WO2023084236A1 - Nouvelle utilisation - Google Patents

Nouvelle utilisation Download PDF

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Publication number
WO2023084236A1
WO2023084236A1 PCT/GB2022/052867 GB2022052867W WO2023084236A1 WO 2023084236 A1 WO2023084236 A1 WO 2023084236A1 GB 2022052867 W GB2022052867 W GB 2022052867W WO 2023084236 A1 WO2023084236 A1 WO 2023084236A1
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seq
referred
iii
navlc
kfl
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PCT/GB2022/052867
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English (en)
Inventor
Paul Beswick
Liuhong CHEN
Yuliya DEMYDCHUK
Maximilian HARMAN
Nicholas Keen
Michael Skynner
Katerine VAN RIETSCHOTEN
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Bicycletx Limited
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Publication of WO2023084236A1 publication Critical patent/WO2023084236A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold.
  • the invention describes peptides which are high affinity binders of ACE2.
  • the invention also includes pharmaceutical compositions comprising said polypeptides and to the use of said polypeptides in suppressing or treating a disease or disorder mediated by ACE2, such as infection of COVID-19 or for providing prophylaxis to a subject at risk of infection of COVID-19.
  • Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • the disease was first identified in December 2019 in Wuhan, the capital of China's Hubei province, and spread globally, resulting in a pandemic.
  • Common symptoms include fever, cough, and shortness of breath.
  • Other symptoms may include fatigue, muscle pain, diarrhea, sore throat, loss of smell, and abdominal pain.
  • the time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days. While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure. As of 6 January 2021, more than 86 million cases have been reported globally, resulting in more than 1.8 million deaths.
  • the virus is primarily spread between people during close contact, often via droplets produced by coughing, sneezing, or talking.
  • a peptide ligand specific for ACE2 comprising a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold for use in the prophylaxis or treatment of an inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • a pharmaceutical composition which comprises the peptide ligand as defined herein, in combination with one or more pharmaceutically acceptable excipients, for use in the prophylaxis or treatment of an inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • a peptide ligand specific for ACE2 comprising a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold for use in the prophylaxis or treatment of an inflammatory bowel disease (IBD).
  • ACE2 refers to angiotensin-converting enzyme 2 which is an enzyme attached to the outer surface (cell membranes) of cells in the lungs, arteries, heart, kidney, and intestines.
  • the inflammatory bowel disease (IBD) is colitis.
  • the inflammatory bowel disease (IBD) is ulcerative colitis.
  • ACE2 inhibitors may have therapeutic utility for inflammatory bowel disease.
  • said loop sequences comprise 4, 5, 6 or 8 amino acids.
  • said loop sequences comprise 4, 6 or 8 amino acids.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids. In a further embodiment, said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i HKFPC ii RDPQQYLFC iii (SEQ ID NO: 1); C i TSPMC ii YVLKHQNRC iii (SEQ ID NO: 2); C i TRPWC ii HSLLPRATC iii (SEQ ID NO: 3); C i GRQFC ii HTLMPRHLC iii (SEQ ID NO: 4); C i VRSHC ii SSLLPRIHC iii (SEQ ID NO: 5); C i APILC ii RWAERQGYC iii (SEQ
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i HKFPC ii RDPQQYLFC iii (SEQ ID NO: 1); C i TSPMC ii YVLKHQNRC iii (SEQ ID NO: 2); C i TRPWC ii HSLLPRATC iii (SEQ ID NO: 3); C i GRQFC ii HTLMPRHLC iii (SEQ ID NO: 4); C i VRSHC ii SSLLPRIHC iii (SEQ ID NO: 5); C i APILC ii RWAERQGYC iii (SEQ ID NO: 9); C i NAVLC ii SWARANSFC iii (SEQ ID NO: 10); C i NAVLC
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i HKFPC ii RDPQQYLFC iii (SEQ ID NO: 1); C i TSPMC ii YVLKHQNRC iii (SEQ ID NO: 2); C i TRPWC ii HSLLPRATC iii (SEQ ID NO: 3); C i GRQFC ii HTLMPRHLC iii (SEQ ID NO: 4); and C i VRSHC ii SSLLPRIHC iii (SEQ ID NO: 5); wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 1)-A (herein referred to as BCY15296); A-(SEQ ID NO: 2)-A (herein referred to as BCY15295); A-(SEQ ID NO: 3)-A (herein referred to as BCY15293); A-(SEQ ID NO: 4)-A (herein referred to as BCY15292); A-(SEQ ID NO: 5)-A (herein referred to as BCY15291); A-(SEQ ID NO: 9)-A (herein referred to as BCY15425); A-(SEQ ID NO: 10)-A (herein referred to as BCY15429); A-(SEQ ID NO:
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 1)-A (herein referred to as BCY15296); A-(SEQ ID NO: 2)-A (herein referred to as BCY15295); A-(SEQ ID NO: 3)-A (herein referred to as BCY15293); A-(SEQ ID NO: 4)-A (herein referred to as BCY15292); A-(SEQ ID NO: 5)-A (herein referred to as BCY15291); A-(SEQ ID NO: 9)-A (herein referred to as BCY15425); and A-(SEQ ID NO: 10)-A (herein referred to as BCY15429).
