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Alpha Helical Mimics, Their Uses and Methods for Their (19) TZZ_¥_T (11) EP 1 737 884 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 7/50 (2006.01) A61K 38/12 (2006.01) 19.10.2016 Bulletin 2016/42 A61P 35/00 (2006.01) A61P 25/00 (2006.01) A61P 25/08 (2006.01) A61P 25/32 (2006.01) (21) Application number: 05714272.1 (86) International application number: (22) Date of filing: 21.03.2005 PCT/AU2005/000400 (87) International publication number: WO 2005/090388 (29.09.2005 Gazette 2005/39) (54) ALPHA HELICAL MIMICS, THEIR USES AND METHODS FOR THEIR PRODUCTION ALPHA-HELIX-MIMETIKA, DEREN ANWENDUNGEN UND VERFAHREN ZU DEREN HERSTELLUNG ALPHA-MIMETIQUES HELICOIDALES, LEURS UTILISATIONS ET LEURS PROCEDES DE PRODUCTION (84) Designated Contracting States: • CONDON ET AL: "The Bioactive Conformation of AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Human Parathyroid Hormone. Structural HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR Evidence for the Extended Helix Postulate" J.AM.CHEM.SOC., vol. 122, 2000, pages (30) Priority: 19.03.2004 AU 2004901447 3007-3014, XP002496104 • BRACKEN CLAY ET AL: "Synthesis and nuclear (43) Date of publication of application: magnetic resonance structure determination of 03.01.2007 Bulletin 2007/01 an alpha-helical, bicyclic, lactam-bridged hexapeptide" JOURNAL OF THE AMERICAN (73) Proprietor: THE UNIVERSITY OF QUEENSLAND CHEMICAL SOCIETY, vol. 116, no. 14, 1994, St Lucia, pages 6431-6432, XP002496089 ISSN: 0002-7863 Queensland 4072 (AU) • BOUVIERM ET AL: "PROBING THE FUNCTIONAL CONFORMATION OF NEUROPEPTIDE Y (72) Inventors: THROUGH THE DESIGN AND STUDY OF CYCLIC • FAIRLIE, David, P. ANALOGUES" JOURNAL OF MEDICINAL Springwood, Queensland 4127 (AU) CHEMISTRY, vol. 35, no. 6, 1992, pages • SHEPHERD, Nicholas, E. 1145-1155, XP002496090 ISSN: 0022-2623 St Lucia, Queensland 4067 (AU) • KAPURNIOTU AFRODITE ET AL: "Structural and conformational requirements for human (74) Representative: D Young & Co LLP calcitonin activity: Design, synthesis, and study 120 Holborn of lactam-bridged analogues" JOURNAL OF London EC1N 2DY (GB) MEDICINAL CHEMISTRY, vol. 38, no. 5, 1995, pages 836-847, XP002496091 ISSN: 0022-2623 (56) References cited: • SANCHEZ J ET AL: "GENETIC FUSION OF A US-B1- 6 169 071 NON-TOXIC HEAT-STABLE ENTEROTOXIN-RELATED DECAPEPTIDE • TAYLOR JOHN W: "The synthesis and study of ANTIGEN TO CHOLERA TOXIN B-SUBUNIT" side-chain lactam-bridged peptides" FEBS LETTERS, ELSEVIER, AMSTERDAM, NL, BIOPOLYMERS, NEW YORK, NY, US, vol. 66, no. vol. 241, no. 1/02, 5 December 1988 (1988-12-05), 1, 1 January 2002 (2002-01-01), pages 49-75, pages 110-114, XP001204927 ISSN: 0014-5793 XP002267340 ISSN: 0006-3525 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 737 884 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 737 884 B1 • SHEPHERD N. ET AL: ’Single Turn Peptide Alpha • SHEPHERD N. ET AL: ’Helical Structures: Helices with Exeptional Stability in Water.’ Consecutive Cyclic Pentapeptide Modules from JOURNAL OF THE AMERICAN CHEMICAL Short a-Helices that are Very Stable to Water and SOCIETY. vol. 127, no. 9, 2005, pages 2974 - 2983, Denaturants.’ ANGEWANDTE CHEMIE, XP008085097 INTERNATIONAL EDITION. vol. 43, no. 20, 2004, pages 2687 - 2690, XP003017536 2 EP 1 737 884 B1 Description FIELD OF THE INVENTION 5 [0001] This invention relates generally to short chain peptides that have been constrained to adopt an alpha helical conformation and to their use as alpha helical scaffolds for directing amino acid side chains into positions analogous to those found in longer chain alpha helical peptides and for attaching peptidic or non-peptidic appendages in order to mimic side chains of longer alpha helical peptides. More particularly the invention relates to alpha helical cyclic pen- tapeptides and their use as alpha helical scaffolds or macrocyclic alpha helical modules, either alone, or within longer 10 chain peptides or attached to other macrocyclic peptides or attached to non-peptidic structures, for the purpose of mimicking naturally occurring peptides or proteins, and as agonists or antagonists of the biological activity of naturally- occurring peptides or proteins or for the preparation of new materials. [0002] Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. 15 BACKGROUND OF THE INVENTION [0003] The alpha helix is a fundamental structural unit in the fabric of proteins, with 30% of all amino acids in proteins occurring in alpha helices. 1 When helical sequences of amino acids are exposed on an exterior surface of a protein, the 20 helix frequently interacts with another protein, a segment of DNA or of RNA. 2,3 This biomolecular recognition is central to a large range of biological processes, for example those summarized in Table 1. In most cases however only a few alpha helical turns are actually involved in the molecular recognition. For example, transcriptional regulators (e.g. p53, NF-kBp65, VP16c)4-6 apoptosis regulators (e.g. Bak) 7 and RNA-transporter proteins (e.g. Rev) 8 all contain a short alpha helical sequence of only 2-4 turns that mediates function by direct interaction with a receptor. 