Inhibitors and uses therefor

Abstract

Disclosed are acid-sensing ion channel (ASIC) inhibitors and their use for treating or inhibiting the development of a condition in which inhibiting an ASIC stimulates or effects treatment or inhibition of the development of the condition. More particularly, this invention relates to proteinaceous ASIC inhibitors and their use for treating or inhibiting the development of a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, arthritis and retinal detachment. The ASIC inhibitors are also useful for inhibiting damage to an organ during organ transplantation.

Description

TITLE OF THE INVENTIONINHIBITORS AND USES THEREFOR

[0001] This application claims priority to Australian Provisional Patent Application No. 2024903337 entitled "Inhibitors and Uses Therefor" filed 16 October 2024, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This invention relates generally to acid-sensing ion channel (ASIC) inhibitors and their use for treating or inhibiting the development of a condition in which inhibiting an ASIC stimulates or effects treatment or inhibition of the development of the condition. More particularly, this invention relates to proteinaceous ASIC inhibitors and their use for treating or inhibiting the development of a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, arthritis and retinal detachment. The ASIC inhibitors are also useful for inhibiting damage to an organ during organ transplantation.BACKGROUND OF THE INVENTION

[0003] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0004] Acid-sensing ion channels (ASICs) are voltage-independent proton-gated cation channels that belong to the degenerin / epithelial sodium channel superfamily. There are six ASIC isoforms, including ASICla, ASIClb, ASIC2a, ASIC2b, ASIC3 and ASIC4, which arise from four genes, ASIC1, ASIC2, ASIC3 and ASIC4. Functional channels are either homotrimers or heterotrimers. ASICs are permeable to sodium ions and most subtypes are activated by extracellular acidosis. Upon activation, the channel undergoes a conformational change, resulting in an influx of sodium ions through the transmembrane domain and membrane depolarisation (Redd et al. (2021) Circulation, 144: 947-960; Chassagnon et al. (2017) PNAS, 114(14): 3750-3755).

[0005] ASICs are widely expressed throughout the central and peripheral nervous system, in immune cells and in cardiomyocytes, and they have been associated with neurological conditions, ischaemia, pain, cancer and stroke.

[0006] ASICla is the most pH-sensitive ASIC, with activation of this channel beginning at pH of ≤7 and half-maximal activation occurring at pH 6.6. Unlike the other isoforms, ASICla is permeable to both sodium and calcium ions and, as a result, may play a role in intracellular signalling and membrane excitability. This isoform is the primaryacid sensor in mammalian brain and is a key mediator of neuronal damage following ischaemia (Redd et al. (2021) Circulation, 144: 947-960; Chassagnon et al. (2017) PNAS, 114(14): 3750-3755).

[0007] A number of conditions are associated with ischaemia, including stroke and myocardial infarction. Ischaemia leads to an ischaemic cascade that can lead to cellular apoptosis, necroptosis or necrosis, in some cases leading to irreparable organ damage, such as to the brain and heart.

[0008] Ischaemic stroke accounts for about 85% of all strokes worldwide. The extent to which blood flow is impeded is related to the tissue damage, with the core zone of tissue damage suffering from complete impedance of blood flow and the penumbral (peri-infarct) zone suffering from partial impedance of blood flow. Due to complete loss of blood flow, the core zone tissue is mortally injured and undergoes necrotic cell death. The tissue in the penumbral zone, however, undergoes programmed cell death over a period of hours to days. As such, there is an opportunity to prevent loss of this tissue with therapeutics. This is significant, as the penumbral zone can compose up to 50% of the total lesion volume during the initial stages of ischaemia (Chassagnon et al. (2017) PNAS, 114(14): 3750-3755).

[0009] During a period of ischaemia, the brain switches from oxidative phosphorylation to anaerobic glycolysis due to oxygen depletion, resulting in tissue acidosis as a result of increased lactate levels (Chassagnon et al. (2017) PNAS, 114(14): 3750- 3755). The pH of the core zone can fall from 7.2 to as low as 6, whereas the pH in the penumbral zone ranges between about 6.5 and 6.9 (Larkin et al. (2022) Front Physiol, 12: 793741). This acidic pH results in activation of ASIC channels, and potentiation of ASIC currents (Chassagnon et al. (2017) PNAS, 114(14): 3750-3755). ASICs have been shown to play a critical role in mediating ischaemia-induced neuronal injury, with inhibition of ASICla being neuroprotective in rodent models of ischaemic stroke (Redd et al. (2021) Circulation, 144: 947-960; Chassagnon et al. (2017) PNAS, 114(14): 3750-3755). Similar roles for ASICla have also been revealed in other conditions associated with ischaemia, including cardiac ischaemia-reperfusion injury (Redd et al. (2021) Circulation, 144: 947- 960).

[0010] Drug hypersensitivity reactions are characterised by a range of symptoms, including urticaria, angioedema, pruritus, upper and lower respiratory tract symptoms, gastrointestinal symptoms, hypotension and anaphylaxis. These reactions can often involve mast cell degranulation via activation of Mas-related G-protein coupled receptor member X2 (MRGPRX2). MRGPRX2 binding and activation is particularly prevalent in cationic peptides.

[0011] Despite a clear need for therapies, there are currently no approved therapeutics that treat the cellular injury caused by ischaemia during a stroke or a cardiac event, such as myocardial infarction. In addition, molecules that substantially avoid or minimise off target effects, such as binding to MRGPRX2 are desired to avoid potential hypersensitivity reactions. Accordingly, safe and effective neuroprotective and cardioprotective therapies are desired.SUMMARY OF THE INVENTION

[0012] The present invention is predicated in part on the design of proteinaceous molecules that inhibit ASIC activity, especially ASICla activity. The inventors have found that proteinaceous molecules with one or more acidic residues at the C-terminus are able to potently inhibit ASIC activity, whilst minimising potential off-target effects, such as MRGPRX2 activation and mast cell degranulation. Based on this activity, the inventors conceived that these proteinaceous molecules will be useful for treating or inhibiting the development of a condition associated with ASIC activity, such as a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, arthritis and retinal detachment; as well as for minimising damage to an organ during organ transplantation.

[0013] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (I) wherein:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal), homotyrosine, levodopa (Dopa), Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), 3-iodo-tyrosine (Tyr(iodo)) or 3,5-diiodo-tyrosine(Tyr(diiodo))); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit), canavanine (Cav) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze) or a-methylproline);X4 is T or a modified form thereof; or S or a modified form thereof; X5 is selected from cyclohexylalanine (Cha); cyclohexylglycine (Chg); and hydrophobic amino acid residues including V, L, I and modified forms thereof;X6 is R;X7 is selected from basic amino acid residues including R, K and modified forms thereof;X8 is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg or 2-aminobutyric acid (Abu));X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg, 2-aminoisobutyric acid (Aib) or Abu); and amide containing amino acid residues including N, Q and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi) or homocysteine), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (isoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-lysine (D-Lys) or Orn); a poly(ethylene glycol) (PEG); and amide containing amino acid residues including N, Q and modified forms thereof;X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X17 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys, Orn or Orn(Ac)); and a PEG;X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.

[0014] In some embodiments:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal)) ;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp));X4 is T or a modified form thereof;X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. cyclohexylalanine (Cha) or cyclohexylglycine (Chg)); hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is R;X? is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and basic amino acid residues including R, K and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi)), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (isoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-lysine (D-Lys) or Orn); and a poly(ethylene glycol) (PEG);X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X1? is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.

[0015] In some embodiments, X1 is selected from Y, W, Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, V and Q. In some embodiments, X1 is selected from Y, W and Nal; such as Y.

[0016] In some embodiments, X2 is selected from R, Orn, K(me2), Cit, Cav,Orn(Ac), A, V, L and Q. In some embodiments, X2 is selected from R, K, Orn, K(me2), Cit,Orn(Ac), A, G, S, T, V, L, I, N and Q; such as R, Orn, K(me2), Cit, Orn(Ac), A, V, L and Q. In some embodiments, X2 is R.

[0017] In some embodiments, X3 is P, Aze, Hyp or a-methylproline. In some embodiments, X3 is P or Hyp; such as P.

[0018] In some embodiments, X4 is T or S. In particular embodiments, X4 is T.

[0019] In some embodiments, X5 is selected from A, G, S, T, Cha, Chg, V, L andI; such as Cha, Chg or I. In particular embodiments, X5 is I.

[0020] In some embodiments, X7 is R or K; such as R.

[0021] In some embodiments, Xs is R, K, D or E; such as R, K or E; such as R.

[0022] In particular embodiments, X9 is R, K or Me-R; such as R or Me-R.

[0023] In some embodiments, X10 is V, Tie, A, L, Abu or Chg. In some embodiments, X10 is selected from V, L, I and Tie; such as V or Tie.

[0024] In some embodiments, X11 is selected from R, K and Cit; such as R or Cit.

[0025] In some embodiments, X12 is selected from V, L, I, Tie, R and K; such as I, Tie, L or K. In some embodiments, X12 is I, Tie, L, A, Abu, Aib, Chg, Q or K. In particular embodiments, X12 is I.

[0026] In particular embodiments, X13 is C.

[0027] In some embodiments, X14 is selected from D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys and Orn; such as E, G or K. In some embodiments, X14 is E, G, Q or K.

[0028] In some embodiments, X15 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a poly(ethylene glycol). In particular embodiments, X15 is absent or is E, isoE, D- Glu or a PEG. In some embodiments, X15 is absent or is E, D, isoE, D-Glu or a PEG.

[0029] In some embodiments, X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; such as absent or is E, D, isoE or D-Glu; or absent or is E, isoE or D-Glu.

[0030] In some embodiments, X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In particular embodiments, X17 is absent or is E, K, D-Lys, Orn or a PEG. In some embodiments, X17 is absent or is E, K, D-Lys, Orn, Orn(Ac) or a PEG. In some embodiments, X17 is a PEG, such as PEG12.

[0031] In some embodiments, X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; such as absent or is E, K or a PEG.

[0032] In some embodiments, X19 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; such as absent or is E, K or a PEG.

[0033] In some embodiments, X20 is a bsent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In some embodiments, X20 is absent or is E or a PEG. In particular embodiments, X20 is absent or is E.

[0034] In some embodiments, X16, X19 and X20 are absent. In some embodiments, X14 is E and X15 to X20 are absent. In alternative embodiments, X15 and X16 are E and X17 to X20 are absent.

[0035] In some embodiments, X15 and X16 are E, X17 is E, K or Orn and X16 to X20 are absent.

[0036] In some embodiments, X15 is a PEG such as PEG2, and X16 and X17 are acidic amino acid residues.

[0037] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73 and 262-315 :YRPTIRRRRVRICGEE [SEQ ID NO: 1];YRPTIRRRRVRICGX21EE [SEQ ID NO: 2];YRPTIRRRRVRICE [SEQ ID NO: 3];YRPTIRRRRVRICGEEE [SEQ ID NO: 4];YRPTIRRRRVRICGX21EEE [SEQ ID NO: 5];YRPTIRRRRVRICGX21EEEE [SEQ ID NO: 6];YRPTIRRRX22VRICGX21EE [SEQ ID NO: 7];WRPTIRRRX22VRICGX21EE [SEQ ID NO: 8];WRPTX23RRRX22VRICGX21EE [SEQ ID NO: 9];YRPTIRRRRVRICEEE [SEQ ID NO: 10];YRPTIRRRRVRICGee [SEQ ID NO: 11];YRPTIRRRX22VRICGEE [SEQ ID NO: 12];YX24PTIRRRRVRICGEE [SEQ ID NO: 13];YAPTIRRRRVRICGEE [SEQ ID NO: 14];YRPTIRRRRVX24ICGEE [SEQ ID NO: 15];YX24PTIRRRRVRICGEEE [SEQ ID NO: 16];YRX25TIRRRRVRICGEEE [SEQ ID NO: 17];YRPTIRRRRVRICEE [SEQ ID NO: 18];YRPTIRRRRVRICGEEEE [SEQ ID NO: 19];YRPTIRRRRVRICGEEEEE [SEQ ID NO: 20];YRPTIRRRRVRICGEEEEEE [SEQ ID NO: 21];YRPTIRRRRVRICEEEE [SEQ ID NO: 22];YRPTIRRRRVRICGEEX26 [SEQ ID NO: 23];YRPTIRRRRVRICGEEX26X26 [SEQ ID NO: 24];YRPTIRRRX22VRICGEEE [SEQ ID NO: 25];YX24PTIRRRX22VRICGEE [SEQ ID NO: 26];YX24PTIRRRX22VRICGEEE [SEQ ID NO: 27];YX24PTIRRRRX27RICGEE [SEQ ID NO: 28];YQPTIRRRX22VRICGEE [SEQ ID NO: 29];YX28PTIRRRX22VRICGEE [SEQ ID NO: 30];YLPTIRRRX22VRICGEE [SEQ ID NO: 31];YVPTIRRRX22VRICGEE [SEQ ID NO: 32];YRPTIRRRX22VRICGEX29 [SEQ ID NO: 33];YRPTIRRRX22VRICGX29X29 [SEQ ID NO: 34];YRPTIRRRRVRICGEEK [SEQ ID NO: 35];YRPTIRRRRVRICGEEX30 [SEQ ID NO: 36];YRPTIRRRRVRICKEE [SEQ ID NO: 37];YRPTIRRRRVRICX30EE [SEQ ID NO: 38];YRPTIRRRRVRKCGEE [SEQ ID NO: 39];YRPTIRRRRVRX30CGEE [SEQ ID NO: 40];YX31PTIRRRRVRICGEE [SEQ ID NO: 41];YX32PTIRRRX22VRICGEE [SEQ ID NO: 42];YRPTIRRRX22VRICEE [SEQ ID NO: 43];YRPTIRRRRVRICGEEX26X26K [SEQ ID NO: 44];YRPTIRRRRVRICGEEX26X26X33 [SEQ ID NO: 45];YRPTIRRRRVRICGEEX26X26X34 [SEQ ID NO: 46];YRPTIRRRRVRICGEEX35 [SEQ ID NO: 47];X49RPTIRRRRVRICGEEX44 [SEQ ID NO 265];X50RPTIRRRRVRICGEEX44 [SEQ ID NO 266];YRPTIRRKRVRICGEE [SEQ ID NO 267];YRPTIRRRKVRICGEE [SEQ ID NO 268];CYRPTIRRRRVRICGEE [SEQ ID NO 269];YRPTIRRRRVRIX51GEE [SEQ ID NO 270];ARPTIRRRRVRICGEE [SEQ ID NO 271];VRPTIRRRRVRICGEE [SEQ ID NO 272];YRPTIRRRRARICGEE [SEQ ID NO 273];QRPTIRRRRVRICGEE [SEQ ID NO 274];YRPSIRRRRVRICGEE [SEQ ID NO 275];YRPTIRRRRLRICGEE [SEQ ID NO 276];YRPTIRRRRVRQCGEE [SEQ ID NO 277];YRPTIRRRRVRIX52GEE [SEQ ID NO 278];YRPTIRRRRVRICQEE [SEQ ID NO 279];YRPTIRRRRVRICGDE [SEQ ID NO 280];YRPTIRRRRVRICGED [SEQ ID NO 281];YX53PTIRRRRVRICGEE [SEQ ID NO 282];YRPTIRRRRX40RICGEE [SEQ ID NO 283];YRPTX40RRRRVRICGEE [SEQ ID NO 284];YRPTIRRRRVRX40CGEE [SEQ ID NO 285];YRX25TIRRRRVRICGEE [SEQ ID NO 286];YRX54TIRRRRVRICGEE [SEQ ID NO 287];YRX55TIRRRRVRICGEE [SEQ ID NO 288];XssRPTIRRRRVRICGEE [SEQ ID NO 289];X57RPTIRRRRVRICGEE [SEQ ID NO 290];XssRPTIRRRRVRICGEE [SEQ ID NO 291];X59RPTIRRRRVRICGEE [SEQ ID NO 292];YRPTIRRRRVRACGEE [SEQ ID NO 293];YRPTIRRRRVRXsoCGEE [SEQ ID NO 294];YRPTIRRRRVRXeiCGEE [SEQ ID NO 295];YRPTIRRRRXeoRICGEE [SEQ ID NO 296];X62RPTIRRRRVRICGEE [SEQ ID NO 297];YRPTIRRRRVRICGEEX32 [SEQ ID NO 298];YRPTIRRRRVRICGEEX26X33 [SEQ ID NO 299];YRPTIRRRRVRICGEEX26X26X63 [SEQ ID NO 300];YRPTIRRRRVRICGEEX26X26X64 [SEQ ID NO 301];YRPTIRRRRVRICGEEX26X26X65 [SEQ ID NO 302];YRPTIRRRRVRICGEEX26X26X66 [SEQ ID NO 303];YRPTIRRRRVRICGEEX26X26X67 [SEQ ID NO 304];YRPTIRRRRVRICGEEX26X34 [SEQ ID NO 305];YRPTIRRRRVRICGEEXes [SEQ ID NO 306];YRPTIRRRRVRICGEEEEXes [SEQ ID NO 307];YRPTIRRRRVRICGEEEXes [SEQ ID NO 308];YRPTIRRRRVRICGEEXesEE [SEQ ID NO 309];YRPTIRRRRVRICGEEX44X69 [SEQ ID NO 310];YRPTIRRRRVRICGEEX48X70 [SEQ ID NO 311];YRPTIRRRRVRICGEEX48X71 [SEQ ID NO 312];YRPTIRRRRVRICGEEX48X48X71 [SEQ ID NO 313];YRPTIRRRRVRICGEEX72X71 [SEQ ID NO 314]; andYRPTIRRRRVRICGEEX73 [SEQ ID NO 315], wherein :X21 is PEG2; X22 is Me-R; X23 is Cha ; X24is Cit; X25 is Hyp; X26is PEG12; X27 is Tie; X28is Orn; X29 is isoE; X30 is K(PEG37); X31 is K(me2); X32 is Orn(Ac) ; X33 is K(isoE-C18A); X34 is K(isoE-C16) ; X35 is K(PEG 5kDa) ; X36 is K(PEG lOkDa); X37 is K(PEG 20kDa); X3s is K(PEG 40kDa) ; X39 is Nal ; X40 is Chg ; X41 is C(oxi); X42 is K(albutag) ; X43 is K(isoE-albutag) ; X44 is Orn(PEG37); X45is k(PEG37) ; X48is PEG4; X49 is Tyr(iodo) ; X50 is Tyr(diiodo) ; X51 is Pen; X52 is homocysteine; X53 is canavanine; X54 is Aze; X55 is a-methylproline; Xse is homotyrosine; X57 is Dopa ; Xss is Phe(4-MeOH); X59 is Phe(4-COOH); Xso is Abu; Xsi is Aib; X&2 is Phe(4-N H2) ; X&3 is K(isoE-C14A) ; X64 is K(isoE-C14) ; Xes is K(isoE-C12) ; Xes is K(isoE-CIO); X67 is K(isoE-C16A); Xes is K(C16); X69 is K(PEG4-biotin); X70 is K(C12); X71 is K(C18A); X72 is PEG24; and X73 is Orn(PEG4-MPA).