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 1)-A (herein referred to as BCY15296); A-(SEQ ID NO: 2)-A (herein referred to as BCY15295); A-(SEQ ID NO: 3)-A (herein referred to as BCY15293); A-(SEQ ID NO: 4)-A (herein referred to as BCY15292); and A-(SEQ ID NO: 5)-A (herein referred to as BCY15291).
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl)
  • a labelling moiety such as fluorescein (Fl)
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 4 amino acids and the other of which consists of 8 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl)
  • a labelling moiety such as fluorescein (Fl)
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids. In a further embodiment, said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i LELYQC ii WRGKC iii (SEQ ID NO: 15); C i PSQYKC ii WRGKC iii (SEQ ID NO: 16); C i LEVYKC ii WRGKC iii (SEQ ID NO: 17); C i AEIYKC ii WRGRC iii (SEQ ID NO: 59); C i DTLYKC ii WRGRC iii (SEQ ID NO: 60); C i ESLYKC ii WRGRC iii (SEQ ID NO: 61); C
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i LELYQC ii WRGKC iii (SEQ ID NO: 15); C i PSQYKC ii WRGKC iii (SEQ ID NO: 16); and C i LEVYKC ii WRGKC iii (SEQ ID NO: 17); wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 15)-A (herein referred to as BCY15426); A-(SEQ ID NO: 16)-A (herein referred to as BCY15427); A-(SEQ ID NO: 17)-A (herein referred to as BCY15428); A-(SEQ ID NO: 59)-A (herein referred to as BCY17152); A-(SEQ ID NO: 60)-A (herein referred to as BCY17153); A-(SEQ ID NO: 61)-A (herein referred to as BCY17154); A-(SEQ ID NO: 62)-A (herein referred to as BCY17155
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 15)-A (herein referred to as BCY15426); A-(SEQ ID NO: 16)-A (herein referred to as BCY15427); and A-(SEQ ID NO: 17)-A (herein referred to as BCY15428).
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl)
  • a labelling moiety such as fluorescein (Fl)
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 8 amino acids.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 8 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is: C i AN[Aib]VLC ii SWARANSFC iii (SEQ ID NO: 18); wherein C i , C ii and C ii represent first, second and third cysteine residues, respectively, Aib represents aminoisobutyric acid, or a pharmaceutically acceptable salt thereof.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 5 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl)
  • a labelling moiety such as fluorescein (Fl)
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 6 amino acids and the other of which consists of 4 amino acids.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 6 amino acids and the other of which consists of 4 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is selected from: C i GREELPC ii RIKLC iii (SEQ ID NO: 6); and C i LRSYNLC ii PRINC iii (SEQ ID NO: 7); wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 6 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is selected from: A-(SEQ ID NO: 6)-A (herein referred to as BCY15298); and A-(SEQ ID NO: 7)-A (herein referred to as BCY15294).
  • said loop sequences comprise three reactive groups separated by two loop sequences one of which consists of 6 amino acids and the other of which consists of 4 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl)
  • a labelling moiety such as fluorescein (Fl)
  • said loop sequences comprise three reactive groups separated by two loop sequences both of which consist of 6 amino acids.
  • said loop sequences comprise three reactive groups separated by two loop sequences both of which consist of 6 amino acids and the bicyclic peptide ligand comprises an amino acid sequence which is: C i HRDFPRC ii TWETQWC iii (SEQ ID NO: 8); wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.
  • said loop sequences comprise three reactive groups separated by two loop sequences both of which consist of 6 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide ligand additionally comprises N- and/or C-terminal additions and comprises an amino acid sequence which is: A-(SEQ ID NO: 8)-A (herein referred to as BCY15297).
  • said loop sequences comprise three reactive groups separated by two loop sequences both of which consist of 6 amino acids
  • the molecular scaffold is TATA
  • the bicyclic peptide additionally comprises N- and/or C-terminal additions and a labelling moiety, such as fluorescein (Fl), and comprises an amino acid sequence which is: A-(SEQ ID NO: 8)-A-[Sar 6 ]-[KFl] (herein referred to as BCY15289).
  • Fl fluorescein
  • BCY15289 a labelling moiety
  • the bicyclic peptide of the invention binds to the active site of ACE2.
  • the bicyclic peptide of the invention binds to an epitope of ACE2 which is other than the active site.
  • the bicyclic peptide of the invention binds to and inhibits ACE2.
