4: 8742.77 g / mol (average), 8737.24 g / mol (monoisotopic)

[1183] LCMS36: found [M+4H]4+: 2185.53; [M+5H]5+: 1748.63; [M+6H]6+: 1457.36; [M+7H]7+:

[1184] 1249.31 (monoisotopic) Sequence:

[1185] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVRE

[1186] YIEELEKS (SEQ ID No. 36) where X is PyroGlu.

[1187] Segment composition: N-terminal segment 2 - C-terminal segment 29

[1188] Compound 36 pGlu-

[1189] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQQWVREY

[1190] INSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1191] Molecular weight calculated for C388 Hsss N100 O119 S4: 8685.68 g / mol (average), 8680.19 g / mol (monoisotopic)

[1192] LCMS36: found [M+4H]4+: 2171.27; [M+5H]5+: 1737.22; [M+6H]6+: 1447.86; [M+7H]7+:

[1193] 1241.16 (monoisotopic)

[1194] Sequence:

[1195] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQQWVRE YINSLEKS (SEQ ID No. 37) where X is PyroGlu.

[1196] Segment composition: N-terminal segment 2 - C-terminal segment 31

[1197] Compound 37 pGlu-

[1198] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1199] Molecular weight calculated for C390 H592 N98 O120 S4: 8701.72 g / mol (average), 8696.21 g / mol (monoisotopic)

[1200] LCMS34: found [M+4H]4+: 2175.33; [M+5H]5+: 1740.47; [M+6H]6+: 1450.55; [M+7H]7+:

[1201] 1243.47 (monoisotopic)

[1202] Sequence:

[1203] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1204] YIESLEKS (SEQ ID No. 38) where X is PyroGlu.

[1205] Segment composition: N-terminal segment 2 - C-terminal segment 10

[1206] Compound 38 pGlu-

[1207] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1208] EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1209] Molecular weight calculated for C392 H594 N98 O121 S4: 8743.75 g / mol (average), 8738.22 g / mol (monoisotopic)

[1210] LCMS36: found [M+4H]4+: 2185.78; [M+5H]5+: 1748.83; [M+6H]6+: 1457.53; [M+7H]7+: 1249.37 (monoisotopic) Sequence:

[1211] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1212] YIEELEKS (SEQ ID No. 39) where X is PyroGlu.

[1213] Segment composition: N-terminal segment 2 - C-terminal segment 25

[1214] Compound 39 pGlu-

[1215] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVREYI

[1216] EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1217] Molecular weight calculated for C392 H594 N98 O121 S4: 8743.75 g / mol (average), 8738.22 g / mol (monoisotopic)

[1218] LCMS36: found [M+4H]4+: 2185.78; [M+5H]5+: 1748.83; [M+6H]6+: 1457.53; [M+7H]7+:

[1219] 1249.31 (monoisotopic)

[1220] Sequence:

[1221] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKEWVRE

[1222] YIEELEKS (SEQ ID No. 40) where X is PyroGlu.

[1223] Segment composition: N-terminal segment 2 - C-terminal segment 26 pGlu-

[1224] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1225] EELE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1226] Molecular weight calculated for C391 H589 N97 O123 S4: 8744.7 g / mol (average), 8739.17 g / mol (monoisotopic)

[1227] LCMS36: found [M+4H]4+: 2186.01 ; [M+5H]5+: 1749.02; [M+6H]6+: 1457.68; [M+7H]7+:

[1228] 1249.44 (monoisotopic)

[1229] Sequence:

[1230] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1231] YIEELEKS (SEQ ID No. 41) where X is PyroGlu.

[1232] Segment composition: N-terminal segment 2 - C-terminal segment 27

[1233] Compound 41 pGlu-

[1234] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVREYI

[1235] NSLE-K[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4- carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1236] ]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]e thoxy]acetyl]-S-acid

[1237] Molecular weight calculated for C414 H64o N 4 O129 S4: 9266.39 g / mol (average), 9260.56 g / mol (monoisotopic) LCMS36: found [M+4H]4+: 2316.36; [M+5H]5+: 1853.29; [M+6H]6+: 1544.57; [M+7H]7+: 1324.07 (monoisotopic)

[1238] Sequence:

[1239] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEKKWVRE

[1240] YINSLEKS (SEQ ID No. 6) where X is PyroGlu.

[1241] Segment composition: N-terminal segment 2 - C-terminal segment 5

[1242] Compound 42 pGlu-

[1243] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1244] NSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1245] Molecular weight calculated for Cass H587 N97 O118 S4: 8590.62 g / mol (average), 8585.18 g / mol (monoisotopic)

[1246] LCMS34: found [M+4H]4+: 2147.57; [M+5H]5+: 1718.26; [M+6H]6+: 1432.04; [M+7H]7+: 1227.45 (monoisotopic)

[1247] Sequence:

[1248] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE YINSLEKS (SEQ ID No. 15) where X is PyroGlu.

[1249] Segment composition: N-terminal segment 2 - C-terminal segment 32

[1250] Compound 43 pGlu-

[1251] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEEEWVREYI

[1252] NSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1253] Molecular weight calculated for C385 H586 N96 O119 S4: 8591.6 g / mol (average), 8586.16 g / mol (monoisotopic)

[1254] LCMS34: found [M+4H]4+: 2147.82; [M+5H]5+: 1718.45; [M+6H]6+: 1432.20; [M+7H]7+:

[1255] 1227.60 (monoisotopic)

[1256] Sequence:

[1257] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEEEWVRE

[1258] YINSLEKS (SEQ ID No. 42) where X is PyroGlu.