[0038] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 73. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73; such as an amino acid sequence represented by any one of SEQ ID NOs: 1-4, 6, 7-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73.

[0039] In some embodiments, the proteinaceous molecule further comprises a stabilising moiety. In some embodiments, the stabilising moiety is a PEG, such as a PEG comprising between 2 and 50 ethylene glycol units (e.g. 4, 12 or 37 ethylene glycol units). In some embodiments, the PEG has a molecular weight of from about 1 kDa to about 50 kDa. In some embodiments, one of X12 and X15 to X20 is a basic amino acid residue (e.g. K or Orn) and the stabilising moiety is attached to the side chain of the basic amino acid residue.

[0040] In some embodiments, X13 is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X13 position and the N-terminal amine of the amino acid residue in the X1 position.

[0041] In particular embodiments, X13 is C and the side chain of the cysteine residue in the X13 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the X1 position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X13, and R1is C1-6 alkylene (e.g. methylene).

[0042] In some embodiments, the proteinaceous molecule comprises a C- terminal amide.

[0043] Further provided is a composition comprising, consisting or consisting essentially of a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.

[0044] In another aspect, there is provided a proteinaceous molecule of the invention for use in therapy.

[0045] In a further aspect, there is provided a method of inhibiting an activity of an ASIC, comprising contacting the ASIC with a proteinaceous molecule of the invention. In particular embodiments, the ASIC is ASICla.

[0046] In another aspect, there is provided a method of treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, comprising administering a proteinaceous molecule of the invention.

[0047] In particular embodiments, the condition is selected from the group consisting of a neurological condition, neuronal damage, ischaemia, pain, ischaemiareperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment.

[0048] In some embodiments, the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease; especially stroke. In some embodiments, the ischaemia is neuronal, ocular (e.g. acute retinal ischaemia), renal or cardiac ischaemia.

[0049] In some embodiments, the cancer is a glioblastoma.

[0050] In some embodiments, the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.

[0051] In a still further aspect, there is provided a method of treating or at least partially inhibiting the development of a neurological condition in a subject, comprising administering a proteinaceous molecule of the invention. In some embodiments, the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease; especially stroke.

[0052] In another aspect, there is provided a method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising administering a proteinaceous molecule of the invention.

[0053] In a further aspect, there is provided a method of treating or at least partially inhibiting the development of ischaemic damage in a subject, comprising administering a proteinaceous molecule of the invention.

[0054] In some embodiments, the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage. In particular embodiments, the ischaemic damage is cardiac ischaemic damage; especially ischaemic damage associated with a myocardial infarction. In alternative embodiments, the ischaemic damage is neuronal ischaemic damage;especially ischaemic damage associated with a stroke, traumatic brain injury or perinatal brain injury.

[0055] Also provided herein, in another aspect, is a method of at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue, comprising contacting the tissue with a proteinaceous molecule of the invention. In particular embodiments, the tissue is an organ transplant. In some embodiments, the tissue is a heart, lung or kidney; especially a heart.

[0056] In another aspect, there is provided a method of at least partially inhibiting damage to an organ during organ transplantation, comprising contacting the organ with a proteinaceous molecule of the invention. In some embodiments, the organ is a heart, lung or kidney; especially a heart. In particular embodiments, the damage is ischaemic damage.BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 is a scheme for the synthesis and cyclisation of IB212.

[0058] Figure 2 is a mass spectrum of pure IB212 showing the expected [M + 4H]+4, [M + 3H]+3and [M + 2H]+2ions, plus TFA adducts [M + 3H+TFA]+3(a), [M + 2H+TFA]42(b) and [M + 2H + 2TFA]+2(c).

[0059] Figure 3 is a chromatogram from analytical RP-HPLC elution of purified IB212 using a Phenomenex C18 Luna column at 45°C. The peptide was eluted using a gradient of 10 to 36% buffer B (90% acetonitrile in water / 0.05% TFA) in buffer A (0.1% TFA in water) over 13 minutes. The flow rate was 0.5 miymin. Peptide purity estimated from area under the IB212 peak was >95%.

[0060] Figure 4 is a scheme for the synthesis and cyclisation of IB324.

[0061] Figure 5 is a mass spectrum of pure IB324 showing the expected [M + 7H]+7, [M + 6H]+6and [M + 5H]+5ions, plus TFA adducts [M + 6H+TFA]+6(a) and [M + 5H+TFA]+5(b).

[0062] Figure 6 is a chromatogram from analytical RP-HPLC elution of purified IB324 using a Phenomenex C18 Aeris column at 50°C. The peptide was eluted using a gradient of 10 to 45% buffer B (90% acetonitrile in water / 0.05% TFA) in buffer A (0.05% TFA in water) over 30 minutes. The flow rate was 0.2 miymin. Peptide purity estimated from area under the IB324 peak was > 95%.

[0063] Figure 7 is a concentration-response curve showing the inhibition of hASICla-mediated sodium currents by IB212. Data are mean ± SEM (n = 3). A fit of the Hill equation to the concentration-response data yielded an IC50 of 0.5 nM, with complete inhibition (100% efficacy) observed at an IB212 concentration of 10 nM.

[0064] Figure 8 is a schematic of the experimental protocol used to test the ability of IB212 and IB324 to prevent loss of cardiac function in a rat model of myocardial infarction (MI).

[0065] Figure 9 is a series of graphs showing the cardioprotection efficacy of IB212 compared to IB100. IB212 shows superior cardioprotection efficacy in a rat MI model when dosed at 1 mg / kg over 10-min intravenous infusion, as shown by improved recovery of cardiofunction after induced cardiac ischaemia according to fractional shortening parameters. Data presented as mean ± SEM. p < 0.05 was considered statistically significant. (****, p <0.001).

[0066] Figure 10 is a series of graphs showing the cardioprotection efficacy of IB324 compared to IB212. IB324 shows superior cardioprotection efficacy in a rat MI model when both peptides are dosed at 143 nmols / kg over 10-min intravenous infusion, as shown by improved recovery of cardiofunction after induced cardiac ischaemia according to fractional shortening parameters. Data presented as mean ± SEM. p < 0.05 was considered statistically significant. (****, p <0.001).

[0067] Figure 11 is a graph showing the correlation between mast cell degranulation and activation of MRGPRX2 of a subset of peptides. The rising level of induced mast cell degranulation (MCD, EC50) observed in human LAD-2 mast cells was strongly correlated to the potency of a subset of peptides to activate the MRGPRX2 receptor (EC50). Both properties also correlated well with the increase in overall positive charge of the peptides.

[0068] Figure 12 is a heat map of the results of the Eurofins SafetyScreen 44 Panel, showing the in vitro pharmacological profiling of potential off-target interactions of IB100 and IB212 at 10 pM concentration (n = 2). The peptides were screened against native ligands of 44 different receptors, ion channels and enzymes. Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test peptides.

[0069] Figure 13 shows the fraction (percentage) of human induced pluripotent stem cell-derived card io myocytes (hiPSC-CMs) that die as a result of exposure to culture medium at pH 5 under hypoxic condititions for 18 hours followed by exposure to culture medium at pH 7.4 under normoxic conditions for an additional 4 hours. Release of lactate dehydrogenase (LDH) was used as a proxy for cell death. Addition of 50 nM IB212 rescued hiPSC-CMs from acidosis-induced cell death. Data are mean ± SEM. ****p < 0.0001 using one-way ANOVA.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0070] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0071] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0072] By "about" is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0073] The terms "administration concurrently" or "administering concurrently" or "co-administering" and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and / or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition. By "simultaneously" is meant that the agents are administered at substantially the same time, and desirably together in the same composition. By "contemporaneously" it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term "same site" includes the exact location, but can be within about 0.5 to about 15 centimetres, preferably from within about 0.5 to about 5 centimetres. The term "separately" as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order. The term "sequentially" as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.

[0074] The term "agent" includes a compound that induces a desired pharmacological and / or physiological effect. The term also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those compounds specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogues and the like. When the above term is used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogues, etc. The term "agent" is not to be construed narrowly but extends to small molecules, proteinaceous molecules such as peptides, polypeptides and proteins as well as compositions comprising them and genetic molecules such as RNA, DNA and mimetics and chemical analogues thereof as well as cellular agents.

[0075] As used herein, the term "alkyl" refers to straight or branched aliphatic hydrocarbon groups having from 1 to 6 carbon atoms, including from 1 to 5 carbon atoms, from 1 to 3 carbon atoms and from 1 to 2 carbon atoms. Examples of such alkyl groups include methyl (-CH3), ethyl (-CH2CH3), propyl, including n-propyl (-CH2CH2CH3), butyl, including n-butylene (-CH2CH2CH2CH3), and the like.

[0076] As used herein, the term "alkylene" refers to divalent straight or branched aliphatic hydrocarbon groups having from 1 to 6 carbon atoms, including from 1 to 5 carbon atoms, from 1 to 3 carbon atoms and from 1 to 2 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene, including n-propylene (-CH2CH2CH2-), butylene, including n-butylene (-CH2CH2CH2CH2-), and the like.

[0077] As used herein, the term "alkenylene" refers to divalent aliphatic hydrocarbon groups containing at least one carbon-carbon double bond and which may be straight or branched. Suitable alkenylene groups have from 2 to 6 carbon atoms, including from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, and from 2 to 3 carbon atoms. Representative alkenylene groups include ethenylene (vinylene) (-CH=CH-), 1- propenylene (-CH=CHCH2-), 2-propenylene (-CH2CH=CH-), 1-butenylene (- CH=CHCH2CH2-), 2-butenylene (-CH2CH = CHCH2-) and 3-butenylene (-CH2CH2CH = CH-).

[0078] Amino acid residues are referred to herein interchangeably using their full name or the one or three letter codes standard in the art. Abbreviations used for unnatural or modified amino acid residues or derivatives thereof are defined herein where appropriate.

[0079] Amino acid residues are defined herein on the basis of the side chain classification in some instances. Families of amino acid residues having similar side chains have been defined in the art, which can be generally sub-classified as follows:TABLE 1AMINO ACID SUB-CLASSIFICATION

[0080] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0081] The term "antagonist" and grammatical equivalents thereof as used herein refers to a molecule that partially or completely inhibits, by any mechanism, an effect of another molecule such as an enzyme, receptor or intracellular mediator. In the context of the present invention, the term "antagonist" refers to a molecule that is a direct antagonist that binds to or otherwise interacts with an ASIC, especially ASICla, more especially human ASICla. Antagonism of an ASIC may inhibit or reduce ASIC activity and / or function, including any one or more of transport of sodium ions across a cellular membrane (e.g. cellular influx), transport of calcium ions across a cellular membrane (e.g. cellular influx), ASIC activation, ASIC desensitisation, proton binding, extracellular signal- regulated kinase (ERK) activation, receptor-interacting serine / threonine-protein kinase 1 (RIPK1) phosphorylation and / or ERK phosphorylation. By way of example, "antagonise" can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in an activity, or function relative to the activity or function of ASIC, especially ASICla, in the absence of the antagonist.

[0082] The term "any amino acid residue" is used herein to refer to any of the 20 naturally occurring amino acid residues and modified versions thereof, includingresidues with modified side chains, N-methyl amino acids, a-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0083] The term "aryl" as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or anthryl), including from 6-10 carbon atoms (and all integer carbon atoms therebetween). Where multiple rings are present, at least one of the rings is aromatic. Each ring may be, for example, a 6-membered ring. In some embodiments, the aryl group is Ce-io aryl. In preferred embodiments, the aryl group is phenyl or naphthyl; especially phenyl.

[0084] The term "associated with" when used in relation to conditions associated with ASIC activity, means that ASIC activity contributes, either directly or indirectly, to the pathogenesis or progression of the condition, including of one or more symptoms of the disease, disorder or condition. The specified activity may, for example, directly lead to the pathogenesis (i.e. development) of the disease, disorder or condition or the development of one or more symptoms of the disease, disorder or condition (e.g. via infarction or cellular death). Alternatively or in addition, the specified activity may result in the progression (i.e. worsening) of the disease, disorder or condition or one or more symptoms of the disease, disorder or condition.

[0085] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term "comprising" and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements. In specific embodiments, the term "consisting essentially of", in the context of a specific amino acid sequence disclosed herein, includes within its scope about 1 to about 50 optional amino acids (and all integer optional amino acids in between) upstream of the specific amino acid sequence and / or about 1 to about 50 optional amino acids (and all integer optional amino acids in between) downstream of the specific amino acid sequence.

[0086] By "derivative" is meant a molecule, such as a polypeptide or an amino acid residue, that has been derived from the basic molecule by modification, for example by conjugation or complexing with other chemical moieties or by post-translational modification techniques as would be understood in the art. The term "derivative" also includes within its scope alterations that have been made to a parent molecule including additions or deletions that provide for functionally equivalent molecules.

[0087] As used herein, the term "dosage unit form" refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.

[0088] By "effective amount", in the context of treating or at least partially inhibiting the development of a condition, is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and / or treating existing symptoms, of that condition. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. An "effective amount", in the context of at least partially inhibiting the development of damage or an injury, is meant the administration or application of an amount of an agent or composition that is effective for inhibiting, minimising or reducing the damage or injury, such as cell death.

[0089] As used herein, the phrase "inhibit the development of" (also referred to herein as "preventing") refers to a prophylactic treatment which increases the resistance of a subject to developing the disease, disorder or condition or, in other words, decreases the likelihood that the subject will develop the disease, disorder or condition, as well as a treatment after the disease, disorder or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse. This phrase also includes within its scope preventing the disease, disorder or condition from occurring in a subject which may be predisposed to the disease, disorder or condition but has not yet been diagnosed as having it. "At least partially inhibit the development of" means that the treatment inhibits the development of at least one or more symptoms of the disease, disorder or condition.

[0090] The term "inhibitor" as used herein refers to an agent that decreases or at least partially inhibits at least one function or biological activity of a target molecule. For example, an ASIC inhibitor is an agent that inhibits at least one function or biological activity of an ASIC, especially ASICla, such as any one or more of transport of sodiumions across a cellular membrane (e.g. cellular influx), transport of calcium ions across a cellular membrane (e.g. cellular influx), ASIC activation, ASIC desensitisation, proton binding, extracellular signal-regulated kinase (ERK) activation, RIPK1 phosphorylation and / or ERK phosphorylation.

[0091] The term "PEGX" is used herein to refer to a poly(ethylene glycol) group, with X number of ethylene glycol units, i.e. wherein X is the number of ethylene glycol units. In particular embodiments, X is from 2 to 50. For example, "PEG2" refers to a PEG with 2 ethylene glycol units. The term "PEG YkDa" is used herein to refer to a poly(ethylene glycol) group having an average molecular weight of Y kDa. For example, "PEG 5kDa" refers to a PEG having an average molecular weight of 5 kDa.

[0092] By "pharmaceutically acceptable carrier" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, fillers, detergents, colouring agents, wetting or emulsifying agents, pH buffering agents, preservatives and the like. Similarly, a "pharmaceutically acceptable" salt, ester, amide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.

[0093] As used herein, the terms "polypeptide", "proteinaceous molecule", "peptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. The term "proteinaceous" as used in for example "proteinaceous molecule" refers to the presence of at least a part of the molecule that resembles or is a protein, wherein "protein" is to be understood to include a chain of amino-acid residues at least two residues long, thus including a peptide, a polypeptide and a protein and an assembly of proteins or protein domains. These terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non- naturally-occurring amino acid, such as a chemical analogue of a corresponding naturally- occurring amino acid, or a PEG group, as well as to naturally-occurring amino acid polymers. These terms do not exclude modifications, for example, glycosylations, acetylations, phosphorylations, attachment of protecting / stabilising moieties and the like as described in detail herein. Soluble forms of the subject proteinaceous molecules are particularly useful. Included within the definition are, for example, polypeptides containing one or more analogues of an amino acid including, for example, unnatural amino acids, polypeptides with substituted linkages and polypeptides with polyethylene glycol (PEG) groups as described in detail herein.