  • ACE2 inhibitors include BCY15291, BCY15292, BCY15293, BCY15294, BCY15295, BCY15296, BCY15297 and BCY15298, such as BCY15291, BCY15292, BCY15293, BCY15294, BCY15295, BCY15296, and BCY15297.
  • all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art, such as in the arts of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry.
  • cysteine residues (C i , C ii and C iii ) are omitted from the numbering as they are invariant, therefore, the numbering of amino acid residues within peptides of the invention is referred to as below: C i -H 1 -K 2 -F 3 -P 4 -C ii -R 5 -D 6 -P 7 -Q 8 -Q 9 -Y 10 -L 11 -F 12 -C iii (SEQ ID NO: 1).
  • peptide sequences disclosed herein would also find utility in their retro-inverso form.
  • the sequence is reversed (i.e. N-terminus becomes C-terminus and vice versa) and their stereochemistry is likewise also reversed (i.e. D-amino acids become L-amino acids and vice versa).
  • Peptide Ligands A peptide ligand, as referred to herein, refers to a peptide covalently bound to a molecular scaffold. Typically, such peptides comprise two or more reactive groups (i.e.
  • the peptides comprise at least three cysteine residues (referred to herein as C i , C ii and C iii ), and form at least two loops on the scaffold.
  • Certain ligands demonstrate cross-reactivity across Lipid II from different bacterial species and hence are able to treat infections caused by multiple species of bacteria.
  • Other ligands may be highly specific for the Lipid II of certain bacterial species which may be advantageous for treating an infection without collateral damage to the beneficial flora of the patient; - Protease stability.
  • Bicyclic peptide ligands should ideally demonstrate stability to plasma proteases, epithelial ("membrane-anchored") proteases, gastric and intestinal proteases, lung surface proteases, intracellular proteases and the like. Protease stability should be maintained between different species such that a bicycle lead candidate can be developed in animal models as well as administered with confidence to humans; - Desirable solubility profile.
  • salt forms are within the scope of this invention, and references to peptide ligands include the salt forms of said ligands.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • D-glucuronic D-glucuronic
  • glutamic e.g. L-glutamic
  • ⁇ -oxoglutaric glycolic, hippuric
  • hydrohalic acids e.g. hydrobromic, hydrochloric, hydriodic
  • isethionic lactic (e.g.
  • salts consist of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, sulfuric, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • One particular salt is the hydrochloride salt.
  • Another particular salt is the acetate salt.
  • a salt may be formed with an organic or inorganic base, generating a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Li + , Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ or Zn + .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH3)4 + .
  • peptides of the invention contain an amine function
  • these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person.
  • Such quaternary ammonium compounds are within the scope of the peptides of the invention.
  • Modified Derivatives It will be appreciated that modified derivatives of the peptide ligands as defined herein are within the scope of the present invention.
  • suitable modified derivatives include one or more modifications selected from: N-terminal and/or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (such as replacement of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues; replacement of one or more amino acid residues with an alanine, replacement of one or more L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds within the bicyclic peptide ligand; replacement of one or more peptide bonds with a surrogate bond; peptide backbone length modification; substitution of the hydrogen on the alpha-carbon of one or more amino acid residues with
  • the modified derivative comprises an N-terminal and/or C-terminal modification.
  • the modified derivative comprises an N- terminal modification using suitable amino-reactive chemistry, and/or C-terminal modification using suitable carboxy-reactive chemistry.
  • said N-terminal or C- terminal modification comprises addition of an effector group, including but not limited to a cytotoxic agent, a radiochelator or a chromophore.
  • the modified derivative comprises an N-terminal modification.
  • the N-terminal modification comprises an N-terminal acetyl group.
  • the N-terminal cysteine group (the group referred to herein as C i ) is capped with acetic anhydride or other appropriate reagents during peptide synthesis leading to a molecule which is N-terminally acetylated.
  • C i the group referred to herein as C i
  • the N-terminal modification comprises the addition of a molecular spacer group which facilitates the conjugation of effector groups and retention of potency of the bicyclic peptide to its target.
  • the modified derivative comprises a C-terminal modification.
  • the C-terminal modification comprises an amide group.
  • the C-terminal cysteine group (the group referred to herein as C iii ) is synthesized as an amide during peptide synthesis leading to a molecule which is C-terminally amidated.
  • C iii the C-terminal cysteine group
  • the modified derivative comprises replacement of one or more amino acid residues with one or more non-natural amino acid residues.
  • non-natural amino acids may be selected having isosteric/isoelectronic side chains which are neither recognised by degradative proteases nor have any adverse effect upon target potency.
  • non-natural amino acids may be used having constrained amino acid side chains, such that proteolytic hydrolysis of the nearby peptide bond is conformationally and sterically impeded.