[1259] Segment composition: N-terminal segment 2 - C-terminal segment 33

[1260] Compound 44 pGlu-

[1261] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEEKWVREYI

[1262] ESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1263] Molecular weight calculated for C387 H592 N96 O118 S4: 8605.67 g / mol (average), 8600.22 g / mol (monoisotopic)

[1264] LCMS34: found [M+4H]4+: 2151.30; [M+5H]5+: 1721.25; [M+6H]6+: 1434.54; [M+7H]7+: 1229.60 (monoisotopic) Sequence:

[1265] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEEKWVRE YIESLEKS (SEQ ID No. 43) where X is PyroGlu.

[1266] Segment composition: N-terminal segment 2 - C-terminal segment 34

[1267] Compound 45 pGlu-

[1268] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1269] ESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1270] Molecular weight calculated for C386 H588 N96 O119 S4: 8605.63 g / mol (average), 8600.18 g / mol (monoisotopic)

[1271] LCMS34: found [M+4H]4+: 2151.31 ; [M+5H]5+: 1721.25; [M+6H]6+: 1434.54; [M+7H]7+:

[1272] 1229.61 (monoisotopic)

[1273] Sequence:

[1274] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE YIESLEKS (SEQ ID No. 23) where X is PyroGlu.

[1275] Segment composition: N-terminal segment 2 - C-terminal segment 35

[1276] Compound 46 pGlu-

[1277] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1278] NELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1279] Molecular weight calculated for C387 H589 N97 O119 S4: 8632.66 g / mol (average), 8627.19 g / mol (monoisotopic)

[1280] LCMS34: found [M+4H]4+: 2158.07; [M+5H]5+: 1726.65; [M+6H]6+: 1439.05; [M+7H]7+:

[1281] 1233.47 (monoisotopic)

[1282] Sequence:

[1283] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1284] YINELEKS (SEQ ID No. 24) where X is PyroGlu.

[1285] Segment composition: N-terminal segment 2 - C-terminal segment 36

[1286] Compound 47 pGlu-

[1287] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1288] EELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1289] Molecular weight calculated for C389 H595 N97 O118 S4: 8646.73 g / mol (average), 8641.24 g / mol (monoisotopic)

[1290] LCMS34: found [M+4H]4+: 2161.59; [M+5H]5+: 1729.46; [M+6H]6+: 1441.38; [M+7H]7+: 1235.61 (monoisotopic) Sequence:

[1291] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YIEELEKS (SEQ ID No. 39) where X is PyroGlu.

[1292] Segment composition: N-terminal segment 2 - C-terminal segment 37

[1293] Compound 48 pGlu-

[1294] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEQKWVREY

[1295] I EELE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1296] Molecular weight calculated for C388 H594 N98 O116 S4: 8615.72 g / mol (average), 8610.25 g / mol (monoisotopic)

[1297] LCMS34: found [M+4H]4+: 2153.80; [M+5H]5+: 1723.25; [M+6H]6+: 1436.21 (monoisotopic)

[1298] Sequence:

[1299] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEQKWVRE YIEELEKS (SEQ ID No. 44) where X is PyroGlu.

[1300] Segment composition: N-terminal segment 3 - C-terminal segment 38

[1301] Compound 49 pGlu-

[1302] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEEWVREYI

[1303] NSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1304] Molecular weight calculated for C385 H586 Ngs Ons Ss: 8635.68 g / mol (average), 8630.15 g / mol (monoisotopic)

[1305] LCMS36: found [M+4H]4+: 2158.54; [M+5H]5+: 1727.04; [M+6H]6+: 1439.36; [M+7H]7+: 1233.88 (monoisotopic)

[1306] Sequence:

[1307] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1308] YINSLECS (SEQ ID No. 45) where X is PyroGlu.

[1309] Segment composition : N-terminal segment 3 - C-terminal segment 39

[1310] Compound 50 pGlu-

[1311] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1312] ESLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1313] Molecular weight calculated for C387 H592 N98 O117 S5: 8649.75 g / mol (average), 8644.2 g / mol (monoisotopic)

[1314] LCMS36: found [M+4H]4+: 2162.07; [M+5H]5+: 1729.85; [M+6H]6+: 1441.71 ; [M+7H]7+: 1235.90 (monoisotopic) Sequence:

[1315] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1316] YIESLECS (SEQ ID No. 46) where X is PyroGlu.

[1317] Segment composition : N-terminal segment 3 - C-terminal segment 42

[1318] Compound 51 pGlu-

[1319] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1320] ESLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1321] Molecular weight calculated for C389 H590 N98 O119 S4: 8671 .69 g / mol (average), 8666.2 g / mol (monoisotopic)

[1322] LCMS36: found [M+5H]5+: 1734.24; [M+6H]6+: 1445.37 (monoisotopic)

[1323] Sequence:

[1324] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1325] YIESLEKS (SEQ ID No. 47) where X is PyroGlu.

[1326] Segment composition: N-terminal segment 3 - C-terminal segment 10

[1327] Compound 52 pGlu-

[1328] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1329] ESLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4- (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1330] ]ethylamino]-2-oxoethyl]-S-acid

[1331] Molecular weight calculated for C390 H591 N99 O120 S5: 8746.78 g / mol (average), 8741.18 g / mol (monoisotopic)

[1332] LCMS36: found [M+4H]4+: 2186.30; [M+5H]5+: 1749.24; [M+6H]6+: 1457.87; [M+7H]7+:

[1333] 1249.88 (monoisotopic)

[1334] Sequence:

[1335] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1336] YIESLECS (SEQ ID No. 46) where X is PyroGlu.

[1337] Segment composition: N-terminal segment 3 - C-terminal segment 45

[1338] Compound 53 pGlu-

[1339] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENREVCANPEEKWVREYI

[1340] ESLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1341] Molecular weight calculated for C387 H591 N97 O118 S5: 8650.74 g / mol (average), 8645.18 g / mol (monoisotopic)

[1342] LCMS34: found [M+4H]4+: 2162.30; [M+5H]5+: 1730.05; [M+6H]6+: 1441.87; [M+7H]7+: 1236.03 (monoisotopic) Sequence:

[1343] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENREVCANPEEKWVRE

[1344] YIESLECS (SEQ ID No. 48) where X is PyroGlu.