[0094] The terms "reduce", "inhibit", "decrease", and grammatical equivalents when used in reference to the level of a substance and / or phenomenon in a first sample relative to a second sample, mean that the quantity of substance and / or phenomenon in the first sample is lower than in the second sample by any amount that is statistically significant using any art-accepted statistical method of analysis. When these terms are used to refer to the action of a molecule or agent, the first sample may be a sample in the presence of the molecule or agent and the second sample may be a comparative sample without the molecule or agent. In one embodiment, the reduction may be determined subjectively, for example when a patient refers to their subjective perception of disease symptoms, such as pain, confusion, motor symptoms, etc. In another embodiment, the reduction may be determined objectively, for example when the size of an infarct in a sample from a patient is smaller than in an earlier sample from the patient or smaller than in a sample from an untreated patient. In another embodiment, the quantity of substance and / or phenomenon in the first sample is at least 10% lower than the quantity of the same substance and / or phenomenon in a second sample. In another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 25% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 50% lower than the quantity of the same substance and / or phenomenon in a second sample. In a further embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 75% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 90% lower than the quantity of the same substance and / or phenomenon in a second sample.

[0095] As used herein, the terms "salts" and "prodrugs" include any pharmaceutically acceptable salt, ester, hydrate or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a proteinaceous molecule of the invention, or an active metabolite or residue thereof. The term "pharmaceutically acceptable salts" refers without limitation to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g. by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate and valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts can be synthesised from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in, for example, Remington: The Science and Practice of Pharmacy, Adeboye Adejare and Joseph Remington (Ed), Academic Press, London, 23rdEdition, 2021; Stahl and Wermuth (2002) Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; and Berge et al. (1977) Journal of Pharmaceutical Science, 66: 1-19, each of which is incorporated herein by reference in its entirety.

[0096] The term "sequence identity" as used herein refers to the extent that sequences are identical on an amino acid-by-amino acid basis over a window of comparison. Thus, a "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical amino acid residue (e.g. Ala, Pro, Ser, Thr, Gly, Vai, Leu, lie, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e. the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0097] "Similarity" refers to the percentage number of amino acids that are identical or constitute conservative substitutions as defined in Tables 1 and 2 herein. Similarity may be determined using sequence comparison programs such as GAP (Deveraux et al. (1984), Nucleic Acids Research 12: 387-395). In this way, sequences of a similar or substantially different length to those cited herein might be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.

[0098] Terms used to describe sequence relationships between two or more polypeptides include "reference sequence," "comparison window", "sequence identity," "percentage of sequence identity" and "substantial identity". A "reference sequence" is at least 8 but frequently 10 to 20 amino acid residues in length. As two amino acid sequences may each comprise (1) a sequence (i.e. only a portion of the complete proteinaceous molecule) that is similar between the two proteinaceous molecules, and (2) a sequence that is divergent between the two proteinaceous molecules, sequence comparisons between two (or more) proteinaceous molecules are typically performed by comparing sequences of the two proteinaceous molecules over a "comparison window" to identify and compare local regions of sequence similarity. A "comparison window" refers to a conceptual segment of at least 6 contiguous positions in which a sequence is compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. The comparison window may comprise additions or deletions (i.e. gaps) of about 20% or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by computerized implementations of algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, WI, USA) or by inspection and the best alignment (i.e. resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et a / . (1997) Nucl. Acids Res. 25: 3389. A detailed discussion of sequence analysis can be found in Unit 19.3 of Ausubel et al. (1998) Current Protocols in Molecular Biology, John Wiley & Sons Inc, Chapter 15; Lambert et al. (2003) Current Genomics, 4: 131-146; and Bawano et al. (2017) Bioinformatics, Volume 1: Data, Sequence Analysis and Evolution (Methods in Molecular Biology (1525)), Humana Press, pages 167-189.

[0099] The term "subject" as used herein refers to a vertebrate subject, particularly a mammalian or avian (bird) subject, for whom therapy or prophylaxis is desired. Suitable subjects include, but are not limited to, primates; avians (birds); livestock animals such as sheep, cows, horses, deer, donkeys and pigs; laboratory test animals such as rabbits, mice, rats, guinea pigs and hamsters; companion animals such as cats and dogs; and captive wild animals such as foxes, deer and dingoes. In particular embodiments, the subject is a primate, suitably a human. However, it will be understood that the aforementioned terms do not imply that symptoms are present.

[0100] As used herein, the terms "treatment", "treating", and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease, disorder or condition and / or adverseeffect or symptom attributable to the disease, disorder or condition. These terms also cover any treatment of a condition or disease in a subject, particularly in a human, and include: (a) inhibiting the disease or condition, i.e. arresting its development; or (b) relieving the disease or condition, i.e. causing regression of the disease or condition.

[0101] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Abbreviations

[0102] The following abbreviations are used throughout the application:PEG = polyethylene glycolASIC =acid-sensing ion channelASICla =acid-sensing ion channel la hASICla =human acid-sensing ion channel laPen =penicillamineDip =3,3-diphenyl-L-alanineBip =4,4'-biphenyl-L-alanineNal = l-naphthyl-L-alanineOrn =ornithine b-Arg = beta-arginineHArg =homoarginineAgb =2-amino-4-guanidino-butyric acidCit =citrulline gArg = guan id i nyl-a Ikylated-argi nineMe-F =N-methyl-phenylalanineCha =cyclohexylalanineTie =tert-LeucineMe-R =N-methyl-arginineSar =sarcosine aMe-R =alpha-methyl-arginineAva =5-aminovaleric acidTAT =TAT peptideANG =angiopep2ERK =extracellular signal-regulated kinase eq. =equivalentsDMF =dimethylformamideFmoc =fluorenylmethyloxycarbonylMBHA =4-methylbenzhydrylamineDCM =dichloromethaneTFA =trifluoroacetic acidHPLC = high-performance liquid chromatographyRP-HPLC =reversed-phase high-performance liquid chromatographyLC-MS =HPLC-mass spectrometryHEPES =N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acidMES =4-(2-sulfonatoethyl)morpholin-4-iumBSA =bovine serum albumin sec = secondSEM =standard error of the meanMI =myocardial infarctionLAD = left anterior descending coronary artery i.v. =intravenous i.m. intramuscularECG = echocardiographyFS =fractional shorteningAA =amino acidDDM =n-dodecyl-β-D-maltoside tBuF =4-tert-butyl-phenylalanineFLIPR =Fluorescence Imaging Plate Reader hr =hour min =minuteK(Ac) =Ne-acetyl-L-lysineArg(Me) =(S)-2-amino-5-(3-methylguanidino)pentanoic acidHyp = hydroxyprolineK(me2) =Ne-dimethyl-L-lysineOrn(Ac) =N5-acetyl-ornithineChg =cyclohexylglycineMRGPRX2 =Mas-related G-protein coupled receptor member X2IsoE =isoglutamic acidD-Glu =D-glutamic acid (also referred to as e)D-Lys =D-lysine (also referred to as k)Albutag =6-(4-(4-iodophenyl)butanamido)hexa noateFITC =fluorescein isothiocyanateDIPEA =N,N-diisopropylethylamineMtt = MethyltritylGlu-OtBu =glutamic acid 1-tert-butyl esterMCD =Mast cell degranulationAze =Azetidine-2-carboxylic acidDopa = LevodopaPhe(4-MeOH) =4-hydroxymethyl-L-phenylalaninePhe(4-C00H) = 4-carboxy-L-phenylalanineAbu =2-aminobutyric acidAib =2-aminoisobutyric acidPhe(4-NH2) =4-amino-L-phenylalanineCav =CanavanineTyr(iodo) =3-iodo-tyrosineTyr(diiodo) =3,5-diiodo-tyrosineTic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3. Proteinaceous Molecules

[0103] The present invention is based, in part, on the design of proteinaceous molecules that inhibit ASIC activity and minimise activation of MRGPRX2. Based on this activity, the inventors conceived that these proteinaceous molecules, including proteinaceous molecules of Formula I, will be useful for treating or inhibiting the development of a condition associated with ASIC activity, such as a neurological condition (e.g. stroke), neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, arthritis and retinal detachment; as well as for at least partially inhibiting damage to an organ during organ transplantation.

[0104] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (I) wherein:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal), homotyrosine, levodopa (Dopa), Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), 3-iodo-tyrosine (Tyr(iodo)) or 3,5-diiodo-tyrosine(Tyr(diiodo))); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit), canavanine (Cav) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xs is P or a modified form thereof (e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze) or a-methylproline);X4 is T or a modified form thereof; or S or a modified form thereof;X5 is selected from cyclohexylalanine (Cha); cyclohexylglycine (Chg); and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is R;X7 is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg or 2-aminobutyric acid (Abu)); X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg, 2-aminoisobutyric acid (Aib) or Abu); and amide containing amino acid residues including N, Q and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi) or homocysteine), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (isoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-lysine (D-Lys) or Orn); a poly(ethylene glycol) (PEG); and amide containing amino acid residues including N, Q and modified forms thereof;X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X1? is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys, Orn or Orn(Ac)); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.

[0105] In some embodiments:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal)) ;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp));X4 is T or a modified form thereof;X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. cyclohexylalanine (Cha) or cyclohexylglycine (Chg)); hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof;X7 is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie));X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and basic amino acid residues including R, K and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi)), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a poly(ethylene glycol) (PEG);X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X1? is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.

[0106] In some embodiments, X1 is selected from Y, W, F Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, G, S, T, V, L, I, N and Q. In some embodiments, X1 is selected from Y, W, Nal, homotyrosine, Dopa, Phe(4- MeOH), Phe(4-C00H), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, V and Q. In some embodiments, X1 is selected from Y, W, V, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-COOH), Phe(4-NH2), Tyr(iodo) and Tyr(diiodo). In some embodiments, X1 is selected from Y, W, F and Nal; such as Y, W or Nal. In particular embodiments, X1 is Y.

[0107] In some embodiments, X2 is selected from R, K, Orn, Cav, K(me2), Cit, Orn(Ac), A, G, S, T, V, L, I, N and Q; such as R, Orn, Cav, K(me2), Cit, Orn(Ac), A, V, L or Q. In some embodiments, X2 is selected from R, K, Orn, K(me2), Cit, Orn(Ac), A, G, S, T, V, L, I, N and Q; such as R, Orn, K(me2), Cit, Orn(Ac), A, V, L or Q. In some embodiments, X2 is a basic amino acid residue, such as R, K, Orn, K(me2), Cit or Orn(Ac). In some embodiments, X2 is R.

[0108] In some embodiments, X3 is P, Aze, Hyp or a-methylproline. In some embodiments, X3 is P or Hyp; such as P.

[0109] In particular embodiments, X4 is T or S, such as T.

[0110] In some embodiments, X5 is selected from Cha, Chg, V, L and I; such as Cha, Chg or I. In some embodiments, X5 is a hydrophobic amino acid residue, such as V, L or I; such as I.

[0111] In some embodiments, Xs is R.

[0112] In some embodiments, X7 is R or K; such as R.

[0113] In some embodiments, Xs is R, K, D or E. In particular embodiments, Xs is a basic amino acid residue, such as R or K, especially R.

[0114] In some embodiments, X9 is R, K or Me-R; such as R or Me-R. In particular embodiments, X9 is R.

[0115] In some embodiments, Xw is selected from V, L, I, Tie A, G, S, T, Chg and Abu. In some embodiments, Xw is V, Tie, A, L, Abu or Chg. In some embodiments, Xw is selected from V, L, I and Tie; such as V or Tie. In particular embodiments, Xw is V.

[0116] In some embodiments, X11 is selected from R, K and Cit; such as R or Cit. In particular embodiments, X11 is R.

[0117] In some embodiments, X12 is selected from V, L, I, Tie, R, K, A, G, S, T, Chg, Aib, Abu, N and Q. In some embodiments, X12 is I, Tie, L, A, Abu, Aib, Chg, Q or K. In some embodiments, X12 is selected from V, L, I, Tie, R and K. In particular embodiments, X12 is I, Tie, L or K. In particular embodiments, X12 is a hydrophobic amino acid residue, such as I or Tie, especially I.

[0118] In some embodiments, X13 is C, homocysteine, C(oxi), Pen or Ava. In some embodiments, X13 is C, homocysteine, C(oxi) or Pen. In some embodiments, X13 is C or Pen. In particular embodiments, X13 is C. In alternative embodiments, X13 is Pen or Ava.

[0119] In some embodiments, X14 is selected from D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys, Orn, N and Q. In some embodiments, X14 is selected from D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys and Orn. In some embodiments, X14 is a small amino acid residue, such as G. In alternative embodiments, X14 is an acidic amino acid residue, such as E. In some embodiments, X14 is Q. Alternatively, X14 may be a basic amino acid residue, such as K. In some embodiments, the basic amino acid residue may have a stabilising moiety attached to the side chain, such as a PEG. For example, in some embodiments, X14 is K(PEG37).

[0120] In some embodiments, X15 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a polyethylene glycol). In some embodiments, X15 is absent. In such embodiments, X16-X20 are also absent and X14 is an acidic amino acid residue, such as E. In alternative embodiments, X15 is an acidic amino acid residue, such as E, isoE or D-Glu, or E, D, isoE or D-Glu. In particular embodiments, X15 is E. In some embodiments, X15 is a PEG, such as a PEG comprising between 1 and 50 ethylene glycol units (and all integer units in between), such as about 1 to 40, about 1 to 30, about 1 to 20, about 2 to 15, about 2 to 12 or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 units. In some embodiments, the PEG comprises 2, 4 or 12 ethylene glycol units. In particular embodiments, the PEG is represented by the Formula: -NH[(CH2)2O]n-(CH2)2- C(O)-; wherein n is an integer from 1 to 20 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. When the PEG is at the C-terminus of the proteinaceous molecule, the PEG is represented by the Formula: -NH-[(CH2)2O]n-(CH2)2-COOH; wherein n is an integer from 1 to 20 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0121] In some embodiments, X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG (e.g. the PEG moieties described for X15). In some embodiments, X16 is absent. In such embodiments, X17-X20 are also absent, and at least one of X14 and X15 is an acidic amino acid residue.

[0122] In some embodiments, X16 is an acidic amino acid residue such as D, E, isoE or D-Glu; such as E, isoE or D-Glu. In particular embodiments, X16 is E.

[0123] In some embodiments, X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In some embodiments, X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn, Orn(Ac) or a PEG. In some embodiments, X17 is absent. In such embodiments, X16- X20 are also absent, and at least one of X14, X15 and X16 is an acidic amino acid residue.

[0124] In alternative embodiments, X17 is E, K, D-Lys, Orn or a PEG (e.g. the PEG moieties described for X15). In some embodiments, X17 is an acidic amino acid residue, such as E. In alternative embodiments, X17 is a basic amino acid residue, such as K, D- Lys or Orn, or K, D-Lys, Orn or Orn(Ac). In some embodiments, the basic amino acidresidue has a stabilising moiety attached to the side chain, such as a PEG. For example, in some embodiments, X17 is K(PEG37). In some embodiments, X17 is Orn(PEG37). In some embodiments, X17 is Orn(PEG4-MPA).

[0125] In some embodiments, X17 is a PEG. Suitable PEG moieties are as described above for X15. In some embodiments, X17 is PEG12.

[0126] In some embodiments, X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In some embodiments, X16 is absent. In such embodiments, X19 and X20 are also absent. In alternative embodiments, X16 is an acidic amino acid residue, such as E or a basic amino acid residue, such as K. In such embodiments, the basic amino acid residue may have a stabilising moiety attached to the side chain, such as a PEG. For example, in some embodiments, X16 is K(PEG37). Alternatively, in some embodiments, X16 is a PEG, such as a PEG moiety as described for X15. In some embodiments, X16 is PEG12.

[0127] In some embodiments, X19 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In particular embodiments, X19 is absent. In such embodiments, X20 is also absent. In alternative embodiments, X19 is an acidic amino acid reside such as E, or a basic amino acid residue such as K. In some embodiments, the basic amino acid residue may have a stabilising moiety attached to the side chain, such as a PEG as described supra. In some embodiments, X19 is a PEG, such as a PEG moiety as described for X15.

[0128] In some embodiments, X20 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG. In particular embodiments, X20 is absent. In alternative embodiments, X20 is an acidic amino acid reside such as E, or a basic amino acid residue such as K. In some embodiments, the basic amino acid residue may have a stabilising moiety attached to the side chain, such as a PEG as described supra. In some embodiments, X20 is a PEG, such as a PEG moiety as described for X15. In particular embodiments, X20 is absent or is E.

[0129] In some embodiments, X16, X19 and X20 are absent. In some embodiments, X14 is E and X15 to X20 are absent. In alternative embodiments, X15 and X16 are E and X17 to X20 are absent.

[0130] In some embodiments, X15 and X16 are E, X17 is E, K or Orn and X16 to X20 are absent.

[0131] In some embodiments, X15 is a PEG such as PEG2, and X16 and X17 are acidic amino acid residues.

[0132] In some embodiments:X1 is Y, W, F, Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, G, S, T, V, L, I, N or Q;X2is R, K, Orn, Cav, K(me2), Cit, Orn(Ac), A, G, S, T, V, L, I, N or Q;Xs is P, Aze, Hyp or a-methylproline;X4 is T or S;X5 is Cha, Chg, V, L or I;Xs is R;X7 is R or K;X8 is R, K, D or E;X9 is R, K or Me-R;X10 is V, L, I, Tie, A, G, S, T, Chg or Abu; X11 is R, K or Cit;X12 is V, L, I, Tie, R, K, A, G, S, T, Chg, Aib, Abu, N or Q;X13 is C, C(oxi), homocysteine, Pen or Ava;X14 is D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys, Orn, N or Q;X15 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG;X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn, Orn(Ac) or a PEG; X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG;X19 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; and / orX20 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.