25 TABLE 1 Some Biological Processes Mediated by Interaction of Alpha-Helices with Other Biomolecules α-Helical Peptide Biological target Process Mediated Reference 30 Protein-DNA interactions Zif268 G/C rich major groove DNA transcription 9 Protein-RNA interactions HIV Reverse Transcriptase Rev Response Element RNA reverse transcription 10 35 (RRE) λ-N peptide BoxB RNA Transcriptional anti-termination 10 α-Helical Peptide Biological target Process Mediated Reference 40 P22 peptides BoxB RNA Transcriptional anti-termination 10 Protein-Protein interactions p53 HDM2 Tumor Suppressor silencing 4 Bak Bcl-XL Apoptosis Regulation 7 45 VHL peptide Elongin C DNA transcription 11 VP16 activation domain HTAFII31 DNA transcription 12 hPTH hPTHrP Calcium homeostasis 13 50 Dynorphin A κ,δ-Opioid receptors Pain signal transmission 14,15 Apolipoprotein-E LDL receptor Lipid metabolism, cholesterol 16 homeostasis Neuropeptide-Y NPY receptors Multiple functions 17 55 Galanin Gal receptors Multiple functions 18 Corticotropin Releasing Factor CRF receptors Stress responses 19 3 EP 1 737 884 B1 (continued) Protein-Protein interactions Calcitonin Gene Related Peptide CGRP receptors Multiple functions 20 5 Nociceptin ORL1 receptor Pain transmission Vasointestinal Peptide VPAC1&2 Multiple functions 21 Nuclear Coactivators (eg. SRC1, Nuclear Receptors DNA Transcription 22,23 10 GRIP1) [0004] Short peptide sequences of less than 15 amino acid residues that correspond to these helical protein regions are not thermodynamically stable structures in water when removed from their protein environments. 24,25 Short synthetic peptides corresponding to such alpha helical recognition motifs tend not to display appreciable helical structure in water, 15 away from the helix-stabilizing hydrophobic environments of proteins. If short peptide alpha helices could be stabilized or mimicked by small molecules, such compounds might be valuable chemical or biological probes and lead to devel- opment of novel pharmaceuticals, vaccines, diagnostics, biopolymers, and industrial agents. The goal of structurally mimicking short alpha helices with small molecules that have biological activity comparable to proteins has not yet been realized. 20 [0005] Attempts to stabilize short alpha helical peptides have met with limited success to date. Examples of methods used to stabilize alpha helicity in peptides longer than 15 residues are helix-nucleating templates26-29, metals30-35, unnatural amino acids36,37, non-covalent side chain constraints 38,39 and covalent side chain linkers (e.g. disulfide- 40,41, hydrazone-42, lactam- 43-50, aliphatic linkers51-53). Although mimics of short alpha helical segments have remained elusive, some recent attempts have been reported using non-peptidic oligoamide and terphenyl scaffolds that project 25 2-3 substituents into similar three dimensional space as the side chains of an alpha helix 54-56. [0006] Helix nucleating templates are organic molecules at the N- or C-terminus of a peptide which can make hydrogen bonds with the first or last four NH or C=O groups in the peptide, and thus nucleate helicity throughout the rest of the peptide. Such a task is not trivial due to the specific position, pitch and orientation of the required NH or C=O groups. Several attempts have had some success, these include Kemp’s triacid, cyclic proline molecules, 26,57-61, Mueller’s Cage 30 compound62, Bartlett’s cap28, and Kahn’s cap 63. There have also been some attempts to synthesize capping groups by replacing a hydrogen bond with a covalent link as in the case of Satterthwait’s cap 64. [0007] Transition metals30-35 are often found in proteins serving both catalytic and structural roles. By exploiting the ability of transition metals such as Cu 2+, Zn2+, Cd2+, Ru3, Pd2+ to bind both acidic and basic residues it has been possible to achieve helix stabilization. Chelation of metals to donor groups generally yields∼ 1 kcal/mol-1 in helix stabilization, 35 however stabilization is very dependent on solvent, salt concentration and pH. [0008] Unnatural amino acids have also been reported to favor helix stabilization. In general n-alkyl substitution, α,α- and γγ-disubstitution increases helix stability. β,β-Disubstitution reduces helicity, and β-tertiary substitution totally abol- ishes helix propensity, thus it appears the helix is quite sensitive to steric effects at the beta position 65. α-Aminoisobutyric acid (Aib) in particular is known to stabilize α- and 3 10-helical conformations and has been used to improve the biological 40 activity of several peptides.
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