[1345] Segment composition: N-terminal segment 3 - C-terminal segment 40

[1346] Compound 54 pGlu-

[1347] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVEEYI

[1348] NSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1349] Molecular weight calculated for C385 H586 Nge Ons Ss: 8607.67 g / mol (average), 8602.14 g / mol (monoisotopic)

[1350] LCMS34: found [M+5H]5+: 1721.43; [M+6H]6+: 1434.69 (monoisotopic)

[1351] Sequence:

[1352] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVEE

[1353] YINSLECS (SEQ ID No. 49) where X is PyroGlu.

[1354] Segment composition: N-terminal segment 4 - C-terminal segment 41 pGlu-

[1355] GPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1356] EELE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1357] Molecular weight calculated for C389 H594 Ngs Ons Ss: 8691.79 g / mol (average), 8686.21 g / mol (monoisotopic)

[1358] LCMS34: found [M+6H]6+: 1448.71 ; [M+7H]7+: 1241.89 (monoisotopic)

[1359] Sequence:

[1360] XGPPLQAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1361] YIEELECS (SEQ ID No. 50) where X is PyroGlu.

[1362] Segment composition: N-terminal segment 3 - C-terminal segment 43

[1363] Compound 56 pGlu-

[1364] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTDENRQVCANPEEKWVREYI

[1365] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1366] Molecular weight calculated for C388 H589 N99 O119 S4: 8672.68 g / mol (average), 8667.2 g / mol (monoisotopic)

[1367] LCMS36: found [M+5H]5+: 1734.40; [M+6H]6+: 1445.51 (monoisotopic)

[1368] Sequence:

[1369] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTDENRQVCANPEEKWVRE

[1370] YINSLEKS (SEQ ID No. 51) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 60

[1371] Compound 57 pGlu-

[1372] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEDNRQVCANPEEKWVREYI

[1373] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1374] Molecular weight calculated for C388 H589 N99 O119 S4: 8672.68 g / mol (average), 8667.2 g / mol (monoisotopic)

[1375] LCMS36: found [M+5H]5+: 1734.40; [M+6H]6+: 1445.51 (monoisotopic)

[1376] Sequence:

[1377] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEDNRQVCANPEEKWVRE

[1378] YINSLEKS (SEQ ID No. 52) where X is PyroGlu.

[1379] Segment composition: N-terminal segment 2 - C-terminal segment 46 pGlu-

[1380] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTDDNRQVCANPEEKWVREYI

[1381] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1382] Molecular weight calculated for C387 H587 N99 O119 S4: 8658.65 g / mol (average), 8653.18 g / mol (monoisotopic)

[1383] LCMS36: found [M+4H]4+: 2164.23; [M+5H]5+: 1731.60; [M+6H]6+: 1443.16; [M+7H]7+:

[1384] 1237.30 (monoisotopic)

[1385] Sequence:

[1386] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTDDNRQVCANPEEKWVRE

[1387] YINSLEKS (SEQ ID No. 53) where X is PyroGlu.

[1388] Segment composition: N-terminal segment 2 - C-terminal segment 47

[1389] Compound 59 pGlu-

[1390] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1391] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-acid

[1392] Molecular weight calculated for C391 H595 N99 O119 S4: 8714.76 g / mol (average), 8709.24 g / mol (monoisotopic)

[1393] LCMS36: found [M+5H]5+: 1742.80; [M+6H]6+: 1452.52; [M+7H]7+: 1245.30 (monoisotopic)

[1394] Sequence:

[1395] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YINSLEKS (SEQ ID No. 27) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 48

[1396] Molecular weight calculated for C389 H591 N99 O119 S4: 8686.71 g / mol (average), 8681.21 g / mol (monoisotopic)

[1397] LCMS36: found [M+5H]5+: 1737.21 ; [M+6H]6+: 1447.84 (monoisotopic)

[1398] Sequence:

[1399] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1400] YINSLEKS (SEQ ID No. 27) where X is PyroGlu.

[1401] Segment composition: N-terminal segment 2 - C-terminal segment 49 pGlu-

[1402] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1403] NSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1404] Molecular weight calculated for C386 H592 N98 O116 S4: 8589.68 g / mol (average), 8584.23 g / mol (monoisotopic)

[1405] LCMS36: found [M+5H]5+: 1717.81 ; [M+6H]6+: 1431.69 (monoisotopic)

[1406] Sequence:

[1407] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1408] YINSLEKS (SEQ ID No. 27) where X is PyroGlu.

[1409] Segment composition: N-terminal segment 2 - C-terminal segment 6

[1410] Compound 62 pGlu-

[1411] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1412] NSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acety

[1413] Molecular weight calculated for C388 H596 N98 O116 S4: 8617.73 g / mol (average), 8612.26 g / mol (monoisotopic)

[1414] LCMS36: found [M+4H]4+: 2154.00; [M+5H]5+: 1723.61 ; [M+6H]6+: 1436.35; [M+7H]7+:

[1415] 1231.45 (monoisotopic)

[1416] Sequence:

[1417] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1418] YINSLEKS (SEQ ID No. 27) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 50

[1419] Compound 63 pGlu-

[1420] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1421] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[1422] (19- carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino] ethylamino]-2-oxoethyl]-S-acid

[1423] Molecular weight calculated for C392 H596 N100 O120 S5: 8789.85 g / mol (average), 8784.22 g / mol (monoisotopic)

[1424] LCMS34: found [M+5H]5+: 1757.81 ; [M+6H]6+: 1465.01 (monoisotopic)

[1425] Sequence:

[1426] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1427] YINSLECS (SEQ ID No. 32) where X is PyroGlu.