[0133] In some embodiments:X1 is Y, W, Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, V or Q;X2 is R, Orn, Cav, K(me2), Cit, Orn(Ac), A, V, L or Q;X3 is P, Aze, Hyp or a-methylproline;X4 is T or S;X5 is Cha, Chg or I;Xs is R;X7 is R or K;X8 is R, K or E;X9 is R or Me-R;X10 is V, Tie, A, L, Abu or Chg;X11 is R, K or C it;X12 is I, Tie, L, A, Abu, Aib, Chg, Q or K;X13 is C, homocysteine, Pen or C(oxi);X14 is E, G, K or Q;X15 is absent or is E, isoE, D, D-Glu or a PEG (e.g. PEG2); X16 is absent or is E, isoE, D or D-Glu;X1? is absent or is E, K, D-Lys, Orn, Orn(Ac) or a PEG (e.g. PEG12); X16 is absent or is E, K or a PEG (e.g. PEG12);X19 is absent or is E or K; and / orX20 is absent or is E or a PEG (e.g. PEG4).

[0134] In some embodiments:X1 is Y, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-COOH), Phe(4-NH2), Tyr(iodo), Tyr(diiodo) or V;X2 is R, Orn, Orn(Ac), L, V, K(me2), Cav or Cit; such as R;X3 is P or Hyp;X4 is T or S; such as T;X5 is Cha, Chg or I; such as I;Xs is R;X7 is R;Xs is R or K;X9 is R, K or Me-R;X10 is V, A, Abu or Tie; X11 is R or K;X12 is I, Tie, Chg or Abu;X13 is C or Pen; for example C;X14 is E or G;X15 is absent or is E, D or a PEG (e.g. PEG2); X16 is absent or is E, isoE, D-Glu or D;X17 is absent or is E, D, K, Orn, Orn(Ac) or a PEG (e.g. PEG12); X16 is absent or is E, K or a PEG (e.g. PEG12);X19 is absent or is E or K; and / orX20 is absent or is E or a PEG (e.g. PEG4).

[0135] In some embodiments:X1 is Y, W, F or Nal;X2 is R, K, Orn, K(me2), Cit, Orn(Ac), A, G, S, T, V, L, I, N or Q;X3 is P or Hyp;X4 is T;X5 is Cha, Chg, V, L or I;Xs is R;X7 is R or K;X8 is R, K, D or E;X9 is R, K or Me-R;X10 is V, L, I or Tie; X11 is R, K or Cit;X12 is V, L, I, Tie, R or K;X13 is C, C(oxi), Pen or Ava;X14 is D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys or Orn;X15 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG;X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG;X19 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG; and / orX20 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.

[0136] In some embodiments:X1 is Y, W or Nal;X2 is R, Orn, K(me2), Cit, Orn(Ac), A, V, L or Q;X3 is P or Hyp;X4 is T;X5 is Cha, Chg or I;Xs is R;X? is R or K;Xs is R or E;X9 is R or Me-R;X10 is V or Tie; X11 is R or Cit;X12 is L, I, Tie or K;X13 is C or C(oxi);X14 is E, G or K;X15 is absent or is E, isoE, D-Glu or a PEG (e.g. PEG2); X16 is absent or is E, isoE or D-Glu;X17 is absent or is E, K, D-Lys, Orn or a PEG (e.g. PEG12); X16 is absent or is E, K or a PEG (e.g. PEG12);X19 is absent or is E, K or a PEG; and / orX20 is absent or is E.

[0137] In some embodiments:X1 is Y;X2 is R, Orn, K(me2) or Cit; such as R;X3 is P;X4 is T;X5 is Cha or I;Xs is R;X7 is R;Xs is R;X9 is R or Me-R;X10 is V or Tie; X11 is R;X12 is I;X13 is C;X14 is E or G;X15 is absent or is E or a PEG (e.g . PEG2) ; X16 is absent or is E;X17 is absent or is E, K, Orn or a PEG (e.g . PEG12); X16 is absent or is E, K or a PEG (e.g . PEG12);X19 is absent or is E, K or a PEG; and / orX20 is absent or is E.

[0138] In some embodiments, X15 and X16 are E and X17 is K or Orn with a stabilising moiety attached to the side chain, such as a PEG. For example, in some embodiments, X15 and X16 are E and X17 is K(PEG37) or Orn(PEG37).

[0139] When one of the amino acid residues are absent, the amino acid residues to the C-terminus of the absent amino acid residue a re also absent. For exa mple, when X15 is absent, X1S-X20 a re also absent; when X16 is absent, X17-X20 a re also absent and the like. Similarly, when an amino acid residue is present, the amino acid residues to the N- terminus of the subject amino acid residue (that may be absent) are also present. For example, when X20 is present, X15-X19 are present; when X19 is present, X15-X18 are present; when X16 is present, X15-X17 are present; when X17 is present, X15 and X16 are present; and when X16 is present, X15 is present.

[0140] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73 or 262-315 :YRPTIRRRRVRICGEE [SEQ ID NO: 1];YRPTIRRRRVRICGX21EE [SEQ ID NO: 2];YRPTIRRRRVRICE [SEQ ID NO: 3] ;YRPTIRRRRVRICGEEE [SEQ ID NO: 4] ;YRPTIRRRRVRICGX21EEE [SEQ ID NO: 5] ;YRPTIRRRRVRICGX21EEEE [SEQ ID NO: 6] ;YRPTIRRRX22VRICGX21EE [SEQ ID NO: 7];WRPTIRRRX22VRICGX21EE [SEQ ID NO: 8];WRPTX23RRRX22VRICGX21EE [SEQ ID NO: 9];YRPTIRRRRVRICEEE [SEQ ID NO: 10] ;YRPTIRRRRVRICGee [SEQ ID NO: 11];YRPTIRRRX22VRICGEE [SEQ ID NO: 12];YX24PTIRRRRVRICGEE [SEQ ID NO: 13];YAPTIRRRRVRICGEE [SEQ ID NO: 14];YRPTIRRRRVX24ICGEE [SEQ ID NO: 15];YX24PTIRRRRVRICGEEE [SEQ ID NO: 16];YRX25TIRRRRVRICGEEE [SEQ ID NO: 17];YRPTIRRRRVRICEE [SEQ ID NO: 18];YRPTIRRRRVRICGEEEE [SEQ ID NO: 19];YRPTIRRRRVRICGEEEEE [SEQ ID NO: 20];YRPTIRRRRVRICGEEEEEE [SEQ ID NO: 21];YRPTIRRRRVRICEEEE [SEQ ID NO: 22];YRPTIRRRRVRICGEEX26 [SEQ ID NO: 23];YRPTIRRRRVRICGEEX26X26 [SEQ ID NO: 24];YRPTIRRRX22VRICGEEE [SEQ ID NO: 25];YX24PTIRRRX22VRICGEE [SEQ ID NO: 26];YX24PTIRRRX22VRICGEEE [SEQ ID NO: 27];YX24PTIRRRRX27RICGEE [SEQ ID NO: 28];YQPTIRRRX22VRICGEE [SEQ ID NO: 29];YX28PTIRRRX22VRICGEE [SEQ ID NO: 30];YLPTIRRRX22VRICGEE [SEQ ID NO: 31];YVPTIRRRX22VRICGEE [SEQ ID NO: 32];YRPTIRRRX22VRICGEX29 [SEQ ID NO: 33];YRPTIRRRX22VRICGX29X29 [SEQ ID NO: 34];YRPTIRRRRVRICGEEK [SEQ ID NO: 35];YRPTIRRRRVRICGEEX30 [SEQ ID NO: 36];YRPTIRRRRVRICKEE [SEQ ID NO: 37];YRPTIRRRRVRICX30EE [SEQ ID NO: 38];YRPTIRRRRVRKCGEE [SEQ ID NO: 39];YRPTIRRRRVRX30CGEE [SEQ ID NO: 40];YX31PTIRRRRVRICGEE [SEQ ID NO: 41];YX32PTIRRRX22VRICGEE [SEQ ID NO: 42];YRPTIRRRX22VRICEE [SEQ ID NO: 43];YRPTIRRRRVRICGEEX26X26K [SEQ ID NO: 44];YRPTIRRRRVRICGEEX26X26X33 [SEQ ID NO: 45];YRPTIRRRRVRICGEEX26X26X34 [SEQ ID NO: 46];YRPTIRRRRVRICGEEX35 [SEQ ID NO: 47];YRPTIRRRRVRICGEEX36 [SEQ ID NO: 48];YRPTIRRRRVRICGEEX37 [SEQ ID NO: 49];YRPTIRRRRVRICGEEXss [SEQ ID NO: 50];YRPTIRRRRX27RICGEE [SEQ ID NO: 51];X39RPTIRRRRX27RICGEE [SEQ ID NO: 52];YRPTIRKRRX27RICGEE [SEQ ID NO: 53];YRPTIRRERX27RICE [SEQ ID NO: 54];YRPTIRRRRX27RX27CGEE [SEQ ID NO: 55];YRPTX40RRRRX27RICGEE [SEQ ID NO: 56];YRPTIRRRRVRIX41GEE [SEQ ID NO: 57];YRPTIRRRRVRICGEEX42 [SEQ ID NO: 58];YRPTIRRRRVRICGEEX26X43 [SEQ ID NO: 59];YRPTIRRRRVRICX42EE [SEQ ID NO: 60];YRPTIRRRRVRICGEEX26X26X43 [SEQ ID NO: 61];YRPTIRRRRVRICGEEX28 [SEQ ID NO: 62];YRPTIRRRRVRICGEEX44 [SEQ ID NO: 63];YRPTIRRRRVRICGEEk [SEQ ID NO: 64];YRPTIRRRRVRICGEEX45 [SEQ ID NO: 65];YRPTIRRRRVRLCGEEK [SEQ ID NO: 66];YRPTIRRRRVRLCGEEX30 [SEQ ID NO: 67];YRPTIRRRRVRICGEEEK [SEQ ID NO: 68];YRPTIRRRRVRICGEEEX30 [SEQ ID NO: 69];YRPTIRRRRVRICGEEEEK [SEQ ID NO 70];YRPTIRRRRVRICGEEEEX30 [SEQ ID NO 71];YRPTIRRRRVRICGEEKEE [SEQ ID NO 72];YRPTIRRRRVRICGEEX30EE [SEQ ID NO 73];YRPTIRRRRVRICGEEEEEX48 [SEQ ID NO 262];YRPTIRRRRVRICGEEEEEX4SX48 [SEQ ID NO 263];YRPTIRRRRVKICGEE [SEQ ID NO 264];X49RPTIRRRRVRICGEEX44 [SEQ ID NO 265];X50RPTIRRRRVRICGEEX44 [SEQ ID NO 266];YRPTIRRKRVRICGEE [SEQ ID NO 267];YRPTIRRRKVRICGEE [SEQ ID NO 268];CYRPTIRRRRVRICGEE [SEQ ID NO 269];YRPTIRRRRVRIX51GEE [SEQ ID NO 270];ARPTIRRRRVRICGEE [SEQ ID NO 271];VRPTIRRRRVRICGEE [SEQ ID NO 272];YRPTIRRRRARICGEE [SEQ ID NO 273];QRPTIRRRRVRICGEE [SEQ ID NO 274];YRPSIRRRRVRICGEE [SEQ ID NO 275];YRPTIRRRRLRICGEE [SEQ ID NO 276];YRPTIRRRRVRQCGEE [SEQ ID NO 277];YRPTIRRRRVRIX52GEE [SEQ ID NO 278];YRPTIRRRRVRICQEE [SEQ ID NO 279];YRPTIRRRRVRICGDE [SEQ ID NO 280];YRPTIRRRRVRICGED [SEQ ID NO 281];YX53PTIRRRRVRICGEE [SEQ ID NO 282];YRPTIRRRRX40RICGEE [SEQ ID NO 283];YRPTX40RRRRVRICGEE [SEQ ID NO 284];YRPTIRRRRVRX40CGEE [SEQ ID NO 285];YRX25TIRRRRVRICGEE [SEQ ID NO 286];YRX54TIRRRRVRICGEE [SEQ ID NO 287];YRXssTIRRRRVRICGEE [SEQ ID NO 288];XssRPTIRRRRVRICGEE [SEQ ID NO 289];X57RPTIRRRRVRICGEE [SEQ ID NO 290];XssRPTIRRRRVRICGEE [SEQ ID NO 291];X59RPTIRRRRVRICGEE [SEQ ID NO 292];YRPTIRRRRVRACGEE [SEQ ID NO 293];YRPTIRRRRVRXeoCGEE [SEQ ID NO 294];YRPTIRRRRVRXeiCGEE [SEQ ID NO 295];YRPTIRRRRXeoRICGEE [SEQ ID NO 296];X62RPTIRRRRVRICGEE [SEQ ID NO 297];YRPTIRRRRVRICGEEX32 [SEQ ID NO 298];YRPTIRRRRVRICGEEX26X33 [SEQ ID NO 299];YRPTIRRRRVRICGEEX26X26X63 [SEQ ID NO 300];YRPTIRRRRVRICGEEX26X26X64 [SEQ ID NO 301];YRPTIRRRRVRICGEEX26X26X65 [SEQ ID NO 302];YRPTIRRRRVRICGEEX26X26X66 [SEQ ID NO 303];YRPTIRRRRVRICGEEX26X26X67 [SEQ ID NO 304];YRPTIRRRRVRICGEEX26X34 [SEQ ID NO 305];YRPTIRRRRVRICGEEXes [SEQ ID NO 306];YRPTIRRRRVRICGEEEEXes [SEQ ID NO 307];YRPTIRRRRVRICGEEEXes [SEQ ID NO 308];YRPTIRRRRVRICGEEXesEE [SEQ ID NO 309];YRPTIRRRRVRICGEEX44X69 [SEQ ID NO 310];YRPTIRRRRVRICGEEX48X70 [SEQ ID NO 311];YRPTIRRRRVRICGEEX48X71 [SEQ ID NO 312];YRPTIRRRRVRICGEEX48X48X71 [SEQ ID NO 313];YRPTIRRRRVRICGEEX72X71 [SEQ ID NO 314]; andYRPTIRRRRVRICGEEX73 [SEQ ID NO 315],wherein:X21 is PEG2; X22 is Me-R; X23 is Cha; X24 is Cit; X25 is Hyp; X26 is PEG12; X27 is Tie; X28 is Orn; X29 is isoE; X30 is K(PEG37); X31 is K(me2); X32 is Orn(Ac); X33 is K(isoE-C18A); X34 is K(isoE-C16); X35 is K(PEG 5kDa); X3e is K(PEG lOkDa); X37 is K(PEG 20kDa); X38 is K(PEG 40kDa); X39 is Nal; X4o is Chg; X4i is C(oxi); X42 is K(albutag); X43 is K(isoE-albutag); X44 is Orn(PEG37); X45 is k(PEG37); X48 is PEG4; X49 is Tyr(iodo); X50 is Tyr(diiodo); X51 is Pen; X52 is homocysteine; X53 is canavanine; Xs4 is Aze; X55 is a-methylproline; Xse is homotyrosine; X57 is Dopa; Xss is Phe(4-MeOH); X59 is Phe(4-COOH); Xso is Abu; Xsi is Aib; X62 is Phe(4-NH2); X63 is K(isoE-C14A); X64 is K(isoE-C14); Xes is K(isoE-C12); Xee is K(isoE- C10); X67 is K(isoE-C16A); Xes is K(C16); Xeg is K(PEG4-biotin); X70 is K(C12); X71 is K(C18A); X72 is PEG24; and X73 is Orn(PEG4-MPA).

[0141] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65, 68-73, 262-270, 272, 273, 275, 279-286, 289-294, 296-298, 300-305, 310, 314 and 315. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 1-4, 6-8, 10-12, 18-20, 36, 41, 43, 47, 61, 63, 65, 69, 71, 73, 262, 263, 265, 266, 292, 300, 304, 310 or 315.

[0142] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 73 or any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1- 4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 1-4, 6-8, 10-12, 18-20, 36, 41, 43, 7, 61, 63, 65, 69, 71 or 73. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 1, 35, 36, 62-65 or 68-73, or SEQ ID NO: 1, 36, 63, 65, 69, 71 or 73.

[0143] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula III:X1X2PTX5RRRX9X1oRX12CX14X15X16X17X18X19X2o (III) wherein:X1, X2, X5, X9, X10, X12 and XM-X20 are as defined for Formula I supra.

[0144] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IV:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17 (IV) wherein:X1-X17 are as defined for Formula I supra.

[0145] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula V:X1X2PTX5RRRX9X10RX12CX14X15X16X17 (V) wherein:X1, X2, X5, X9, X10, X12 and X14-X17 a re as defined for Formula I supra.

[0146] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VI:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X46 (VI) wherein:X1-X20 are as defined for Formula I supra; andX46 is absent or is a PEG.

[0147] Suitable PEGs include those described for X15 supra. In some embodiments, the PEG is represented by the Formula: -NH-[(CH2)2O]n-(CH2)2-COOH; wherein n is an integer from 1 to 20 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, X46 is PEG4.

[0148] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VII:Z1X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20Z2 (VII) wherein:X1-X20 are as defined for Formula I supra; andZi and Z2 are independently absent or are independently selected from at least one of a proteinaceous moiety consisting of from about 1 to about 50 amino acid residues (and all integer residues in between), and a protecting moiety.

[0149] In some embodiments, Zi is absent or is a proteinaceous moiety consisting of from about 1 to about 10 amino acid residues (and all integer residues in between); especially about 2 to about 4 amino acid residues (and all integer residues in between). The amino acid residues are selected from any amino acid residues.