  • these concern proline analogues, bulky sidechains, C ⁇ - disubstituted derivatives (for example, aminoisobutyric acid, Aib), and cyclo amino acids, a simple derivative being amino-cyclopropylcarboxylic acid.
  • the modified derivative comprises the addition of a spacer group.
  • the modified derivative comprises the addition of a spacer group to the N-terminal cysteine (C i ) and/or the C-terminal cysteine (C iii ).
  • the modified derivative comprises replacement of one or more oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues. In one embodiment, the modified derivative comprises replacement of one or more charged amino acid residues with one or more hydrophobic amino acid residues. In an alternative embodiment, the modified derivative comprises replacement of one or more hydrophobic amino acid residues with one or more charged amino acid residues.
  • the correct balance of charged versus hydrophobic amino acid residues is an important characteristic of the bicyclic peptide ligands. For example, hydrophobic amino acid residues influence the degree of plasma protein binding and thus the concentration of the free available fraction in plasma, while charged amino acid residues (in particular arginine) may influence the interaction of the peptide with the phospholipid membranes on cell surfaces.
  • the modified derivative comprises replacement of one or more L-amino acid residues with one or more D-amino acid residues. This embodiment is believed to increase proteolytic stability by steric hindrance and by a propensity of D-amino acids to stabilise ⁇ -turn conformations (Tugyi et al (2005) PNAS, 102(2), 413–418).
  • the modified derivative comprises removal of any amino acid residues and substitution with alanines.
  • This embodiment provides the advantage of removing potential proteolytic attack site(s).
  • each of the above mentioned modifications serve to deliberately improve the potency or stability of the peptide.
  • Further potency improvements based on modifications may be achieved through the following mechanisms: - Incorporating hydrophobic moieties that exploit the hydrophobic effect and lead to lower off rates, such that higher affinities are achieved; - Incorporating charged groups that exploit long-range ionic interactions, leading to faster on rates and to higher affinities (see for example Schreiber et al, Rapid, electrostatically assisted association of proteins (1996), Nature Struct.
  • the present invention includes all pharmaceutically acceptable (radio)isotope-labeled peptide ligands of the invention, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and peptide ligands of the invention, wherein metal chelating groups are attached (termed “effector”) that are capable of holding relevant (radio)isotopes, and peptide ligands of the invention, wherein certain functional groups are covalently replaced with relevant (radio)isotopes or isotopically labelled functional groups.
  • isotopes suitable for inclusion in the peptide ligands of the invention comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I, 125 I and 131 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, sulfur, such as 35 S, copper, such as 64 Cu, gallium, such as 67 Ga or 68 Ga, yttrium, such as 90 Y and lutetium, such as 177 Lu, and Bismuth, such as 213 Bi.
  • hydrogen such as 2 H (D) and 3 H (T)
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 Cl
  • fluorine such as 18 F
  • iodine such as 123 I, 125 I and 131 I
  • nitrogen such as
  • Certain isotopically-labelled peptide ligands of the invention are useful in drug and/or substrate tissue distribution studies.
  • the peptide ligands of the invention can further have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H (D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of peptide ligands of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Molecular Scaffold Molecular scaffolds are described in, for example, WO 2009/098450 and references cited therein, particularly WO 2004/077062 and WO 2006/078161.
  • the molecular scaffold may be a small molecule, such as a small organic molecule.
  • the molecular scaffold may be a macromolecule.
  • the molecular scaffold is a macromolecule composed of amino acids, nucleotides or carbohydrates.
  • the molecular scaffold comprises reactive groups that are capable of reacting with functional group(s) of the polypeptide to form covalent bonds.
  • the molecular scaffold may comprise chemical groups which form the linkage with a peptide, such as amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, azides, anhydrides, succinimides, maleimides, alkyl halides and acyl halides.
  • the molecular scaffold of the invention contains chemical groups that allow functional groups of the polypeptide of the encoded library of the invention to form covalent links with the molecular scaffold.
  • Said chemical groups are selected from a wide range of functionalities including amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, anhydrides, succinimides, maleimides, azides, alkyl halides and acyl halides.
  • Scaffold reactive groups that could be used on the molecular scaffold to react with thiol groups of cysteines are alkyl halides (or also named halogenoalkanes or haloalkanes).
  • scaffold reactive groups that are used to selectively couple compounds to cysteines in proteins are maleimides, ⁇ ⁇ unsaturated carbonyl containing compounds and ⁇ -halomethylcarbonyl containing compounds.
  • maleimides which may be used as molecular scaffolds in the invention include: tris-(2-maleimidoethyl)amine, tris-(2-maleimidoethyl)benzene, tris- (maleimido)benzene.
  • the molecular scaffold is 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en- 1-one (also known as triacryloylhex TATA.
  • the molecular scaffold forms a tri-substituted 1 ,1',1"-(1 ,3,5-triazinane-1 ,3,5- triyl)tripropan-1-one derivative of TATA having the following structure: wherein * denotes the point of attachment of the three cysteine residues.