[1428] Segment composition: N-terminal segment 2 - C-terminal segment 55

[1429] Compound 64 pGlu-

[1430] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1431] NSLE-C[2-[2-[[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2-[[(2S)-4-carboxy-2- (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1432] ]ethylamino]-2-oxoethyl]-S-acid

[1433] Molecular weight calculated for C390 H592 N100 O120 S5: 8761.8 g / mol (average), 8756.19 g / mol (monoisotopic)

[1434] LCMS34: found [M+5H]5+: 1752.19; [M+6H]6+: 1460.34 (monoisotopic)

[1435] Sequence:

[1436] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1437] YINSLECS (SEQ ID No. 32) where X is PyroGlu.

[1438] Segment composition: N-terminal segment 2 - C-terminal segment 56

[1439] Compound 65 pGlu-

[1440] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1441] NSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1442] Molecular weight calculated for C387 H593 N99 O117 S5: 8664.77 g / mol (average), 8659.21 g / mol (monoisotopic)

[1443] LCMS34: found [M+4H]4+: 2165.73; [M+5H]5+: 1732.79; [M+6H]6+: 1444.17; [M+7H]7+: 1238.02 (monoisotopic) Sequence:

[1444] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1445] YINSLECS (SEQ ID No. 32) where X is PyroGlu.

[1446] Segment composition: N-terminal segment 2 - C-terminal segment 58

[1447] Compound 66 pGlu-

[1448] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1449] NSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19- carboxynonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acety l]amino]ethylamino]-2-oxoethyl]-S-acid

[1450] Molecular weight calculated for C389 H597 N99 O117 S5: 8692.82 g / mol (average), 8687.24 g / mol (monoisotopic)

[1451] LCMS34: found [M+4H]4+: 2172.74; [M+5H]5+: 1738.42; [M+6H]6+: 1448.85 (monoisotopic)

[1452] Sequence:

[1453] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YINSLECS (SEQ ID No. 32) where X is PyroGlu.

[1454] Segment composition: N-terminal segment 2 - C-terminal segment 57

[1455] Compound 67 pGlu-

[1456] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEDKWVREYI

[1457] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S- acid

[1458] Molecular weight calculated for C388 H589 N99 O119 S4: 8672.68 g / mol (average), 8667.2 g / mol (monoisotopic)

[1459] LCMS34: found [M+4H]4+: 2167.73; [M+5H]5+: 1734.40; [M+6H]6+: 1445.51 (monoisotopic)

[1460] Sequence:

[1461] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEDKWVRE

[1462] YINSLEKS (SEQ ID No. 54) where X is PyroGlu.

[1463] Segment composition: N-terminal segment 2 - C-terminal segment 51

[1464] Compound 68 pGlu-

[1465] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEDWVREYI

[1466] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1467] Molecular weight calculated for C387 H584 N98 O121 S4: 8673.62 g / mol (average), 8668.14 g / mol (monoisotopic)

[1468] LCMS34: found [M+4H]4+: 2167.98; [M+5H]5+: 1734.60; [M+6H]6+: 1445.66 (monoisotopic)

[1469] Sequence:

[1470] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEDWVRE YINSLEKS (SEQ ID No. 55) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 52

[1471] Compound 69 pGlu-

[1472] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1473] DSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1474] Molecular weight calculated for C389 H590 N98 O120 S4: 8687.69 g / mol (average), 8682.2 g / mol (monoisotopic)

[1475] LCMS34: found [M+5H]5+: 1737.53; [M+6H]6+: 1448.10 (monoisotopic)

[1476] Sequence:

[1477] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1478] YIDSLEKS (SEQ ID No. 56) where X is PyroGlu.

[1479] Segment composition: N-terminal segment 2 - C-terminal segment 53 pGlu-

[1480] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1481] NSLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[1482] (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1483] ]ethylamino]-2-oxoethyl]-S-acid

[1484] Molecular weight calculated for C389 H587 N99 O122 S5: 8762.74 g / mol (average), 8757.14 g / mol (monoisotopic)

[1485] LCMS34: found [M+5H]5+: 1752.40; [M+6H]6+: 1460.49 (monoisotopic)

[1486] Sequence:

[1487] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE

[1488] YINSLECS (SEQ ID No. 57) where X is PyroGlu.

[1489] Segment composition: N-terminal segment 2 - C-terminal segment 59

[1490] Compound 71 pGlu-

[1491] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVREYI

[1492] NSLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1493] Molecular weight calculated for C386 Hsss N98 O119 S5: 8665.71 g / mol (average), 8660.16 g / mol (monoisotopic)

[1494] LCMS34: found [M+5H]5+: 1733.00; [M+6H]6+: 1444.33 (monoisotopic)

[1495] Sequence:

[1496] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEEWVRE YINSLECS (SEQ ID No. 57) where X is PyroGlu. Segment composition: N-terminal segment 2 - C-terminal segment 39

[1497] Compound 72 pGlu-

[1498] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1499] ESLE-C[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-

[1500] (17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]amino

[1501] ]ethylamino]-2-oxoethyl]-S-acid

[1502] Molecular weight calculated for C391 H593 N99 O121 S5: 8776.81 g / mol (average), 8771.19 g / mol (monoisotopic)

[1503] LCMS34: found [M+5H]5+: 1755.18; [M+6H]6+: 1462.93 (monoisotopic)

[1504] Sequence:

[1505] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YIESLECS (SEQ ID No. 58) where X is PyroGlu.

[1506] Segment composition: N-terminal segment 2 - C-terminal segment 45

[1507] Compound 73 pGlu-

[1508] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1509] ESLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1510] Molecular weight calculated for C387 H593 N97 O117 S4: 8604.69 g / mol (average), 8599.23 g / mol (monoisotopic)

[1511] LCMS34: found [M+5H]5+: 1720.94; [M+6H]6+: 1434.27 (monoisotopic)

[1512] Sequence:

[1513] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1514] YIESLEKS (SEQ ID No. 38) where X is PyroGlu.