[0150] In some embodiments, Z2 is absent or is a proteinaceous moiety consisting of from about 1 to about 10 amino acid residues (and all integer residues inbetween); especially about 3 to about 5 amino acid residues (and all integer residues in between). The amino acid residues are selected from any amino acid residues.

[0151] In particular embodiments, Zi and Z2 are absent.

[0152] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VIII:Z1X1X2PTX5RRRX9X10RX12CX14X15X16X17X18X19X20Z2 (VIII) wherein:X1, X2, X5, X9, X10, X12 and X14-X20 are as defined for Formula I supra; andZi and Z2 are as defined for Formula VII supra.

[0153] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IX:Z1X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17Z2 (IX) wherein:X1-X17 are as defined for Formula I supra; andZi and Z2 are as defined for Formula VII supra.

[0154] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula X:Z1X1X2PTX5RRRX9X10RX12CX14X15X16X17Z2 (X) wherein:X1, X2, X5, X9, X10, X12 and X14-X17 are as defined for Formula I supra; andZi and Z2 are as defined for Formula VII supra.

[0155] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XI:Z1X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X46Z2 (XI) wherein:X1-X20 and X46 are as defined for Formula VI supra; andZi and Z2 are as defined for Formula VII supra.

[0156] In some embodiments, the proteinaceous molecule comprises an intramolecular linkage, such as a thioether bond, a disulfide bond, a thioether linkage, a lanthionine bridge, an amide bond, an ester linkage, a thioester linkage, a carbamoyl linkage, an alkyl linkage, an alkenyl linkage, an ether linkage, a thioether linkage, an amine linkage or a thioamide linkage.

[0157] For example, in some embodiments of Formulae I and III-XI, X13 is C and the proteinaceous molecule comprises an intramolecular linkage between the side chain of the cysteine residue in the X13 position and the N-terminal amine of the N-terminal amino acid residue (i.e. the amino acid residue in the X1 position). In particular embodiments, X13 is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X13 position and the N-terminal amine of the amino acid residue in the X1 position.

[0158] In particular embodiments, X13 is C and the side chain of the cysteine residue in the X13 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the X1 position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X13, and R1is C1-6 alkylene.

[0159] In some embodiments, R1is methylene or ethylene, especially methylene.

[0160] Alternatively, the side chain of the amino acid residue in the X13 position may form an amide bond with the N-terminal amine of the N-terminal amino acid residue (i.e. the amino acid residue in the X1 position). For example, in some embodiments, X13 is Ava and the N-terminal amine of X1 and the C-terminal acid of X13 form an amide bond.

[0161] The proteinaceous molecule may, alternatively comprise a disulfide bond. Accordingly, in some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XII:X47X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (XII) wherein:X1-X12 and X14-X20 are as defined for Formula I supra; andX13 and X47 are selected from C and modified forms thereof, and Pen.

[0162] In some embodiments, X13 and X47 are C. In alternative embodiments, X13 and X47 are Pen.

[0163] In particular embodiments, the proteinaceous molecule comprises a disulfide bond between the side chains of X13 and X47.

[0164] For example, in some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XIII:X47X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (XIII) wherein:X1-X12 and X14-X20 are as defined for Formula I supra;X13 and X47 are selected from C and modified forms thereof, and Pen; and the side chains of X13 and X47 form a linkage represented by Formula XIV:wherein each sulfur atom is the sulfur atom from X13 and X47, and R2is a bond or a divalent linker selected from the group consisting of C1-6 alkylene, C2-6 alkenylene and -C1-6 alkylene-6-10 membered aryl-C1-6 alkylene-.

[0165] In some embodiments, R2is a bond or a divalent linker selected from the group consisting of C1-3 alkylene, C2-4 alkenylene and -C1-3 alkylene-phenyl-Ci-3 alkylene-; especially a bond or a divalent linker selected from the group consisting of methylene, ethylene, C4 alkenylene and -methylene-phenyl-methylene-. In some embodiments, R2is a bond or a divalent linker selected from the group consisting of: methylene, ethylene,

[0166] In particular embodiments, R2is a bond. In alternative embodiments, R2

[0167] In some embodiments, the proteinaceous molecule represented by Formula XIII is a proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by SEQ ID NO: 269, wherein R2is a bond or adivalent linker selected from the group consisting of:and

[0168] In some embodiments, the proteinaceous molecule is cyclised through N- to-C cyclisation (head to tail cyclisation), such as through an amide bond (e.g. an amide bond between the N- and C-termini of the linear peptide or via an amide bond between a C-terminal Ava residue and the N-terminus of the peptide as discussed supra). In some embodiments, the proteinaceous molecules of the invention have an amide-cyclised peptide backbone.

[0169] In some embodiments, the N- and C-termini are linked using a linking moiety. Suitable linking moieties include a thioether linkage, an amide bond, an ester linkage, a thioester linkage, a carbamoyl linkage, an alkyl linkage, an alkenyl linkage, an ether linkage, a thioether linkage, an amine linkage or a thioamide linkage. The linking moiety may, alternatively, be a peptide linker such that cyclisation produces an amide- cyclised peptide backbone. The linking moiety will be of suitable length to span the distance between the N- and C-termini of the peptide without substantially altering the structural conformation of the proteinaceous molecule, for example, a peptidic linking moiety may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues in length. In some embodiments, longer or shorter peptidic linking moieties may be required. In alternative embodiments, the proteinaceous molecule is an acyclic molecule.

[0170] In some embodiments where the proteinaceous molecules of the invention comprise an N- and / or C-terminus, the proteinaceous molecules of the invention have a primary, secondary or tertiary amide, a hydrazide, a hydroxamide, a methyl group or a free-carboxyl group at the C-terminus and / or a primary amine or acetamide at the N- terminus. In some embodiments, the proteinaceous molecules of the invention are cyclic peptides and, thus, may not comprise N- and / or C-terminal amino acid residues. In preferred embodiments, the proteinaceous molecules of the invention have a primary amide, a methyl group or a free carboxyl group (C-terminal acid) at the C-terminus and a primary amine at the N-terminus, especially a primary amide or a free carboxyl group at the C-terminus (C-terminal acid) and a primary amine at the N-terminus. In some embodiments, the proteinaceous molecule comprises a C-terminal amide. In some embodiments, the proteinaceous molecule comprises an N-terminal acetamide (i.e. the N- terminus is acetylated).

[0171] The proteinaceous molecule of the invention may be between 14 amino acid residues and 50 amino acid residues in length (and all integer amino acid residuestherebetween); especially between 14 amino acid residues and 40 amino acid residues in length, between 14 amino acid residues and 30 amino acid residues in length or between 14 amino acid residues and 21 amino acid residues in length; more especially between about 14 amino acid residues and 17 amino acid residues in length; including about 14, 15, 16, 17, 18, 19, 20 or 21 amino acid residues in length.

[0172] In some embodiments, the proteinaceous molecule is a selective antagonist of an ASIC, for example, ASICla, over at least one other ASIC isoform, such as ASIClb, ASIC2a, ASIC2b, ASIC3 or ASIC4. In some embodiments, the proteinaceous molecule exhibits ASICla selectivity of greater than about 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or greater than about 100-fold with respect to antagonism of another ASIC isoform. In some embodiments, the proteinaceous molecule has substantially reduced binding to MRGPRX2 compared to a proteinaceous molecule having a comparable sequence but does not comprise one or more acidic amino acid residues in the X14 to X20 positions.

[0173] In some embodiments, the proteinaceous molecule of Formula I or III- XIII as discussed supra is one of the proteinaceous molecules defined in Tables 6 and / or 7. In some embodiments, the proteinaceous molecule of Formula I or III-XIII as discussed supra is IB212, IB229, IB261, IB262, IB264, IB278, IB IB286, IB287, IB301, IB302, IB303, IB324, IB328, IB342, IB355, IB404, IB IB422, IB423, IB424, IB489, IB490, IB692, IB693, IB668, IB699, IB70 r IB678. In some embodiments, the proteinaceous molecule of Formulaas discussed supra is IB212, IB324, IB409, IB422, IB423 or IB424.

[0174] In some embodiments, the proteinaceous molecule of Formula I or III- XIII as discussed supra has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to the amino acid sequence of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73. In some embodiments, the proteinaceous molecule of Formula I or III-XIII as discussed supra has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73. In such molecules, the variance occurs at one or more of X1 to X20, X46, X47, Zi or Z2 when present in the subject Formula.

[0175] The present invention also contemplates proteinaceous molecules that are variants of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61- 65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73. Such "variant" proteinaceous molecules include proteinaceous molecules derived from any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, by deletion or addition of one or more amino acids (such as from 1-50 amino acid residues and all integer amino acids therebetween) to the N-terminal and / or C-terminal end of the proteinaceous molecule, deletion or addition of one or more amino acids (such as from 1-5 amino acid residues and all integer amino acids therebetween) at one or more sites in the proteinaceous molecule, or substitution of one or more amino acids at one or more sites in the proteinaceous molecule. For example, in some embodiments, the variant proteinaceous molecule comprises an addition of one amino acid residue or deletion of one amino acid residue.

[0176] Variant proteinaceous molecules encompassed by the present invention are biologically active, that is, they continue to possess the desired biological activity of the parent proteinaceous molecule, for example, ASICla antagonism. Such variants may result from, for example, genetic polymorphism or from human manipulation.

[0177] The proteinaceous molecules of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1 to 73 may be altered in various ways, including amino acid substitutions, deletions, truncations and insertions. Methods for such manipulations are generally known in the art. For example, amino acid sequence variants of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73 may be prepared by mutagenesis of nucleic acids encoding the amino acid sequence of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73. Methods for mutagenesis and nucleotide sequence alterations are well known in the art. Refer to, for example, Kunkel (1985) Proc. Natl. Acad. Sci. USA. 82: 488-492; Kunkel, et al. (1987) Methods in Enzymol, 154: 367- 382; and Daggett, et al. (2009) ACS Chem Biol, 4(2): 109-113. Recursive ensemble mutagenesis (REM), a technique which enhances the frequency of functional mutants in the libraries, can be used in combination with screening assays to identify active variants (Arkin and Yourvan (1992) Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave et al., (1993) Protein Engineering, 6: 327-331). Variant proteinaceous molecules may also be designed using medicinal chemistry approaches standard in the art.

[0178] Conservative substitutions, such as exchanging one amino acid with another having similar properties, may be particularly desirable. Variant proteinaceousmolecules of the invention may contain conservative amino acid substitutions (e.g. 1, 2 or 3 substitutions) at various locations along their sequence, as compared to a parent or reference amino acid sequence, such as any one of SEQ ID NOs: 1 to 73.

[0179] Variant proteinaceous molecules of the invention may contain conservative amino acid substitutions at various locations along their sequence, as compared to a parent (e.g. naturally-occurring or reference) amino acid sequence, such as any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art as discussed in detail below.

[0180] Acidic: The residue has a negative charge due to loss of a proton at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH. Amino acids having an acidic side chain include glutamic acid and aspartic acid.

[0181] Basic: The residue has a positive charge due to association with protons at physiological pH or within one or two pH units thereof (e.g. histidine) and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH. Amino acids having a basic side chain include arginine, lysine and histidine.

[0182] Charged: The residue is charged at physiological pH and, therefore, includes amino acids having acidic or basic side chains, such as glutamic acid, aspartic acid, arginine, lysine and histidine.

[0183] Hydrophobic: The residue is not charged at physiological pH and the residue is repelled by aqueous solution so as to seek the inner positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH. Amino acids having a hydrophobic side chain include tyrosine, valine, isoleucine, leucine, methionine, norleucine, phenylalanine and tryptophan. In particular embodiments, hydrophobic amino acids include valine, leucine and isoleucine.

[0184] Neutral / polar: The residues are not charged at physiological pH but the residue is not sufficiently repelled by aqueous solutions so that it would seek inner positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH. Amino acids having a neutral / polar side chain include asparagine, glutamine, cysteine, histidine, serine and threonine.

[0185] Amide-containing: The residues contain an amide in their side chain, such as glutamine and asparagine.

[0186] Aromatic: The residues contain an aromatic group in their side chain and include phenylalanine, tyrosine and tryptophan.

[0187] This description also characterizes certain amino acids as "small" since their side chains are not sufficiently large, even if polar groups are lacking, to confer hydrophobicity. With the exception of proline, "small" amino acids are those with four carbons or less when at least one polar group is on the side chain and three carbons or less when not. Amino acids having a small side chain include glycine, serine, alanine and threonine. The gene-encoded secondary amino acid proline is a special case due to its known effects on the secondary conformation of peptide chains. The structure of proline differs from all the other naturally-occurring amino acids in that its side chain is bonded to the nitrogen of the a-amino group, as well as the a-carbon. For the purposes of the present invention, proline is not classified as a "small" amino acid unless otherwise specified. Small amino acid residues include glycine, serine, alanine and threonine.

[0188] The degree of attraction or repulsion required for classification as polar or non-polar is arbitrary and, therefore, amino acids specifically contemplated by the invention have been classified as one or the other. Most amino acids not specifically named can be classified on the basis of known behaviour.

[0189] Amino acid residues can be further sub-classified as cyclic or non-cyclic, and aromatic or non-aromatic, self-explanatory classifications with respect to the side chain substituent groups of the residues, and as small or large. The residue is considered small if it contains a total of four carbon atoms or less, inclusive of the carboxyl carbon, provided an additional polar substituent is present; three or less if not. Small amino acid residues are, of course, always non-aromatic. Dependent on their structural properties, amino acid residues may fall in two or more classes. For the naturally-occurring protein amino acids, sub-classification according to this scheme is presented in Table 1 in Section 1 supra.

[0190] Conservative amino acid substitution also includes groupings based on side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. For example, it is reasonable to expect that replacement of an aspartic acid with a glutamic acid, a threonine with a serine, a lysine with an arginine,a tyrosine with a phenylalanine, an asparagine with a glutamine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the properties of the resulting variant peptide of the invention. Whether an amino acid change results in a proteinaceous molecule that inhibits ASICla can readily be determined by assaying its activity. Conservative substitutions are shown in Table 2 under the headings of 'Exemplary Substitutions' and 'Preferred Substitutions'. Amino acid substitutions falling within the scope of the invention, are, in general, accomplished by selecting substitutions that do not differ significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. After the substitutions are introduced, the variants are screened for biological activity.TABLE 2EXEMPLARY AND PREFERRED AMINO ACID SUBSTITUTIONS

[0191] Alternatively, similar amino acids for making conservative substitutions can be grouped into three categories based on the identity of the side chains. The first group includes glutamic acid, aspartic acid, arginine, lysine and histidine, which all have charged side chains; the second group includes glycine, serine, threonine, cysteine, tyrosine, glutamine and asparagine; and the third group includes leucine, isoleucine, valine, alanine, proline, phenylalanine, tryptophan, methionine and norleucine, as described in Zubay, Biochemistry, third edition, Wm.C. Brown Publishers (1993).

[0192] Thus, a predicted non-essential amino acid residue in a proteinaceous molecule of the invention is typically replaced with another amino acid residue from the same side chain family. Alternatively, mutations can be introduced randomly along all or part of the coding sequence of a proteinaceous molecule of the invention, if it contains naturally occurring amino acid residues, such as by saturation mutagenesis, and the resultant mutants can be screened for an activity of the parent polypeptide, as described for example herein, to identify mutants which retain that activity. Following mutagenesis of the coding sequences, the encoded proteinaceous molecule can be expressed recombinantly and its activity determined. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequence of an embodiment proteinaceous molecule of the invention without abolishing or substantially altering one or more of its activities. Suitably, the alteration does not substantially alter one of these activities; for example, the activity is at least 20%, 40%, 60%, 70% or 80% of that of the wild-type. By contrast, an "essential" amino acid residue is a residue that, when altered from the wild-type sequence of an embodiment proteinaceous molecule of the invention, results in abolition of an activity of the parent molecule such that less than 20% of the wild-type activity is present.

[0193] Accordingly, the present invention also contemplates variants of the proteinaceous molecules of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, wherein the variants are distinguished from the parent sequence by the addition, deletion, or substitution of one or more amino acid residues. In general, variants will display at least about 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to a parent or reference proteinaceous molecule sequence as, for example, set forth in any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, as determined by sequence alignment programs described elsewhere herein using default parameters. Desirably, variants will have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to a parent or reference proteinaceous molecule sequence as, for example, set forth in any one of SEQ ID NOs: 1- 73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, as determined by sequence alignment programs described herein using default parameters. Variants of any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61- 65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, which fall within the scope of a variant proteinaceous molecule of the invention, may differ from the parent molecule generally by at least 1, but by less than 5, 4, 3, 2 or 1 amino acid residue(s). In some embodiments, a variant proteinaceous molecule of the invention differs from the corresponding sequence in any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1-73, such as any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73 or any one of SEQ ID NOs: 1-4, 6-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73, by at least 1, but by less than 5, 4, 3, 2 or 1 amino acid residue(s). In some embodiments, the amino acid sequence of the variant proteinaceous molecule of the invention comprises the proteinaceous molecule of Formula I or III-XIII. In particular embodiments, the variant proteinaceous molecule of the invention inhibits an activity of ASICla.

[0194] If the sequence comparison requires alignment, the sequences are typically aligned for maximum similarity or identity. "Looped" out sequences from deletions or insertions, or mismatches, are generally considered differences. The differences are, suitably, differences or changes at a non-essential residue or a conservative substitution.