  • the molecular scaffold of the invention may be bonded to the polypeptide via functional or reactive groups on the polypeptide. These are typically formed from the side chains of particular amino acids found in the polypeptide polymer. Such reactive groups may be a cysteine side chain, a [Dap(Me)] group, a lysine side chain, or an N-terminal amine group or any other suitable reactive group. Details may be found in WO 2009/098450. In one embodiment, the reactive groups are all cysteine residues.
  • reactive groups of natural amino acids are the thiol group of cysteine, the amino group of lysine, the carboxyl group of aspartate or glutamate, the guanidinium group of arginine, the phenolic group of tyrosine or the hydroxyl group of serine.
  • Non-natural amino acids can provide a wide range of reactive groups including an azide, a keto-carbonyl, an alkyne, a vinyl, or an aryl halide group.
  • the amino and carboxyl group of the termini of the polypeptide can also serve as reactive groups to form covalent bonds to a molecular scaffold/molecular core.
  • polypeptides of the invention contain at least three reactive groups. Said polypeptides can also contain four or more reactive groups. The more reactive groups are used, the more loops can be formed in the molecular scaffold.
  • polypeptides with three reactive groups are generated. Reaction of said polypeptides with a molecular scaffold/molecular core having a three-fold rotational symmetry generates a single product isomer.
  • the generation of a single product isomer is favourable for several reasons.
  • the nucleic acids of the compound libraries encode only the primary sequences of the polypeptide but not the isomeric state of the molecules that are formed upon reaction of the polypeptide with the molecular core. If only one product isomer can be formed, the assignment of the nucleic acid to the product isomer is clearly defined. If multiple product isomers are formed, the nucleic acid cannot give information about the nature of the product isomer that was isolated in a screening or selection process.
  • a single product isomer is also advantageous if a specific member of a library of the invention is synthesized.
  • the chemical reaction of the polypeptide with the molecular scaffold yields a single product isomer rather than a mixture of isomers.
  • polypeptides with four reactive groups are generated. Reaction of said polypeptides with a molecular scaffold/molecular core having a tetrahedral symmetry generates two product isomers.
  • the isomeric nature of the isolated isomer can be determined by chemically synthesizing both isomers, separating the two isomers and testing both isomers for binding to a target ligand.
  • at least one of the reactive groups of the polypeptides is orthogonal to the remaining reactive groups.
  • the use of orthogonal reactive groups allows the directing of said orthogonal reactive groups to specific sites of the molecular core. Linking strategies involving orthogonal reactive groups may be used to limit the number of product isomers formed.
  • the reactive groups of the polypeptide of the invention are reacted with molecular linkers wherein said linkers are capable to react with a molecular scaffold so that the linker will intervene between the molecular scaffold and the polypeptide in the final bonded state.
  • amino acids of the members of the libraries or sets of polypeptides can be replaced by any natural or non-natural amino acid.
  • exchangeable amino acids Excluded from these exchangeable amino acids are the ones harbouring functional groups for cross-linking the polypeptides to a molecular core, such that the loop sequences alone are exchangeable.
  • the exchangeable polypeptide sequences have either random sequences, constant sequences or sequences with random and constant amino acids.
  • the amino acids with reactive groups are either located in defined positions within the polypeptide, since the position of these amino acids determines loop size.
  • an polypeptide with three reactive groups has the sequence (X) l Y(X) m Y(X) n Y(X) o , wherein Y represents an amino acid with a reactive group, X represents a random amino acid, m and n are numbers between 3 and 6 defining the length of intervening polypeptide segments, which may be the same or different, and l and o are numbers between 0 and 20 defining the length of flanking polypeptide segments.
  • Alternatives to thiol-mediated conjugations can be used to attach the molecular scaffold to the peptide via covalent interactions.
  • these techniques may be used in modification or attachment of further moieties (such as small molecules of interest which are distinct from the molecular scaffold) to the polypeptide after they have been selected or isolated according to the present invention – in this embodiment then clearly the attachment need not be covalent and may embrace non-covalent attachment.
  • These methods may be used instead of (or in combination with) the thiol mediated methods by producing phage that display proteins and peptides bearing unnatural amino acids with the requisite chemical reactive groups, in combination small molecules that bear the complementary reactive group, or by incorporating the unnatural amino acids into a chemically or recombinantly synthesised polypeptide when the molecule is being made after the selection/isolation phase.
  • the peptides of the present invention may be manufactured synthetically by standard techniques followed by reaction with a molecular scaffold in vitro. When this is performed, standard chemistry may be used. This enables the rapid large scale preparation of soluble material for further downstream experiments or validation. Such methods could be accomplished using conventional chemistry such as that disclosed in Timmerman et al. (supra).