[1515] Segment composition: N-terminal segment 2 - C-terminal segment 54

[1516] Compound 74 pGlu-

[1517] GPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1518] ESLE-C[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]amino]ethylamino]-2-oxoethyl]-S-acid

[1519] Molecular weight calculated for C388 H594 Ngs Ons Ss: 8679.78 g / mol (average), 8674.21 g / mol (monoisotopic)

[1520] LCMS34: found [M+5H]5+: 1735.93; [M+6H]6+: 1446.78 (monoisotopic)

[1521] Sequence:

[1522] XGPPLQATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE

[1523] YIESLECS (SEQ ID No. 58) where X is PyroGlu.

[1524] Segment composition: N-terminal segment 2 - C-terminal segment 44 Compound 75 pGlu-

[1525] GPPLMAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVREYI

[1526] NSLE-K[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-S-

[1527] Molecular weight calculated for C388 H590 N98 O117 S5: 8659.75 g / mol (average), 8654.18 g / mol (monoisotopic)

[1528] LCMS34: found [M+5H]5+: 1731.92; [M+6H]6+: 1443.43 (monoisotopic)

[1529] Sequence:

[1530] XGPPLMAAQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVRE

[1531] YINSLEKS (SEQ ID No. 59) where X is PyroGlu.

[1532] Segment composition: N-terminal segment 4 - C-terminal segment 12

[1533] Compound 76 pGlu-

[1534] GPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAWFVTEENRQVCANPEEKWVREYI

[1535] NSLE-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17- carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acet yl]-S-acid

[1536] Molecular weight calculated for C386 H593 N97 O115 S5: 8592.74 g / mol (average), 8587.21 g / mol (monoisotopic)

[1537] LCMS34: found [M+5H]5+: 1718.51 ; [M+6H]6+: 1432.26; [M+7H]7+: 1227.78 (monoisotopic) Sequence: XGPPLMATQSCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTEENRQVCANPEEKWVRE YINSLEKS (SEQ ID No. 8) where X is PyroGlu.

[1538] Segment composition: N-terminal segment 1 - C-terminal segment 6

[1539] Example 1 : Determination of CCR5 inhibition in a p-arrestin translocation assay

[1540] The purpose of this assay is to demonstrate and characterize to what degree the compounds of the invention provided inhibitory effect on the CCL5-induced activation of CCR5 as measured by translocation of p-arrestin to CCR5 in vitro. The assay was performed in comparison to a reference antibody for the purposes of comparing the inhibitory activity of the compounds of the invention to a standard. This reference antibody is commonly known under the name Leronlimab, or alternatively PRO 140, and is identified in further detail below.

[1541] Assay principle

[1542] When CCR5 is activated by binding relevant ligands, a conformational change of CCR5 is inducing interaction with various intracellular signalling molecules including p-arrestin. To assess the degree of p-arrestin translocation, reporter cells have been generated by stably transfecting HEK293 cells with an expression plasmid encoding human CCR5 fused to a fragment of the enzyme luciferase and co-transfected with an expression plasmid encoding human p-arrestin 1 fused to the complementary fragment of luciferase. Upon ligand-activation of these cells, p-arrestin is recruited to CCR5 and a functional luciferase enzyme is formed. Luciferase activity can be measured as luminescence generation after substrate addition. Thus, p-arrestin translocation as a proxy for CCR5 activity can be measured by luciferasegenerated luminescence. Inhibition of CCR5 activity can in turn be assessed by measuring the luminescence signal generated at a constant concentration of a CCR5 activating ligand and various concentrations of inhibitory test compounds. Full dose-response curves have been generated for the below compounds to evaluate their potency to inhibit the CCL5-induced activation of CCR5.

[1543] Reagents

[1544] Human CCL5 / RANTES:

[1545] °Hs - s

[1546] H2N YP Y S S D T T P-N' YN^-F AY I ARP L P RAH I KE Y F YT SG K N I-S N P A VV F VT RKN RQVN ^A-I

[1547] OHO i H o 1

[1548] V'

[1549] Backbone:

[1550] SPYSSDTTPCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVREYI

[1551] NSLEMS (SEQ ID No. 1)

[1552] Reference antibody Leronlimab / PRO 140:

[1553] Immunoglobulin G4, anti-(human Chemokine receptor CCR5) (humanized monoclonal PRO 140 y4-chain), disulfide with humanized monoclonal PRO 140 K-chain, dimer

[1554] Registry Number (CAS): 674782-26-4

[1555] Growth medium:

[1556] DMEM (Gibco #31966) + 1% Pen-Strep (Lonza #DE17-602E) + 10 % FBS (Gibco #10091- 148)

[1557] Assay medium:

[1558] DMEM + 1 % PenStrep + 1 % Human serum albumin (Sigma #A9511) + 0.01% Tween 20 (Roche #33766700)

[1559] Methods

[1560] An optimized density of reporter cells (20000 cells / well) were seeded in 25 pL growth medium per well in 384 well plates (Bio-Greiner#781080). The following day, the medium was exchanged by serial diluted compounds in 20 pl assay medium per well. Compounds were incubated with the cells for 30 minutes at 37°C before addition of CCL5 in 5 pL assay medium per well and an additional 30 minutes at 37°C incubation. 25 pL / well luciferase substrate, Steady-Gio (Promega #E2520), was added to all wells followed by luminescence measurement in an Envision plate reader (PerkinElmer).