[0195] In some embodiments, calculations of sequence similarity or sequence identity between sequences are performed as follows:

[0196] To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g. gaps can be introduced in one or both of a first and a second amino acid or nucleic acidsequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In some embodiments, the length of a reference sequence aligned for comparison purposes is at least 40%, more usually at least 50% or 60%, and even more usually at least 70%, 80%, 90% or 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, then the molecules are identical at that position. For amino acid sequence comparison, when a position in the first sequence is occupied by the same or similar amino acid residue (i.e. conservative substitution) at the corresponding position in the second sequence, then the molecules are similar at that position.

[0197] The percent identity between the two sequences is a function of the number of identical amino acid residues shared by the sequences at individual positions, taking into account the number of gaps and the length of each gap, which need to be introduced for optimal alignment of the two sequences. By contrast, the percent similarity between the two sequences is a function of the number of identical and similar amino acid residues shared by the sequences at individual positions, taking into account the number of gaps and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0198] The comparison of sequences and determination of percent identity or percent similarity between sequences can be accomplished using a mathematical algorithm. In certain embodiments, the percent identity or similarity between amino acid sequences is determined using the Needleman and Wiinsch algorithm (1970, J. Mol. Biol., 48: 444-453) which has been incorporated into the GAP program in the GCG software package (Devereaux, et al. (1984) Nucleic Acids Research, 12: 387-395), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity or similarity between amino acid sequences can be determined using the algorithm of Meyers and Miller (1989, Cabios, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In some embodiments, the percent identity or similarity between amino acid sequences can be determined using the CLUSTAL W program (Thompson et al. (1994) Nucleic Acids Research, 22(11): 4673-4680).

[0199] The proteinaceous molecules of the invention may also encompass modified amino acid residues. Modified amino acid residues may include residues with modified side chains, N-methyl amino acids, a-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0200] Examples of side chain modifications include modifications of amino groups, such as by acetylation with acetic anhydride; acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; amidination with methylacetimidate; carbamoylation of amino groups with cyanate; pyridoxylation of lysine with pyridoxal-5- phosphate followed by reduction with sodium borohydride; reductive alkylation by reaction with an aldehyde followed by reduction with sodium borohydride; and trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The carboxyl group may be modified by carbodiimide activation through O-acylisourea formation followed by subsequent derivatization, for example, to a corresponding amide. The guanidine group of arginine residues may be modified by formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal. Tryptophan residues may be modified, for example, by alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfonyl halides, or by oxidation with / V-bromosuccinimide. Tyrosine residues may be modified by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.

[0201] Suitable modified arginine residues include, but are not limited to, Nω- carboxymethyl-L-arginine, Nω-carboxyethyl-L-arginine, Nα-acetyl-L-arginine, di(phenylglyoxal)-L-arginine, N-methyl-arginine (Me-R), alpha-methyl-arginine (aMe-R), beta-arginine (b-Arg), N'-nitro-L-arginine, N',N"-dimethyl-L-arginine, N',N"-diethyl-L- arginine, homoarginine (HArg), 2-amino-4-guanidino-butyric acid (Agb), citrulline (Cit), (S)-2-amino-5-(3-methylguanidino)pentanoic acid [Arg(Me)], canavanine (Cav) and guanidinyl-alkylated-arginine (gArg).

[0202] Suitable modified lysine residues include, but are not limited to, Ne- carboxycarbonyl-L-lysine, Ne-succinimidyl-L-lysine, 2-amino-6-(2- hydroxyacetamido)hexanoic acid, Ne-3-hydroxypropyl-L-lysine, ornithine, N5-acetyl- ornithine [Orn(Ac)], Ne-allyloxycarbonyl-L-lysine, N-methyllysine, a-methyllysine, β- lysine, Nα-acetyl-L-lysine, Ne-acetyl-L-lysine [K(Ac)], Ne-methyl-L-lysine, Ne-dimethyl-L- lysine [K(me2)] and Ne-formyl-L-lysine.

[0203] Representative modified histidine residues include, but are not limited to, Nl-methyl-L-histidine, N3-methyl-L-histidine, N-methyl-L-histidine, a-methylhistidine, homohistidine and [3-histidine.

[0204] Suitable modified alanine residues include, but are not limited to, N- methylalanine, a-methylalanine (2-aminoisobutyric acid), β-alanine, Nα-acetyl-L-alanine, a-aminobutyric acid (or 2-aminobutyric acid, Abu), homoalanine, cyclohexylalanine (Cha) and β-homoalanine.

[0205] Suitable modified leucine residues include, but are not limited to, a- methylleucine, N-methylleucine, β-leucine, t-butylglycine, homoleucine, Nα-acetyl-L- leucine, tert-leucine (Tie) and β-homoleucine.

[0206] Suitable modified glutamine residues include, but are not limited to, a- methylglutamine, Nα-methylglutamine, NY-methylglutamine, β-glutamine, homoglutamine, Nα-acetyl-L-glutamine and β-homoglutamine.

[0207] Exemplary modified asparagine residues include Nβ-methyl- Nβ-methoxy- asparagine, a-methylasparagine, Nα-methylasparagine, Nβ-methylasparagine, β- asparagine, homoasparagine, Nα-acetyl-L-asparagine and β-homoasparagine.

[0208] Modified glycine residues include, but are not limited to, N-methylglycine, P-homoglycine, sarcosine (Sar), cyclohexylglycine (Chg) and Nα-acetyl-L-glycine.

[0209] Modified serine residues may include N-methylserine, a-methylserine, β- serine, Nα-acetyl-L-serine, isoserine, O-methylserine, homoserine and β-homoserine.

[0210] Exemplary modified threonine residues include N-methylthreonine, a- methylthreonine, β-threonine, Nα-acetyl-L-threonine, O-methylthreonine, homothreonine and β-homothreonine.

[0211] Exemplary modified proline residues include a-methylproline, β-proline, Nα-acetyl-L-proline, 4-phenoxy-pyrrolidine-2-carboxylic acid, 5,5-dimethylpyrrolidine-2- carboxylic acid, 5-methylpyrrolidine-2-carboxylic acid, homoproline, hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze) and β-homoproline.

[0212] Suitable modified isoleucine residues include, but are not limited to, a- methylisoleucine, N-methylisoleucine, β-isoleucine, homoisoleucine, Nα-acetyl-L- isoleucine, β-methylisoleucine and β-homoisoleucine.

[0213] Modified valine residues may include, but are not limited to, norvaline, a- methylvaline, N-methylvaline, β-valine, β-homovaline and Nα-acetyl-L-valine.

[0214] Suitable modified phenylalanine residues include, but are not limited to, a-methylphenylalanine, N-methyl-phenylalanine (Me-F), β-phenylalanine, β- methyl phenylalanine, p,β-dimethyl phenylalanine, β-hydroxyphenylalanine, homophenylalanine, Nα-acetyl-L-phenylalanine, β-homophenylalanine, 4-fluoro-L- phenylalanine (4-F-Phe), 4-methyl-L-phenylalanine (4-Me-Phe), 3,3-diphenyl-L-alanine (Dip), 4,4'-biphenyl-L-alanine (Bip), 1-naphthyl-L-alanine (Nal), 4-carboxy-L- phenylalanine (Phe(4-C00H)), 4-amino-L-phenylalanine (Phe(4-NH2)), 4-hydroxymethyl- L-phenylalanine (Phe(4-MeOH)) and 4-tert-butyl-phenylalanine (TBuF).

[0215] Exemplary modified tyrosine residues include D-tyrosine, a- methyltyrosine, N-methyltyrosine, β-tyrosine, β-methyltyrosine, p,β-dimethyltyrosine, β- hydroxytyrosine, homotyrosine, levodopa (Dopa), O-methylhomotyrosine, Nα-acetyl-L- tyrosine, O-methyltyrosine, O-ethyltyrosine, m-tyrosine, 3-iodo-tyrosine (Tyr(iodo)), 3,5- diiodo-tyrosine (Tyr(diiodo)) and β-homotyrosine.

[0216] Suitable modified tryptophan residues include, but are not limited to, a- methyltryptophan, N-methyltryptophan, β-tryptophan, β-methyltryptophan, homotryptophan, N-formyl-tryptophan, 2-methyltryptophan, Nα-acetyl-L-tryptophan and P-homotryptophan.

[0217] Suitable modified cysteine residues include, but are not limited to, N- methylcysteine, a-methylcysteine, N -acetylcysteine, β-cysteine, β-methylcysteine, D-Cys and homocysteine.

[0218] Suitable modified glutamic acid residues include, but are not limited to, N-methylglutamic acid, a-methylglutamic acid, β-glutamic acid, Nα-acetyl-L-glutamic acid, glutamic acid y-methyl ester, y-carboxy glutamic acid, homoglutamic acid, isoglutamic acid (isoE) and β-homoglutamic acid.

[0219] Suitable modified aspartic acid residues include, but are not limited to, N- methylaspartic acid, a-methylaspartic acid, β-aspartic acid, Nα-acetyl-L-aspartic acid, aspartic acid β-methyl ester and β-homoaspartic acid.

[0220] The proteinaceous molecules of the invention also encompass a proteinaceous molecule comprising unnatural amino acid residues and / or their derivatives during peptide synthesis and the use of cross-linkers and other methods which impose conformational constraints on the proteinaceous molecules.

[0221] Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of 4-amino butyric acid, 6- aminohexanoic acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 4-amino-3-hydroxy-6- methylheptanoic acid, t-butylglycine, norleucine, norvaline, phenylglycine, 2-aminobutyric acid, ornithine, / Va-acetyl-L-ornithine, sarcosine, 2-thienyl alanine, penicillamine, Dip, Bip, Nal, Orn, Me-R, b-Arg, HArg, Agb, Cit, gArg, Me-F, Cha, Tie, aMe-R, Ava, K(Ac), Arg(Me), Hyp, K(me2), Orn(Ac), Chg, isoE and / or D-isomers of amino acids. A list of unnatural amino acids contemplated by the present invention is shown in Table 3, in addition to the modified resides discussed supra.TABLE 3EXEMPLARY UNNATURAL AMINO ACIDS

[0222] Also encompassed are amino acid residues with stabilising moieties attached to the side chain. Suitable stabilising moieties are discussed elsewhere herein.

[0223] Additional amino acids or other substituents may be added to the N- or C-termini, if present, of the proteinaceous molecules of the invention. For example, the proteinaceous molecules of the invention may form part of a longer sequence with additional amino acids added to either or both of the N- and C-termini.

[0224] Proteinaceous molecules with high levels of stability may be desired, for example, to increase the half-life of the proteinaceous molecule in a subject. Thus, in some embodiments, the proteinaceous molecules of the invention comprise a stabilising or protecting moiety. The stabilising or protecting moiety may be conjugated at any point on the proteinaceous molecule. The stabilising or protecting moiety may be any moiety which delays or prevents substantial degradation of the proteinaceous molecule. A skilled person will be well aware of suitable stabilising or protecting moieties which may be used. Exemplary stabilising or protecting moieties include, but are not limited to, a peptide or protein such as an albumin including human serum albumin or a fragment or variant thereof, a glycine-rich homo-amino-acid polymer, a PAS sequence comprising a combination of alanine, serine and proline residues, the C-terminal peptide (CTP) of the P subunit of human chorionic gonadotropin or fragment or variant thereof, transferrin or a fragment or variant thereof, an albumin binding moiety, which comprises an albumin binding peptide, a bacterial albumin binding domain, an albumin-binding antibody fragment, an organic molecule such as 6-(4-(4-iodophenyl)butanamido)hexanoate (Albutag) or any combinations thereof, or an XTEN polypeptide (an extended length polypeptide with a non-naturally occurring, substantially non-repetitive sequence that is composed mainly of small hydrophilic amino acids, with the sequence having a low degree or no secondary or tertiary structure under physiologic conditions); an Fc region or single chain Fc region comprising a functional neonatal Fc receptor (FcRn) binding partner comprising an Fc domain, variant, or fragment thereof; a polymer such as a PEG, a polysialic acid or a derivative thereof, hydroxyethyl starch or a derivative thereof, ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran or polyvinyl alcohol; a glycan or polysaccharide; a lipid moiety; or a capping moiety, including an acetyl group, pyroglutamate or an amino group.

[0225] In some embodiments, the protecting or stabilising moiety is a PEG. The PEG can be of any molecular weight and can be branched or unbranched. In one embodiment, the molecular weight is between about 1 kDa and about 100 kDa, such as about 1 kDa to about 50 kDa, about 1 kDa to about 40 kDa, about 1 kDa to about 20 kDa, about 1 kDa to about 10 kDa or about 1 kDa to about 5 kDa. Other sizes can be used, depending on the desired profile (e.g. the duration of sustained release desired, the effects, if any on biological activity, the ease in handling and other known effects of the PEG to a peptide or protein). For example, the PEG can have an average molecular weight of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 kDa. In some embodiments, the PEG has an average molecular weight of about 5, 10, 20 or 40 kDa, such as 5 or 10 kDa.

[0226] The PEG may, in some embodiments, comprise between 1 and 50 ethylene glycol units (and all integer units in between), such as about 1 to 40, about 1 to30, about 1 to 20, about 2 to 15, about 2 to 12, about 20 to 40 or about 30 to 40 ethylene glycol units. In some embodiments, the PEG comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 ethylene glycol units. In some embodiments, the PEG comprises 2, 4, 12 or 37 ethylene glycol units. When the PEG is at the N-terminus of the proteinaceous molecule or attached to a side chain of an amino acid residue, the PEG is, in some embodiments, represented by the Formula: CH3- O-[(CH2)2O]n-(CH2)2-CO-; wherein n is an integer from 1 to 50 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50. In some embodiments, such as when the PEG is at the C- terminus of the proteinaceous molecule or attached to a side chain of an amino acid residue, the PEG is represented by the Formula: -NH-[(CH2)2O]n-(CH2)2-COOH, wherein n is an integer from 1 to 50 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50. In some embodiments, the PEG is incorporated as part of the backbone of the proteinaceous molecule such as at the X15-X20 positions as described herein. In such embodiments, the PEG is represented by the Formula: -NH[(CH2)2O]n-(CH2)2-C(O)-; wherein n is an integer from 1 to 50 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50.

[0227] Exemplary PEGs are provided in Table 4. For example, the exemplary PEG37 may be attached to the side chain of an amino acid residue, such as a basic amino acid residue. The exemplary PEG12, PEG4 and PEG2 may form part of the backbone of the proteinaceous molecule, for example, when incorporated at the X15-X20 positions as described herein.TABLE 4EXEMPLARY STABILISING OR PROTECTING MOIETIES

[0228] In some embodiments, such as when a PEG of at least 4 kDa is used, thePEG is represented by the following structure:wherein n is 120-1000.

[0229] In some embodiments, the stabilising or protecting moiety is a lipid moiety. The lipid moiety may be a lipid moiety comprising 6 to 24 carbon atoms in the alkyl chain (and all integers therebetween); such as from about 14 to 20 carbon atoms. For example, the lipid moiety may be hexanoyl (Cs), heptanoyl (C7), octanoyl (Cs), nonanoyl (C9), decanoyl (C10), undecanoyl (C11), dodecanoyl (C12), tridecanoyl (C13), tetradecanoyl (C14), pentadecanoyl (C15), hexadecanoyl (Cis) (also referred to herein as palmitoyl or "Pal"), heptadecanoyl (C17) or octadecanoyl (Cis). In some embodiments, the lipid moiety is derived from a diacid. For example, in some embodiments, the lipid moiety is - C(O)-C4-C22 alkyl-COOH; especially -C(O)-C4 alkyl-COOH, -C(O)-C5 alkyl-COOH, - C(O)-C6 alkyl-COOH, -C(O)-C7 alkyl-COOH, -C(O)-Cs alkyl-COOH, -C(O)-C9 alkyl-COOH,-C(0)-Cio alkyl-COOH, -C(O)-Cn alkyl-COOH, -C(O)-Ci2 alkyl-COOH (also referred to herein as C14A), -C(O)-Ci3 alkyl-COOH, -C(O)-Ci4 alkyl-COOH (also referred to herein as C16A), -C(O)-Ci5 alkyl-COOH or -C(O)-Ci6 alkyl-COOH (also referred to herein as C18A). Exemplary lipid moieties are provided in Table 4.

[0230] In some embodiments, the stabilising or protecting moiety is an albumin binding moiety such as Albutag.

[0231] The stabilising moiety may be, for example, conjugated to the N-terminal or C-terminal amino acid residue of the proteinaceous molecule or through a side chain of an amino acid residue, including through the amine of the side chain of a basic amino acid residue, such as K or Orn. In particular embodiments, the PEG is attached through the C- terminal amino acid residue, such as through the amino group of the C-terminal amide or the carboxylic acid of the C-terminal acid (e.g. via the formation of an amide bond), or through the amino group of a basic amino acid residue side chain (e.g. the e-amino group of a lysine side chain or the δ-amino group of an ornithine side chain). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue (e.g. wherein X16 is K), with a PEG conjugated to the side chain of the lysine residue.

[0232] The moiety may also be attached to the proteinaceous molecule through a side chain of an alternative amino group in the side chain of an amine- or amide- containing amino acid residue, such as arginine, glutamine and asparagine or other suitably modified side chain.