  • the invention also relates to manufacture of polypeptides selected as set out herein, wherein the manufacture comprises optional further steps as explained below. In one embodiment, these steps are carried out on the end product polypeptide made by chemical synthesis.
  • Peptides can also be extended, to incorporate for example another loop and therefore introduce multiple specificities.
  • To extend the peptide it may simply be extended chemically at its N-terminus or C-terminus or within the loops using orthogonally protected lysines (and analogues) using standard solid phase or solution phase chemistry.
  • Standard (bio)conjugation techniques may be used to introduce an activated or activatable N- or C-terminus.
  • additions may be made by fragment condensation or native chemical ligation e.g. as described in (Dawson et al.1994. Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779), or by enzymes, for example using subtiligase as described in (Chang et al.
  • the peptides may be extended or modified by further conjugation through disulphide bonds. This has the additional advantage of allowing the first and second peptide to dissociate from each other once within the reducing environment of the cell.
  • the molecular scaffold e.g.
  • TATA TATA
  • a further cysteine or thiol could then be appended to the N or C-terminus of the first peptide, so that this cysteine or thiol only reacted with a free cysteine or thiol of the second peptide, forming a disulfide –linked bicyclic peptide- peptide conjugate.
  • Similar techniques apply equally to the synthesis/coupling of two bicyclic and bispecific macrocycles, potentially creating a tetraspecific molecule.
  • compositions comprising a peptide ligand as defined herein in combination with one or more pharmaceutically acceptable excipients for use in the prophylaxis or treatment of an inflammatory bowel disease (IBD), such as colitis, in particular ulcerative colitis.
  • IBD inflammatory bowel disease
  • the present peptide ligands will be utilised in purified form together with pharmacologically appropriate excipients or carriers.
  • these excipients or carriers include aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and/or buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride and lactated Ringer's.
  • Suitable physiologically- acceptable adjuvants if necessary to keep a polypeptide complex in suspension, may be chosen from thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates.
  • Intravenous vehicles include fluid and nutrient replenishers and electrolyte replenishers, such as those based on Ringer's dextrose.
  • Preservatives and other additives such as antimicrobials, antioxidants, chelating agents and inert gases, may also be present (Mack (1982) Remington's Pharmaceutical Sciences, 16th Edition).
  • the compounds of the invention can be used alone or in combination with another agent or agents.
  • the compounds of the invention can also be used in combination with biological therapies such as nucleic acid based therapies, antibodies, bacteriophage or phage lysins.
  • the route of administration of pharmaceutical compositions according to the invention may be any of those commonly known to those of ordinary skill in the art.
  • the peptide ligands of the invention can be administered to any patient in accordance with standard techniques.
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular
  • the pharmaceutical compositions according to the invention will be administered parenterally.
  • the dosage and frequency of administration will depend on the age, sex and condition of the patient, concurrent administration of other drugs, counterindications and other parameters to be taken into account by the clinician.
  • the peptide ligands of this invention can be lyophilised for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective and art-known lyophilisation and reconstitution techniques can be employed. It will be appreciated by those skilled in the art that lyophilisation and reconstitution can lead to varying degrees of activity loss and that levels may have to be adjusted upward to compensate.
  • the compositions containing the present peptide ligands or a cocktail thereof can be administered for therapeutic treatments.
  • an adequate amount to accomplish at least partial inhibition, suppression, modulation, killing, or some other measurable parameter, of a population of selected cells is defined as a "therapeutically- effective dose”. Amounts needed to achieve this dosage will depend upon the severity of the disease and the general state of the patient's own immune system, but generally range from 10 ⁇ g to 250 mg of selected peptide ligand per kilogram of body weight, with doses of between 100 ⁇ g to 25 mg/kg/dose being more commonly used.
  • a composition containing a peptide ligand according to the present invention may be utilised in therapeutic settings to treat a microbial infection or to provide prophylaxis to a subject at risk of infection e.g. undergoing surgery, chemotherapy, artificial ventilation or other condition or planned intervention.
  • the peptide ligands described herein may be used extracorporeally or in vitro selectively to kill, deplete or otherwise effectively remove a target cell population from a heterogeneous collection of cells.
  • Blood from a mammal may be combined extracorporeally with the selected peptide ligands whereby the undesired cells are killed or otherwise removed from the blood for return to the mammal in accordance with standard techniques.
  • Therapeutic Uses The bicyclic peptides of the invention have specific utility as ACE2 binding agents.
  • the present invention relates solely to the use of the enclosed peptide ligands as prophylactic or therapeutic agents for the prophylaxis or treatment of an inflammatory bowel disease (IBD), such as colitis, in particular ulcerative colitis.
  • IBD inflammatory bowel disease
  • a method of treating inflammatory bowel disease (IBD), such as colitis, in particular ulcerative colitis which comprises administering to a patient in need thereof the peptide ligand as defined herein.