[1561] The relationship between luminescence and concentration for each compound was fitted with a four-parameter logistic regression model using either GraphPad Prism or the Python package SciPy Optimize. The apparent potency of a compound was extracted from the fit as the value for the half-maximum inhibitory concentration, named IC50. IC50 relative to the IC50 of an anti-CCR5 antibody, Leronlimab, is reported providing a correction for potential experiment variation and a comparison to a CCR5 inhibitory standard. Results

[1562] The results are shown in Table 6 which summarises inhibitory potencies of the compounds of the invention in the presence of OVA and activity as determined by IC50 is reported as a ratio relative to Leronlimab in the same experiment. Therefore, a value of less than one implies that an analogue has superior inhibitory activity compared to Leronlimab under the experimental conditions.

[1563] Table 6. Inhibitory potency relative to Leronlimab in presence of OVA (value in fold)

[1564] For the purposes of reference, the brute IC50 value of Leronlimab was calculated to be: 2.07 nM (n = 18).

[1565] Analysis of the data showed that the analogues exhibit desirable inhibitory activity towards CCR5 in the presence of ovalbumin. It was demonstrated that the compounds of the invention were subject to a number of mutations in comparison to reference compound 5P12 providing increased inhibitory activity. In summary, Gin (Q) was tolerated in position 6 with respect to potency alongside substitutions in positions 45, 46 and 64 to Asp (D) or Glu (E). Additionally, positions 49, 60 and 65 tolerated substitution to Glu (E), whilst positions 56 and 57 could be substituted with Asp (D), Glu (E) and Gin (Q) without reducing efficacy relative to Leronlimab.

[1566] Substitution to Ala (A) in position 8 was demonstrated without detrimental effect on potency when combined with substitutions described above.

[1567] This set of examples demonstrated that a combination of the features summarised above results in compounds which enhance, or at the very least preserve, CCR5 inhibitory activity. The term preserve, in this case, preferably refers to losing no more than 22% of the CCR5 inhibitory activity of the reference antibody, Leronlimab. As is made clear in the application text above, it may be desirable to strike a balance such that the compounds provide a superior overall performance (potency, stability, and / n-vivo half-life) for use as therapeutic drug. Preserving the CCR5 inhibitory activity in comparison to the reference antibody, Leronlimab, is only one of the performance features taken into consideration.

[1568] Example 2: Assessment of Solubility and Self-Aggregation Behaviour Using Small Angle X-Ray Scattering (SAXS)

[1569] To acquire data on the structural behaviour of the compounds of the invention in solution, a high-throughput SAXS method was employed, as disclosed in J. Appl. Cryst. (2007). 40, s245-s249. SAXS measurements were performed on solutions containing approximately 2 mg / ml of a given compound of the invention and where low SAXS derived aggregation numbers were interpreted as predictive of high solubility and low molecular self-association or aggregation. A highly soluble analogue was considered attractive as high concentrations hereof were desirable to potentially provide for a drug product for once-weekly subcutaneous administration. Samples subjected to SAXS measurements contained the compounds of the invention dissolved in three neutral buffered phosphate solutions containing sodium chloride at 0 mM, 70 mM and 140 mM to emulate low, medium and high ionic strength charge conditions, respectively. SAXS derived aggregation numbers obtained at these conditions for selected analogues of the invention are presented in Table 7 below. Methods

[1570] Preparation of samples used for SAXS:

[1571] Stock solutions containing the compounds of the invention were prepared by dissolution of the API directly in the respective vehicle preparations representing the three charge conditions. After adjustment to pH 7.4 using hydrochloric acid or sodium hydroxide solutions, the protein concentration was measured by liquid chromatography against a predefined in-house standard. Dilution into samples containing 2 mg / ml of the respective analogue were performed and samples were transferred into 96 well plates for analysis.

[1572] SAXS data acquisition

[1573] SAXS experiments were performed at 20 °C using a BioXolver L (Xenocs) with a GeniX3D X-ray source (wavelength of created X-rays: A = 1.54 A) equipped with a motorized detector. The measurements were performed at a sample-detector distance of d = 590 mm (q- range = 0.01 A-1-0.54 A-1 where q = 4TT / A sin(0 / 2) is the length of the scattering vector and 0 is the scattering angle). Sample volumes of 20 pl as well as samples of the corresponding buffer were automatically loaded using the sample handling robot of the BioXolver. Six frames of 120s exposure times were collected and were averaged to yield curves depicting the scattering intensity l(q). Buffer curves were subsequently subtracted from the sample curves to yield the scattering intensity originating from the protein in the dilute solution. All data reduction was performed in the software RAW. To achieve SAXS scattering data descriptive of the structural behaviour of the compounds of the invention, the pair distance distribution function p(r) and the corresponding radius of gyration Rg and zero-angle scattering intensities l(0) were calculated using automated settings of the program GNOM available through the ATSAS package integrated in RAW. To obtain the aggregation number indicative of the level of self-association present in the sample, the SAXS derived molecular mass was divided by the formula mass (E. Mylonasa and D. I. Svergun, Accuracy of molecular mass determination of proteins in solution by small-angle X-ray scattering, J. Appi. Cryst., Volume 40, January 2007).

[1574] Results

[1575] Small-angle X-ray scattering (SAXS) is a useful technique for investigating the selfassociation or self-aggregation propensity of chemical analogues under various formulation conditions. Observation of higher aggregation states for a given analogue by SAXS, may provide indications of increased risk of instabilities under conventional aqueous formulation conditions. The SAXS derived aggregation number was determined for a variety of analogues of the invention at three formulation conditions deemed relevant for a medicinal product.

[1576] Table 7 below shows the average SAXS scattering data from three experimental formulations having 0 mM, 70 mM or 140 mM sodium chloride buffered with 10 mM sodium phosphate. All formulations have a compound concentration of 2 mg / mL. The SAXS scattering data provides an indication of the oligomeric state for each one of the compounds of the invention or of the reference compound. A lower SAXS number indicates a higher stability of the compound in the formulation. Table 7. SAXS derived aggregation numbers and average aggregation numbers for selected chemical analogues of 5P12 RANTES formulated at 2 mg / ml at conditions containing varying levels of sodium chloride.