[0233] While in preferred embodiments, the protecting or stabilising moiety is directly conjugated to the side chain of an amino acid, the invention also contemplates embodiments wherein the stabilising or protecting moiety is conjugated indirectly (e.g. via an intervening spacer) to the side chain of an amino acid of the proteinaceous molecule of any one of Formulae I and III-XIII. For example, in some embodiments, the stabilising or protecting moiety is conjugated via an intervening spacer. Suitable spacers include any atom, molecule or group of molecules which places the proteinaceous molecule and stabilising or protecting moiety in a desirable configuration. In some embodiments, the spacer places the proteinaceous molecule and stabilising or protecting moiety in a configuration which does not substantially reduce the efficacy of the proteinaceous molecule (i.e. the ability to inhibit ASIC activity). Suitable spacers include, but are not limited to, a peptide, such as a peptide of 2-20 residues in length; a small molecule, such as a Ci-20 alkyl chain; an amino acid residue; a polymer, including a PEG; and the like. In some embodiments, longer or shorter spacing moieties may be required. A skilled person will be well aware of suitable spacers, and methods of introducing such spacers. Representative amino acids comprising protecting or stabilising moieties attached to their side chains are provided in Table 5.*Structures shown are where the amino acid residue is at the C-terminus of the proteinaceous molecule. The skilled person will appreciate that when the amino acid residue is attached to amino acid residues at its N- and C-terminus, the acid in the amino acid structures above is replaced by an amide bond.

[0234] In some embodiments, one of X12 and X15 to X20 is a basic amino acid residue (e.g. K or Orn) and the stabilising moiety is attached to the side chain of the basic amino acid residue. In some embodiments, X17 is a basic amino acid residue and the stabilising moiety is attached to the side chain of the basic amino acid residue (e.g. K or Orn). For example, in some embodiments, one of X12 and X14 to X20 is K(PEG37), K(PEG 5kDa), K(PEG lOkDa), Orn(PEG37), Orn(PEG 5kDa) or Orn(PEG lOkDa). In some embodiments, X14 or X17 is K(PEG37) or Orn(PEG37). In some embodiments, X17 is K(PEG37) or Orn(PEG37). In some embodiments, one of X14 to X20 is K(albutag), K(isoE- albutag), Orn(albutag) or Orn(isoE-albutag). In some embodiments, any one of X14 and X17 to X19 is K(albutag) or K(isoE-albutag).

[0235] When present, the acetyl group and / or pyroglutamate may be conjugated to the N-terminal amino acid residue of the proteinaceous molecule. In some embodiments, the N-terminus of the proteinaceous molecule is a pyroglutamide or acetamide. In some embodiments, the amino group is conjugated to the C-terminal amino acid residue of the proteinaceous molecule. In particular embodiments, the proteinaceous molecule of the invention has a primary amide at the C-terminus.

[0236] The proteinaceous molecule may, in some embodiments, comprise a cellpenetrating peptide. Suitable cell penetrating peptides may include, but are not limited to, basic poly(Arg) and poly(Lys) peptides and basic poly(Arg) and poly(Lys) peptides containing non-natural analogues of Arg and Lys residues, a TAT peptide including YGRKKRRQRRR (TAT; SEQ ID NO: 74), TFFYGGSRGKRNNFKTEEY [Angiopep2 (ANG); SEQ ID NO: 75]; RRWRRWWRRWWRRWRR (W / R; SEQ ID NO: 76), CWKis (AlkCWKis; SEQ ID NO: 77), KisWCCWKis (Di-CWKis; SEQ ID NO: 78), WTLNSAGYLLGKINLKALAALAKKIL (Transportan; SEQ ID NO: 79), GLFEALEELWEAK (DipaLytic; SEQ ID NO: 80), KieGGCRGDMFGCAKieRGD (KieRGD; SEQ ID NO: 81), KieGGCMFGCGG (Pl; SEQ ID NO: 82), KielCRRARGDNPDDRCT (P2; SEQ ID NO: 83), KKWKMRRNQFWVKVQRbAK (B) bA (P3; SEQ ID NO: 84), VAYISRGGVSTYYSDTVKGRFTRQKYNKRA (P3a; SEQ ID NO: 85), IGRIDPANGKTKYAPKFQDKATRSNYYGNSPS (P9.3; SEQ ID NO: 86),KETWWETWWTEWSQPKKKRKV (Pep-1; SEQ ID NO: 87), PLAEIDGIELTY (Plae; SEQ ID NO: 88), KieGGPLAEIDGIELGA (Kplae; SEQ ID NO: 89), KieGGPLAEIDGIELCA (cKplae; SEQ IDNO: 90), GALFLGFLGGAAGSTMGAWSQPKSKRKV (MGP; SEQ ID NO: 91), WEAK(LAKA)2- LAKH(LAKA)2LKAC (HA2; SEQ ID NO: 92), (LARL)6NHCH3(LARL4&; SEQ ID NO: 93), KLLKLLLKLWLLKLLL (Hel-11-7; SEQ ID NO: 94), (KKKK)2GGC (KK; SEQ ID NO: 95), (KWKK)2GCC (KWK; SEQ ID NO: 96), (RWRR)2GGC (RWR; SEQ ID NO: 97), PKKKRKV (SV40 NLS7; SEQ ID NO: 98), PEVKKKRKPEYP (NLS12; SEQ ID NO: 99), TPPKKKRKVEDP (NLS12a; SEQ ID NO: 100), GGGGPKKKRKVGG (SV40 NLS13; SEQ ID NO: 101), GGGFSTSLRARKA (AV NLS13; SEQ ID NO: 102), CKKKKKKSEDEYPYVPN (AV RME NLS17; SEQ ID NO: 103), CKKKKKKKSEDEYPYVPNFSTSLRARKA (AV FP NLS28; SEQ ID NO: 104), LVRKKRKTEEESPLKDKDAKKSKQE (SV40 N1 NLS24; SEQ ID NO: 105), and KgK^KsGGKs (Loligomer; SEQ ID NO: 106); HSV-1 tegument protein VP22; HSV-1 tegument protein VP22r fused with nuclear export signal (NES); mutant B-subunit of Escherichia coli enterotoxin EtxB (H57S); detoxified exotoxin A (ETA); the protein transduction domain of the HIV-1 Tat protein, GRKKRRQRRRPPQ (SEQ ID NO: 107); the Drosophila melanogaster Antennapedia domain Antp (amino acids 43-58), RQIKIWFQNRRMKWKK (SEQ ID NO: 108); Buforin II, TRSSRAGLQFPVGRVHRLLRK (SEQ ID NO: 109); hClock-(amino acids 35- 47) (human Clock protein DNA-binding peptide), KRVSRNKSEKKRR (SEQ ID NO: 110); MAP (model amphipathic peptide), KLALKLALKALKAALKLA (SEQ ID NO: 111); K-FGF, AAVALLPAVLLALLAP (SEQ ID NO: 112); Ku70-derived peptide, comprising a peptide selected from the group comprising VPMLKE (SEQ ID NO: 113), VPMLK (SEQ ID NO: 114), PMLKE (SEQ ID NO: 115) or PMLK (SEQ ID NO: 116); Prion, Mouse Prpe (amino acids 1- 28), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO: 117); pVEC, LLIILRRRIRKQAHAHSK (SEQ ID NO: 118); Pep-I, KETWWETWWTEWSQPKKKRKV (SEQ ID NO: 119); SynBI, RGGRLSYSRRRFSTSTGR (SEQ ID NO: 120); Transportan, GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 121); Transportan-10, AGYLLGKINLKALAALAKKIL (SEQ ID NO: 122); CADY, Ac-GLWRALWRLLRSLWRLLWRA- cysteamide (SEQ ID NO: 123); Pep-7, SDLWEMMMVSLACQY (SEQ ID NO: 124); HN-1, TSPLNIHNGQKL (SEQ ID NO: 125); VT5, DPKGDPKGVTVTVTVTVTGKGDPKPD (SEQ ID NO: 126); pISL, RVIRVWFQNKRCKDKK (SEQ ID NO: 127); a peptide described in US 20090047272, US 20150266935 or US 20130136742; a peptide described in Neves et al. (2017) ACS Chem Biol, 12: 1257-1268, such as VQQLTKRFSL (PepHl; SEQ ID NO: 128), KLFMALVAFLRFLT (PepH2; SEQ ID NO: 129), AGILKRW (PepH3; SEQ ID NO: 130) or KSKAINVLRGFRKEIGRMLNILN (PepH4; SEQ ID NO: 131); RKKRRRESRKKRRRES (DPV3; SEQ ID NO: 132); GRPRESGKKRKRKRLKP (DPV6; SEQ ID NO: 133); RQIKIWFQNRRMKWKK (penetratin; SEQ ID NO: 134); GRRRRRRRRRPPQ (R9-TAT; SEQ ID NO: 135); RVRVFVVHIPRLT (ARF 19-31; SEQ ID NO: 136); VSALK (Bip4; SEQ ID NO: 137); GIGAVLKVLTTGLPALISWIKRKRQQ (Melittin; SEQ ID NO: 138); or HGLASTLTRWAHYNALIRAF (gH625; SEQ ID NO: 139); especially a TAT peptide, angiopep2 or PepH3.

[0237] The cell-penetrating peptide may be conjugated to the N-terminal or C- terminal amino acid residue of the proteinaceous molecule or through a side chain of an amino acid residue, such as through the amino group in the side chain of an amine- or amide-containing amino acid residue, such as lysine, arginine, ornithine, glutamine and asparagine or other suitable modified side chain; especially through the amino group of a lysine side chain (i.e. the e-amino group). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue with a cell-penetrating peptide conjugated to the side chain of the lysine residue.

[0238] The cell-penetrating peptide may be directly attached to the proteinaceous molecule or may be attached using a suitable linker, such as a PEG moiety as described above or one or more amino acid residues (e.g. a proteinaceous molecule comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues). For example, the PEG moiety may include a linear or branched PEG having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 oxyethylene units; especially a linear PEG having 2, 3, 4, 5, or 6 oxyethylene units; more especially a linear PEG having 2 oxyethylene units.

[0239] The proteinaceous molecules of the invention may be purified, e.g. at least 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% pure. In a preferred embodiment, the preparation of proteinaceous molecule has less than about 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% (by dry weight), of molecules that are not the subject of this invention. When the proteinaceous molecule is recombinantly produced, it is also desirably substantially free of culture medium, i.e., culture medium represents less than about 20, 15, 10, 5, 4, 3, 2 or 1% of the volume of the preparation.

[0240] The proteinaceous molecules of the invention may also be in the form of salts or prodrugs. The salts of the proteinaceous molecules of the present invention are preferably pharmaceutically acceptable, but it will be appreciated that non- pharmaceutically acceptable salts also fall within the scope of the present invention.

[0241] The proteinaceous molecules may be in crystalline form and / or in the form of solvates, for example, hydrates. Solvation may be performed using methods known in the art.

[0242] The present invention also contemplates nucleic acid molecules which encode a proteinaceous molecule of the invention. Thus, in a further aspect of the present invention, there is provided an isolated nucleic acid molecule comprising a polynucleotide sequence that encodes a proteinaceous molecule of the invention or is complementary to a polynucleotide sequence that encodes a proteinaceous molecule of the invention, such as the proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by any one of Formulae I and III-XIII or any one of SEQ ID NOs: 1- 73 or 262-315, or any one of SEQ ID NOs: 1-73 as described herein.

[0243] The isolated nucleic acid molecules of the present invention may be DNA or RNA. When the nucleic acid is in DNA form, it may be genomic DNA or cDNA. RNA forms of the nucleic acid molecules of the present invention are generally mRNA.

[0244] Although the nucleic acid molecules are typically isolated, in some embodiments the nucleic acid molecules may be integrated into, ligated to, or otherwise fused or associated with other genetic molecules, such as an expression vector. Generally an expression vector includes transcriptional and translational regulatory nucleic acid operably linked to the polynucleotide sequence. Accordingly, in another aspect of the invention, there is provided an expression vector comprising a polynucleotide sequence that encodes a proteinaceous molecule of the invention, such as a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by any one of Formulae I and III-XIII or any one of SEQ ID NOs: 1-73 or 262-315, or any one of SEQ ID NOs: 1 to 73 as described herein.

[0245] In some embodiments, the proteinaceous molecules of the invention may be produced inside a cell by introduction of one or more expression constructs, such as an expression vector, that comprise a polynucleotide sequence that encodes a proteinaceous molecule of the invention.

[0246] The invention contemplates recombinantly producing the proteinaceous molecules of the invention inside a host cell, such as a mammalian cell (e.g. Chinese hamster ovary (CHO) cell, mouse myeloma (NSO) cell, baby hamster kidney (BHK) cell or human embryonic kidney (HEK293) cell), yeast cell (e.g. Pichia pastoris cell, Saccharomyces cerevisiae cell, Schizosaccharomyces pombe cell, Hansenula polymorpha cell, Kluyveromyces lactis cell, Yarrowia lipolytica cell or Arxula adeninivorans cell), insect cell (e.g. Spodoptera frugiperda cell, such as an Sf9 cell) or bacterial cell (e.g. Escherichia coli cell, Corynebacterium glutamicum or Pseudomonas fluorescens cell).

[0247] The expression of natural or synthetic nucleic acids is typically achieved by operably linking a polynucleotide sequence encoding a proteinaceous molecule of the present invention to a regulatory element (e.g. a promoter, which may be either constitutive or inducible), suitably incorporating the construct into an expression vector and introducing the vector into a suitable host cell. Typical vectors contain transcription and translation terminators, transcription and translation initiation sequences and promoters useful for regulation of the expression of the nucleic acid. The vectors optionally comprise generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in eukaryotes, prokaryotes or both (e.g. shuttle vectors), and selection markers for both prokaryotic and eukaryotic systems. Vectors may be suitable for replication and integration in prokaryotes, eukaryotes, or both. See, Giliman and Smith (1979), Gene, 8: 81-97; Roberts et al. (1987)Nature, 328: 731-734; Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology, volume 152, Academic Press, Inc., San Diego, Calif. (Berger); Sambrook et al. (1989), Molecular Cloning - a Laboratory Manual (2nd ed.) Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, N.Y.; Ausubel et al., (1998) Current Protocols in Molecular Biology, eds., John Wiley & Sons, Inc.; Rosano and Ceccarelli (2014) Front Microbiol, 5: 172; and Klint, et al. (2013) PLOS One, 8(5): e63865.

[0248] Expression vectors containing regulatory elements from eukaryotic viruses such as retroviruses are typically used for expression of nucleic acid sequences in eukaryotic cells. Exemplary vectors include SV40 vectors such as pSVT7 and pMT2, vectors derived from bovine papilloma virus such as pBV-lMTHA, and vectors derived from Epstein Bar virus such as pHEBO, and p2O5. Other exemplary vectors include pMSG, pAV009 / A+, pMTO10 / A+, pMAMneo-5, baculovirus pDSVE, and any other vector allowing expression of proteins under the direction of the SV-40 early promoter, SV-40 later promoter, metallothionein promoter, murine mammary tumour virus promoter, Rous sarcoma virus promoter, polyhedrin promoter, or other promoters shown effective for expression in eukaryotic cells.

[0249] While a variety of vectors may be used, it should be noted that viral expression vectors are useful for modifying eukaryotic cells because of the high efficiency with which the viral vectors transfect target cells and integrate into the target cell genome. Illustrative expression vectors of this type can be derived from viral DNA sequences including, but not limited to, adenovirus, adeno-associated viruses, herpes-simplex viruses and retroviruses such as B, C, and D retroviruses as well as spumaviruses and modified lentiviruses. Suitable expression vectors for transfection of animal cells are described, for example, by Wu and Ataai (2000) Curr. Opin. Biotechnol., 11(2): 205-208; Vigna and Naldini (2000) J. Gene Med., 2(5): 308-316; Kay et al. (2001) Nat. Med., 7(1): 33-40; Athanasopoulos et al. (2000) Int. J. Mol. Med., 6(4): 363-375; Walther and Stein (2000) Drugs, 60(2): 249-271; and Makrides (2004) New Comprehensive Biochemistry, 38: 9-26.

[0250] The polypeptide or peptide-encoding portion of the expression vector may comprise a naturally-occurring sequence or a variant thereof, which has been engineered using recombinant techniques. In one example of a variant, the codon composition of a polynucleotide encoding a proteinaceous molecule of the present invention is modified to permit enhanced expression of the proteinaceous molecule in a mammalian host using methods that take advantage of codon usage bias, or codon translational efficiency in specific mammalian cell or tissue types as set forth, for example, in International Publications WO 99 / 02694 and WO 00 / 42215. Briefly, these latter methods are based on the observation that translational efficiencies of different codons vary between different cells or tissues and that these differences can be exploited, together with codon composition of a gene, to regulate expression of a protein in a particular cell or tissue type.Thus, for the construction of codon-optimised polynucleotides, at least one existing codon of a parent polynucleotide is replaced with a synonymous codon that has a higher translational efficiency in a target cell or tissue than the existing codon it replaces. Although it is preferable to replace all the existing codons of a parent nucleic acid molecule with synonymous codons which have that higher translational efficiency, this is not necessary because increased expression can be accomplished even with partial replacement. Suitably, the replacement step affects 5%, 10%, 15%, 20%, 25%, 30%, more preferably 35%, 40%, 50%, 60%, 70% or more of the existing codons of a parent polynucleotide.

[0251] The expression vector is compatible with the cell in which it is introduced such that the proteinaceous molecule of the present invention is expressible by the cell. The expression vector is introduced into the cell by any suitable means which will be dependent on the particular choice of expression vector and cell employed. Such means of introduction are well-known to those skilled in the art. For example, introduction can be effected by use of contacting (e.g. in the case of viral vectors), electroporation, transformation, transduction, conjugation or triparental mating, transfection, infection membrane fusion with cationic lipids, high-velocity bombardment with DNA-coated microprojectiles, incubation with calcium phosphate-DNA precipitate, direct microinjection into single cells, and the like. Other methods also are available and are known to those skilled in the art. Alternatively, the vectors are introduced by means of cationic lipids, e.g., liposomes. Such liposomes are commercially available (e.g. Lipofectin®, Lipofectamine™, and the like, supplied by Invitrogen, Waltham MA, USA).