  • Polypeptide ligands selected according to the method of the present invention may be employed in in vivo therapeutic applications, in vitro and in vivo diagnostic applications, in vitro assay and reagent applications, and the like.
  • the ability to elicit an immune response to predetermined ranges of antigens can be exploited to tailor a vaccine to specific diseases and pathogens.
  • Substantially pure peptide ligands of at least 90 to 95% homogeneity are preferred for administration to a mammal, and 98 to 99% or more homogeneity is most preferred for pharmaceutical uses, especially when the mammal is a human.
  • the selected polypeptides may be used diagnostically or therapeutically (including extracorporeally) or in developing and performing assay procedures, immunofluorescent stainings and the like (Lefkovite and Pernis, (1979 and 1981) Immunological Methods, Volumes I and II, Academic Press, NY).
  • References herein to the term “suppression” refers to administration of the composition after an inductive event, but prior to the clinical appearance of the disease.
  • Treatment involves administration of the protective composition after disease symptoms become manifest. Animal model systems which can be used to screen the effectiveness of the peptide ligands in protecting against or treating the disease are available. The invention is further described below with reference to the following examples.
  • Peptide Synthesis was based on Fmoc chemistry, using a Symphony peptide synthesiser manufactured by Peptide Instruments and a Syro II synthesiser by MultiSynTech. Standard Fmoc-amino acids were employed (Sigma, Merck), with appropriate side chain protecting groups: where applicable standard coupling conditions were used in each case, followed by deprotection using standard methodology. Alternatively, peptides were purified using HPLC and following isolation they were modified with the required molecular scaffold (namely, TATA).
  • linear peptide was diluted with 50:50 MeCN:H 2 O up to ⁇ 35 mL, ⁇ 500 ⁇ L of 100 mM scaffold in acetonitrile was added, and the reaction was initiated with 5 mL of 1 M NH 4 HCO 3 inH 2 O. The reaction was allowed to proceed for ⁇ 30 -60 min at RT, and lyophilised once the reaction had completed (judged by MALDI). Once completed, 1ml of 1M L-cysteine hydrochloride monohydrate (Sigma) in H 2 O was added to the reaction for ⁇ 60 min at RT to quench any excess TATA.
  • 1M L-cysteine hydrochloride monohydrate Sigma
  • the modified peptide was purified as above, while replacing the Luna C8 with a Gemini C18 column (Phenomenex), and changing the acid to 0.1% trifluoroacetic acid. Pure fractions containing the correct scaffold-modified material were pooled, lyophilised and kept at -20oC for storage. All amino acids, unless noted otherwise, were used in the L- configurations.
  • peptides are converted to activated disulfides prior to coupling with the free thiol group of a toxin using the following method; a solution of 4-methyl(succinimidyl 4-(2- pyridylthio)pentanoate) (100mM) in dry DMSO (1.25 mol equiv) was added to a solution of peptide (20mM) in dry DMSO (1 mol equiv). The reaction was well mixed and DIPEA (20 mol equiv) was added. The reaction was monitored by LC/MS until complete. BIOLOGICAL DATA 1.
  • the carboxymethyl dextran surface was activated with a 7 min injection of a 1:1 ratio of 0.4 M 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC) / 0.1 M N-hydroxy succinimide (NHS) at a flow rate of 10 ⁇ l/min.
  • EDC 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride
  • NHS N-hydroxy succinimide
  • ACE2 protein was diluted to 40 nM in 10 mM sodium acetate (pH 4.5) and captured by injecting 16 ⁇ l at a flow rate of 5 ⁇ l/min onto the activated chip surface in pulses. Residual activated groups were blocked with a 7 min injection of 1 M ethanolamine (pH 8.5) and ACE2 captured to a level of approximately 970 RU.
  • Table 1 SPR Binding Assay Results for Selected Bicyclic Peptides of the Invention +4 Reaction 2. Enzymatic Activity Inhibition Inhibition studies were performed using an assay buffer of 50 mM HEPES, 150 mM NaCl, 1 ⁇ M ZnCl 2 , 0.015 % Triton X-100 and 2.5 % dimethylsulfoxide in a black walled 384-well assay plate (Corning - 3575).
  • Dnp (2,4-dinitrophenyl) is no longer able to quench the fluorescence of Mca (7- methoxycoumarin-4-yl) which was observed via a 320400 FI optic module on a Pherastar FS/FSX (BMG Labtech).
  • the initial rates of substrate cleavage were determined for each bicyclic peptide titration point over a 75 minute timecourse with 91 second cycle intervals. These were normalised to low (substrate only) and high (ACE2 with substrate) references and fit via non-linear regression analysis using the following model: log(inhibitor) vs.