[1577] N.D. The compound was inadequate for testing.

[1578] From the results shown in table 7, it can be seen that combining Asp (D) or Glu (E) substitutions in position 45 and 46 with at least one negative charge in the linker domain attached to position 68 surprisingly provided analogues with improved solubility at the relevant formulation conditions such that the self-aggregation propensity can be experimentally determined using SAXS. In addition, analogues with substitutions limited to Asp (D) or Glu (E) in positions 45 and 46 in combination with at least one negative charge in the linker domain attached to position 68 were found to exhibit reduced self-aggregation propensity in the presence of sodium chloride.

[1579] At these conditions, the native molecule of 5P12 RANTES (reference compound) was found not to be soluble to the extent that SAXS measurements could be performed. Likewise, it was shown that providing a protraction to the native 5P12 RANTES (reference compound), as was shown for the protracted 5P12 compound (protracted reference compound) also results in an insoluble structure inadequate for testing.

[1580] The compounds of the invention demonstrated a clear benefit compared to 5P12 RANTES (reference compound) and a protracted 5P12 RANTES (protracted reference compound), which both lacked stability in such a significant manner that data collection was not possible.

[1581] With respect to the previously mentioned modifications in example 1 , the results showed that additional mutations in the peptide backbone in combination with varied linker compositions resulted in analogues with reduced propensity to self-aggregate, such as to provide equivalent SAXS average aggregation numbers below 25, preferably below 20, even more preferably below 10.

[1582] In summary, the results showed that by combining sequence backbone substitutions and negative charge in the linker domain of the albumin binder resulted in analogues with increased solubility and reduced propensity to self-associate or aggregate in comparison to comparator compound 5P12 RANTES and hence improved stability properties for formulation conditions.

[1583] Example 3: Pharmacokinetic study in minipigs

[1584] To determine whether compounds of the invention had a pharmacokinetic profile (PK) with prolonged half-life (such as for the purposes of a once weekly dosing, for instance), selected analogues were administered and assessed in minipigs. Methods

[1585] Animals and test facilities:

[1586] Female Gottingen Minipigs from Ellegaard Minipigs A / S (Dalmose, Denmark) were used for the studies. Upon arrival at the test facility the minipigs had an age of approximately 7 to 9 months. The minipigs were individually housed in a 12hr light cycle and had wood shavings and straw as bedding materials. Altromin 9033 (Brogaarden, Denmark) was offered twice daily, and the animals had free access to domestic quality drinking water. There were no food restrictions during the studies.

[1587] After 3 to 4 weeks of acclimatisation, the minipigs had central venous catheter implanted for blood sampling and i.v. dosing. Silicone catheters (Lifecath, size 6.6 french, 90 cm, Cat. No. 2191.667, Vygon, France) were implanted under general anaesthesia using the seidinger technique and with the tip ending in the caudal caval vein. Two catheters were implanted in each pig.

[1588] During the same anaesthesia used for placement of catheters, the minipigs were examined by ultrasound. An area of 2x2 cm with no underlying muscle mid neck, between ear and scapula, suitable for subcutaneous (s.c.) injection was identified and marked by tattoo.

[1589] Dosing

[1590] S.c. administration was given in the tattooed area on the neck. A 25G needle with a stopper attached, which only allowing 0.5 cm of the needle to be inserted in the skin, was used. The needle was kept in the skin for 10 sec after dosing.

[1591] I.v. administration was done as a bolus injection using one of the central venous catheters. After the injection the catheter was flushed with 10 mL of sterile saline.

[1592] The minipigs were weighed on the day before dosing and the body weights were used for calculation the individual dose volume. Normally the body weights were in the range of 20- 25 kg.

[1593] Blood sampling

[1594] After administration of the CCR5i analogues blood samples of approximately 1.3 mL were obtained from the venous catheters for up to 312 hours post dose for PK evaluation in plasma. Blood was collected in 1.3 mL tubes containing K3EDTA to yield 1.6 mg KsEDTA / mL blood (EDTA Microtubes, Cat. No. 41.1504.005, Sarstedt, Germany), and after each blood sample the catheter was flushed with at least 5 mL of sterile saline. Blood samples were kept on ice for maximum 30 min, before centrifugated at 10 min, 4°C, 2000xg. Plasma samples were stored frozen at approximately -20°C until analysis.

[1595] Pharmacokinetic analysis

[1596] The plasma concentrations values from the bioanalysis were imported as Excel® format with three significant digits into Phoenix® WinNonlin® version 8.1 (Certara L.P. Princeton, NJ, USA) for PK evaluation.

[1597] Individual PK profiles of plasma concentration versus time were evaluated by noncompartmental analysis (NCA).

[1598] The area under the plasma concentration-time curves (AUG) were calculated using the “Linear Up Log Down” method. The terminal elimination phase was fitted via linear regression with uniform weighting. Actual doses were used for calculations.

[1599] Nominal sampling times were used for the NCA calculations. For s.c. administration, the time point for pre-dose samples were set to zero (Ohr) for NCA. Pre-dose time points were excluded from NCA after i.v. administration.

[1600] Pharmacokinetics analysis of animal plasma samples by luminescent oxygen channelling assay (LOCI)

[1601] Animal plasma samples were pre-diluted 50-fold or higher in PBS-T (phosphate- buffered saline, 0.05% polysorbate 20, pH 7.4). 5 pl diluted sample was mixed with 0.5 pg acceptor beads (LOCI latex beads conjugated with a protractor-specific monoclonal antibody) and 11 ng biotinylated hCCL5-specific polyclonal antibody (Invitrogen, cat. no. P230E) in 15 pl LOCI assay buffer (25 mM HEPES, 50 mM NaCI, 10 mM K-EDTA, 2 mg / ml dextran, 0.5% bovine serum albumin, 0.1 % bovine gamma globulin, 0.1 % polysorbate 20, 0.01 % ProCiin™ 300, 0.01% gentamycin, 0.2 mg / ml HBR 1 (Heterophilic Blocking Reagent 1), 0.3 mM Glu-Glu- eicosanedioic acid, pH 7.4).