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Abstract

La présente invention concerne des polypeptides qui sont liés de manière covalente à des échafaudages moléculaires de telle sorte qu'au moins deux boucles peptidiques sont sous-tendues entre des points de fixation à l'échafaudage. En particulier, l'invention concerne des peptides qui sont des liants à haute affinité de ACE2. L'invention concerne également des compositions pharmaceutiques comprenant lesdits polypeptides et l'utilisation desdits polypeptides pour supprimer ou traiter une maladie ou d'un trouble à médiation par ACE2, telle qu'une infection par la COVID-19 ou pour fournir une prophylaxie à un sujet présentant un risque d'infection par la COVID-19.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004077062A2 (fr) 2003-02-27 2004-09-10 Pepscan Systems B.V. Procede pour selectionner un compose medicamenteux d’interet potentiel
WO2006078161A1 (fr) 2005-01-24 2006-07-27 Pepscan Systems B.V. Composes liants, composes immunogenes et composes peptidomimetiques
WO2008031014A1 (fr) * 2006-09-08 2008-03-13 Ore Pharmaceuticals Inc. Procédé pour réduire ou soulager une inflammation dans le tube digestif
WO2009098450A2 (fr) 2008-02-05 2009-08-13 Medical Research Council Procédés et compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004077062A2 (fr) 2003-02-27 2004-09-10 Pepscan Systems B.V. Procede pour selectionner un compose medicamenteux d’interet potentiel
WO2006078161A1 (fr) 2005-01-24 2006-07-27 Pepscan Systems B.V. Composes liants, composes immunogenes et composes peptidomimetiques
WO2008031014A1 (fr) * 2006-09-08 2008-03-13 Ore Pharmaceuticals Inc. Procédé pour réduire ou soulager une inflammation dans le tube digestif
WO2009098450A2 (fr) 2008-02-05 2009-08-13 Medical Research Council Procédés et compositions

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Salts: Properties, Selection, and Use", August 2002, pages: 388
AUSUBEL ET AL.: "Short Protocols in Molecular Biology", 1999, JOHN WILEY & SONS, INC
BYRNES ET AL., INFLAMM. RES., vol. 58, no. 11, 2009, pages 819 - 27
CHANG ET AL., PROC NATL ACAD SCI USA., vol. 91, no. 26, 20 December 1994 (1994-12-20), pages 12544 - 8
DAWSON ET AL.: "Synthesis of Proteins by Native Chemical Ligation", SCIENCE, vol. 266, 1994, pages 776 - 779, XP002064666, DOI: 10.1126/science.7973629
GENTILUCCI ET AL., CURR. PHARMACEUTICAL DESIGN, vol. 16, 2010, pages 3185 - 203
HEINIS ET AL., NAT CHEM BIOL, vol. 5, no. 7, 2009, pages 502 - 7
HIKARI ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, 15 November 2008 (2008-11-15), pages 6000 - 6003
JOHN J BYRNES ET AL: "Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice", INFLAMMATION RESEARCH ; OFFICIAL JOURNAL OF: THE INTERNATIONAL ASSOCIATION OF INFLAMMATION SOCIETIES THE EUROPEAN HISTAMINE RESEARCH SOCIETY, BIRKHÄUSER-VERLAG, BA, vol. 58, no. 11, 11 June 2009 (2009-06-11), pages 819 - 827, XP019751758, ISSN: 1420-908X, DOI: 10.1007/S00011-009-0053-3 *
KAYCIE DEYLE ET AL: "Phage Selection of Cyclic Peptides for Application in Research and Drug Development", ACCOUNTS OF CHEMICAL RESEARCH, vol. 50, no. 8, 18 July 2017 (2017-07-18), US, pages 1866 - 1874, XP055562233, ISSN: 0001-4842, DOI: 10.1021/acs.accounts.7b00184 *
LEFKOVITEPERNIS: "Immunological Methods", vol. 1, 2, 1979, ACADEMIC PRESS
MACK: "Remington's Pharmaceutical Sciences", 1982
NAIR ET AL., J IMMUNOL, vol. 170, no. 3, 2003, pages 1362 - 1373
NESTOR ET AL., CURR. MEDICINAL CHEM, vol. 16, 2009, pages 4399 - 418
PENNINGER JOSEF M ET AL: "The Role of Angiotensin Converting Enzyme 2 in Modulating Gut Microbiota, Intestinal Inflammation, and Coronavirus Infection", GASTROENTEROLOGY, ELSEVIER INC, US, vol. 160, no. 1, 30 October 2020 (2020-10-30), pages 39 - 46, XP086415016, ISSN: 0016-5085, [retrieved on 20201030], DOI: 10.1053/J.GASTRO.2020.07.067 *
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS
SCHREIBER ET AL.: "Rapid, electrostatically assisted association of proteins", NATURE STRUCT. BIOL., vol. 3, 1996, pages 427 - 31
TUGYI ET AL., PNAS, vol. 102, no. 2, 2005, pages 413 - 418

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