[1602] After incubating for 1 hour at room temperature, 2 pg streptavidin-conjugated donor beads in 30 pl LOCI assay buffer were mixed in, followed by an additional 30 min incubation at room temperature in the dark.

[1603] Luminescence was recorded on a 210x series Envision Multilabel Reader using 680 nm excitation and a 615 nm low-pass emission filter.

[1604] Analyte concentrations were back-calculated according to the included calibrator series (the analyte serially diluted in PBS-T) and adjusted according to the effective sample pre-dilution. Results

[1605] Results of pharmacokinetic studies in minipigs are summarised in Table 8 below, where column T1 / 2 shows the circulating half-life. A high circulating half-life value is desirable. Table 8. Summary of pharmacokinetic data for selected compounds of the invention

[1606] The results show that the combination of various sequence substitutions and the protraction at position 68 with the C18 or C20 diacids results in significant improvement to circulating half-life T1 / 2. Yet, it is clear from the circulating half-life of the protracted 5P12 compound (protracted reference compound), shown in table above, that providing only the protraction moiety without the described backbone modifications did not permit achieving superior pharmacokinetic properties.

[1607] A long half-life indicates that the given analogue was capable of providing its inhibitory effect multiple times after dosing in comparison with an analogue having a relatively shorter half-life. Longer half-life permits less frequent dosing when in use, which is desirable to provide an increased convenience for the patients that may, for instance, need to inject themselves. The longer half-life indicates that such a compound would require administration at a lesser frequency.

Claims

CLAIMS1. A CCR5 antagonist comprising a polypeptide comprising a maximum of 9 amino acid modifications relative to the sequence of SEQ ID No. 2 and wherein said polypeptide comprises a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 45; a Glutamic acid (Glu, E) or an Aspartic Acid (Asp, D) at position 46; and a Cysteine (Cys, C) or a Lysine (Lys, K) at position 68, wherein a protraction moiety is ligated to the amino acid at position 68.

2. The CCR5 antagonist according to claim 1 , comprising a polypeptide according to Formula I (SEQ ID No. 60):Xaa1-Gly-Pro-Pro-Leu-Xaa6-Ala-Xaa8-Gln-Ser-Cys-Cys-Phe-Ala-Tyr-lle-Ala-Arg- Pro-Leu-Pro-Arg-Ala-His-lle-Lys-Glu-Tyr-Phe-Tyr-Thr-Ser-Gly-Lys-Cys-Ser-Asn- Pro-Ala-Val-Val-Phe-Val-Thr-Xaa45-Xaa46-Asn-Arg-Xaa49-Val-Cys-Ala-Asn-Pro- Glu-Xaa56-Xaa57-Trp-Val-Xaa60-Glu-Tyr-lle-Xaa64-Xaa65-Leu-Glu-Xaa68-Ser, whereinXaa1 is Pyroglutamic Acid (Pyr),Xaa6 is Met (M) or Gin (Q),Xaa8 is Thr (T) or Ala (A),Xaa45 is Asp (D) or Glu (E),Xaa46 is Asp (D) or Glu (E),Xaa49 is Glu (E) or Gin (Q),Xaa56 is Asp (D), Glu (E), Lys (K) or Gin (Q),Xaa57 is Asp (D), Glu (E), Lys (K) or Gin (Q),Xaa60 is Arg (R) or Glu (E),Xaa64 is Asn (N), Glu (E) or Asp (D),Xaa65 is Ser (S) or Glu (E), and Xaa68 is Lys (K) or Cys (C).

3. The CCR5 antagonist according to any one of the preceding claims, wherein said protraction moiety comprises a fatty acid and a linker comprising a negative charge, wherein said negative charge is selected from Glutamate (Glu) or y-Glutamate (gGlu).

4. The CCR5 antagonist according to any one of the preceding claims, wherein the polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID No. 3-59.

5. The CCR5 antagonist according to claim 4, wherein the polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID No. 4, 6, 8, 13, 15, 27, 31, 32, 34, 46, and 47.

6. The CCR5 antagonist according to any one of the preceding claims, wherein the polypeptide comprises a Glutamic acid (Glu, E) at position 56.

7. The CCR5 antagonist according to any one of the preceding claims, wherein the fatty acid is a C18 diacid or a C20 diacid.

8. The CCR5 antagonist according to any one of the preceding claims, wherein the linker comprises no more than 8 constituents selected from a group consisting of a Glutamate (Glu), a y-Glutamate (gGlu), an Ado group, an ethylenediamine (C2DA) group and an acetamide (Ac) group.

9. The CCR5 antagonist according to claim 8, wherein the linker is selected from a group consisting of(Chem. 4a);(Chem. 4f); and(Chem 4g).

10. A CCR5 antagonist comprising a compound selected from the group consisting of:(Compound 6);(Compound 15);(Compound 27);(Compound 34);(Compound 47).

11. A CCR5 antagonist comprising the compound of(Compound 31).

12. A pharmaceutical composition comprising a CCR5 antagonist according to any one of the preceding claims and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is suitable for parenteral administration such as subcutaneous administration.

14. The CCR5 antagonist according to any one of claims 1-11 or the pharmaceutical composition according to claim 12 or 13 for use as a medicament.

15. The CCR5 antagonist according to any one of claims 1-11 or the pharmaceutical composition according to claim 12 or 13 for use in the prevention, treatment and / or alleviation of inflammation of the liver tissue associated with non-alcoholic steatohepatitis (NASH), such as F3 and / or F4 NASH.

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