[0252] The proteinaceous molecules may be prepared using any suitable method, such as chemical synthesis or recombinant DNA techniques. In some embodiments, the proteinaceous molecules are prepared using standard peptide synthesis methods, such as solution synthesis or solid-phase synthesis. The chemical synthesis of the proteinaceous molecules may be performed manually or using an automated synthesiser. For example, the linear peptides may be synthesised using solid-phase peptide synthesis using either Boc or Fmoc chemistry, as described in Merrifield (1963) J Am Chem Soc, 85(14): 2149- 2154; Schnolzer, et al. (1992) Int J Pept Protein Res, 40: 180-193; Cardoso, et al. (2015) Mol Pharmacol, 88(2): 291-303; and Kumar et al. (2020) ACS Omega, 5: 2345-2354, the entire contents of which are incorporated by reference. Following deprotection and cleavage from the solid support, the linear peptides are purified using suitable methods, such as preparative chromatography. Bonds and linkages may then be formed where appropriate. For example, disuflide bonds may be formed using oxidation. Suitable conditions for oxidation of the peptide will be readily determined by a person skilled in the art. Thioether bonds may be formed using N,N-diisopropylethylamine (DIPEA), followed by acidification in trifluoroacetic acid (TFA).

[0253] In some embodiments, the proteinaceous molecules of the invention may be cyclised. Cyclisation may be performed using several techniques, for example, as described in Davies (2003) J Pept Sci, 9: 471-501; or Thongyoo et al. (2006) Chem Commun (Camb), 27 : 2848-2850. For example, N-to-C cyclisation may be conducted in the solution phase, using a dilute solution of the linear peptide in the presence of a coupling agent such as BOP (1-benzotriazole-tris-dimethyl aminophosphonium hexafluorophosphate), PyBOP (1-benzotriazolyloxy-tris-pyrrolidino phosphonium hexafluorophosphate), PyAOP (7-azabenzotriazol-l-yloxy tris pyrrolidino phosphonium hexafluorophosphate), AOP (7-azabenzotriazol-l-yloxy-tris-dimethyl aminophosphonium hexafluorophosphate), HBTU (O-(benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate), TBTU (O-(benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate), HATU (O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate), HAPyU (O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetra methylene uronium hexafluorophosphate), HAPipU (O-(7-azabenzotriazol-l-yl)-l, 1,3,3- pentamethylene uranium hexafluorophosphate), DCC ( / V, / V'-dicyclohexylcarbodiimide), DIC ( / V, / V'-diisopropylcarbodiimide), and / or EDC [l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride]. The cyclised peptide may then be deprotected (i.e. the side chain protecting groups may then be removed) using standard techniques, followed by purification using suitable methods, such as preparative chromatography. Alternatively, N-to-C cyclisation may be achieved on resin using a suitable coupling agent, such as those described above, and a suitable resin, such as a Kaiser oxime resin, and / or linker (e.g. a safety catch linker), or via native chemical ligation as described in Thongyoo et al. (2006) Chem Commun (Camb), 27: 2848-2850.

[0254] In some embodiments, the proteinaceous molecules of the invention are prepared using recombinant DNA techniques. For example, the proteinaceous molecules of the invention may be prepared by a procedure including the steps of: (a) preparing a construct comprising a polynucleotide sequence that encodes the proteinaceous molecule of the invention and that is operably linked to a regulatory element; (b) introducing the construct into a host cell; (c) culturing the host cell to express the polynucleotide sequence to thereby produce the encoded proteinaceous molecule of the invention; and (d) isolating the proteinaceous molecule of the invention from the host cell. The proteinaceous molecule of the present invention may be prepared recombinantly using standard protocols, for example, as described in Klint, et al. (2013) PLOS One, 8(5): e63865; Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual (Cold Spring Harbour Press), in particular Sections 16 and 17; Ausubel, et al. (1998) Current Protocols in Molecular Biology (John Wiley and Sons, Inc.), in particular Chapters 10 and 16; and Coligan, et al. (1997) Current Protocols in Protein Science (John Wiley and Sons, Inc.), in particular Chapters 1, 5 and 6. Where a disulfide bond is present, it may be desirable to undertake oxidative disulfide bondformation of the expressed peptide after peptide expression under some circumstances. This may be preceded by a reductive step to provide the linear peptide. Suitable conditions for reduction and oxidation of the peptide will be readily determined by a person skilled in the art. Formation of other linkages may be achieved chemically following expression of the peptide.4. Compositions

[0255] The proteinaceous molecules are also useful in compositions for treating or inhibiting the development of a condition associated with ASIC activity, such as a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment; as well as for inhibiting damage to an organ during organ transplantation. Thus, in some embodiments, the proteinaceous molecules may be in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises, consists or consists essentially of a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.

[0256] The proteinaceous molecule may be formulated into the pharmaceutical composition as a neutral or salt form.

[0257] As will be appreciated by those skilled in the art, the choice of pharmaceutically acceptable carrier or diluent will be dependent on the route of administration and on the nature of the condition and subject to be treated. The particular carrier or delivery system and route of administration may be readily determined by a person skilled in the art. The carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the proteinaceous molecule is not depleted during preparation of the formulation and the proteinaceous molecule is able to reach the site of action intact. The pharmaceutical compositions of the invention may be administered through a variety of routes including, but not limited to, oral, topical, intranasal, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebroventricular, intracerebral, intravesical, intravenous or intraperitoneal administration; especially intravenous, intrathecal, intraventricular, intracerebroventricular, intranasal or intracerebral administration; more especially intravenous or intranasal administration; most especially intravenous administration.

[0258] The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and may be preserved against reduction, oxidation and microbial contamination.

[0259] A person skilled in the art will readily be able to determine appropriate formulations for the proteinaceous molecules using conventional approaches. Techniques for formulation and administration may be found in, for example, Remington: The Science and Practice of Pharmacy, Adeboye Adejare and Joseph Remington (Ed), Academic Press, London, 23rdEdition, 2021.

[0260] Identification of preferred pH ranges and suitable excipients, such as antioxidants, is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press). Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane (Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers. Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulfite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.

[0261] For injection, the proteinaceous molecule may be formulated in an aqueous solution, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, dextrose solution or physiological saline buffer, such as phosphate buffered saline (PBS). For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0262] The compositions of the present invention may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline and sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance. Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as non-ionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives and hydrophilic beeswax derivatives.

[0263] Alternatively, the proteinaceous molecule can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the proteinaceous molecules of the invention to beformulated in dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. These carriers may be selected from sugars, chitosan, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water.

[0264] Pharmaceutical formulations for parenteral administration include aqueous solutions of the composition in water-soluble form. Additionally, suspensions of the proteinaceous molecule may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilisers or agents that increase the solubility of the proteinaceous molecules to allow for the preparation of highly concentrated solutions.

[0265] Sterile solutions may be prepared by combining the proteinaceous molecule in the required amount in the appropriate solvent with other excipients as described above as required, followed by sterilisation, such as filtration. Generally, dispersions are prepared by incorporating the various sterilised active agents into a sterile vehicle which contains the basic dispersion medium and the required excipients as described above. Sterile dry powders may be prepared by vacuum- or freeze-drying a sterile solution comprising the active agents and other required excipients as described above.

[0266] Pharmaceutical preparations for oral use can be obtained by combining the proteinaceous molecules with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilising processes.

[0267] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, PEG, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterise different combinations of particle doses.

[0268] Pharmaceuticals which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilisers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilisers may be added.

[0269] Preparations for intranasal administration may include solutions, aerosols, dry powders, suspensions, gels or emulsions; especially a solution or suspension. Intranasal compositions may include, for example, a carrier (e.g. saline or water), cosolvent (e.g. ethanol, polypropylene glycol or a PEG such as PEG400), preservative (e.g. benzyl alcohol, benzalkonium chloride, chlorobutanol, methylparaben, phenylethyl alcohol or propylparaben), surfactant (e.g. a PEG such as PEG3500, polyoxyl 400 stearate, polysorbate 20 or polysorbate 80), pH adjuster (e.g. hydrochloric acid, sodium hydroxide or sulfuric acid), antioxidant (e.g. butylated hydroxyanisole or EDTA), stabiliser (e.g. cellulose microcrystalline), buffering agent or salt (e.g. trisodium citrate, sodium citrate, citric acid, sodium phosphate or sodium chloride), polymer (e.g. cellulose, hydroxypropyl methylcellulose or polyvinylpyrrolidone) and / or sugar or sugar alcohol (e.g. sorbitol, sucrose, glycerol or glucose / dextrose).

[0270] The proteinaceous molecules may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations.

[0271] The proteinaceous molecules may be administered in a local rather than systemic manner, such as by injection directly into a tissue, such as the brain or heart tissue, which is preferably subcutaneous or omental tissue, often in a depot or sustained release formulation. In other embodiments, the proteinaceous molecule is systemically administered.

[0272] Furthermore, the proteinaceous molecule may be administered in a targeted drug delivery system, such as in a particle which is suitable targeted to and taken up selectively by a cell or tissue. In some embodiments, the proteinaceous molecule is contained or otherwise associated with a vehicle selected from liposomes, micelles,dendrimers, biodegradable particles, artificial DNA nanostructure, lipid-based nanoparticles and carbon or old nanoparticles. In illustrative examples of this type, the vehicle is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), PEG, PLA-PEG copolymers and combinations thereof.

[0273] It is advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. The determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0274] While the proteinaceous molecule of the invention may be the sole active ingredient administered to the subject, the administration of other active ingredients concurrently with said proteinaceous molecule is within the scope of the invention. For example, in some embodiments, the proteinaceous molecule may be administered concurrently with one or more anti-inflammatory agents, anticoagulants, thrombolytic agents, antiplatelet agents, antihypertensive agents, diuretics or treatments for a neurological condition. The proteinaceous molecule may be therapeutically used after the other active ingredient or may be therapeutically used together with the other active ingredient. The proteinaceous molecule may be administered separately, simultaneously or sequentially with the other active ingredient.

[0275] Accordingly, in another aspect of the invention, there is provided a composition comprising a proteinaceous molecule of the invention and an antiinflammatory agent, anticoagulant, thrombolytic agent, antiplatelet agent, antihypertensive agent, diuretic or a treatment for a neurological condition.

[0276] Exemplary anti-inflammatory agents include non-steroidal antiinflammatory drugs (NSAIDs) (e.g. acetylsalicylic acid (aspirin), diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, zomepirac, celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib), prednisone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, prednisolone, etanercept, golimumab, infliximab, adalimumab, anakinra, rituximab, natalizumab and abatacept.

[0277] Representative anticoagulants include, but are not limited to, warfarin, heparin, fondaparinux, idraparinux, idrabiotaparinux, rivaroxaban, dabigatran, apixaban,edoxaban, betrixaban, letaxaban, eribaxaban, hirudin, lepirudin, bivalirudin, argatroban, dabigatran, ximelagatran, antithrombin, enoxaparin and dalteparin.

[0278] Representative thrombolytic agents include tissue plasminogen activator (e.g. alteplase, reteplase, tenecteplase and anistreplase), streptokinase and urokinase.

[0279] Suitable antiplatelet agents include acetylsalicylic acid, clopidogrel, dipyridamole, cangrelor, prasugrel, ticagrelor, ticlopidine, apciximab, eptifibatide, tirofiban, triflusal, cilostazol, vorapaxar, terutroban, ifetroban, naproxen and picotamide.

[0280] Suitable antihypertensive agents include, but are not limited to, diuretics (e.g. indapamide, bendroflumethiazide, amiloride and spironolactone), angiotensinconverting enzyme inhibitors (e.g. captopril, enalapril, lisinopril, perindopril and ramipril), calcium channel blockers (e.g. amlodipine, felodipine, nifedipine, diltiazem and verapamil), beta blockers (e.g. atenolol, metoprolol and bisoprolol), alpha blockers (e.g. doxazosin) and angiotensin-2 receptor blockers (e.g. candesartan, irbesartan, losartan, valsartan and olmesartan).

[0281] Concurrent administration with a diuretic is also contemplated. Suitable diuretics include, but are not limited to, chlorothiazole, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid furosemide, torsemide, amiloride, eplerenone, spironolactone and triamterene.

[0282] The present invention also contemplates concurrent administration with a treatment for a neurological condition, such as Parkinson's disease, multiple sclerosis or Alzheimer's disease, representative examples of which include levodopa (optionally with carbidopa), pramipexole, apomorphine, selegiline, rasagiline, safinamide, entacapone, opicapone, tolcapone, benztropine, trihexylphenidyl, amantadine, istradefyl line, nuplazid, corticosteroids such as prednisone and methylprednisolone, glatiramer acetate, ofatumumab, interferon beta (e.g. interferon beta-la), teriflunomide, dimethyl fumarate, diroximel fumarate, monomethyl fumarate, fingolimod, siponimod, ozanimod, ponesimod, cladribine, natalizumab, ocrelizumab, alemtuzumab, donepezil, galantamine, rivastigmine, memantine, aducanumab, lecanemab, tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, olanzapine, aripiprazole, levitiracetam, clonazepam, citalopram, escitalopram, fluoxetine, sertraline, quetiapine, olanzapine, divalproex, carbamazepine and lamotrigine.

[0283] Ranolazine may also be administered concurrently with the proteinaceous molecule of the invention.

[0284] In some embodiments, the proteinaceous molecule of the invention is administered concurrently with an antihistamine (e.g. brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, dimenhydrinate,diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine or fexofenadine) or mast cell stabiliser (e.g. cromoglicic acid, nedocromil, lodoxamide, ketotifen, olopatadine, bepotastine, alcaftadine or azelastine).

[0285] As previously described, the proteinaceous molecule may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. In some embodiments, a dosage unit form may comprise the proteinaceous molecule in an amount in the range of from about 0.25 μg to about 2000 mg. The proteinaceous molecule may be present in an amount of from about 0.25 μg to about 2000 mg / mL of carrier. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

[0286] The present invention also contemplates the use of the proteinaceous molecules of the invention for inhibiting damage to an organ during organ transplantation and for inhibiting ischaemia-reperfusion injury in a tissue. As such, the proteinaceous molecule may be in the form of a composition suitable for this use (e.g. for immersing or perfusing an organ or tissue). The composition may comprise, consist or consist essentially of a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may include any liquid carrier suitable for organ transplantation and storage, representative examples of which include water, saline and the like. The composition may also include one or more salts and electrolytes, such as potassium, calcium, magnesium, sodium, chloride, or a salt thereof, such as sodium chloride, sodium lactate, potassium chloride, calcium chloride, magnesium chloride, magnesium sulfate and / or sodium bicarbonate. For example, the carrier may be selected from lactated Ringer's solution, a cardioplegic solution or an electrolyte composition. The composition may further comprise a buffering agent (e.g. phosphate, bicarbonate, histidine and / or trisaminomethane), a pH adjusting agent (e.g. hydrochloric acid or sodium hydroxide), a colloid or impermeant (e.g. lactobionate, raffinose, mannitol, dextran, trehalose, PEG and / or hydroxyethyl starch such as pentafraction), antioxidant (e.g. glutathione, allopurinol, mannitol, tryptophan and / or alpha-ketoglutarate), glucose, amino acids (e.g. histidine, tryptophan, N-acetylhistidine, glycine, alanine, arginine, aspartic acid and / or glutamic acid), sulfate, adenosine, sucrose, nitroglycerin, dibutyryl cAMP, gluconate and / or deferoxamine LK-614.

[0287] In some embodiments, the composition comprises a Euro-Collins solution, University of Wisconsin solution, histidine-tryptophan-ketoglutarate solution, Custodiol-N solution, Celsior solution, low-potassium dextran glucose solution, EP4 (EP-TU) solution, ET-Kyoto solution, IGL-1 solution, Steen solution or Organ Care System (OCS) perfusate, as discussed in Ji ng et al. (2018) Acta Pharmacologica Sinica, 39: 845-857.

[0288] In some embodiments, the composition has a temperature in the range of from 0-4 °C.5. Methods of Use

[0289] The proteinaceous molecules of the invention have been found to inhibit ASIC, especially ASICla. As such, the inventors have conceived that the proteinaceous molecules will be useful for treating or inhibiting the development of a condition associated with ASIC activity, especially ASICla activity, such as a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment; as well as for inhibiting damage to an organ during organ transplantation. Accordingly, a proteinaceous molecule of the invention for use in therapy is contemplated.

[0290] In another aspect, there is provided a method of inhibiting an activity of an ASIC, comprising, consisting or consisting essentially of contacting the ASIC with a proteinaceous molecule of the invention. The invention also provides a use of a proteinaceous molecule of the invention for inhibiting an activity of an ASIC, a proteinaceous molecule of the invention for use in inhibiting an activity of an ASIC, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for inhibiting an activity of an ASIC.

[0291] In particular embodiments, the ASIC is ASICla.

[0292] The methods involve inhibiting one or more activities of an ASIC including, but not limited to, transport of sodium ions across a cellular membrane (e.g. cellular influx), transport of calcium ions across a cellular membrane (e.g. cellular influx), ASIC activation, ASIC desensitisation, proton binding, ERK activation, RIPK1 phosphorylation and / or ERK phosphorylation; especially transport of sodium ions across a cellular membrane and / or transport of calcium ions across a cellular membrane.

[0293] The methods and uses may comprise contacting a cell expressing ASIC with a proteinaceous molecule of the invention. Suitable cells include, but are not limited to, a neuron (e.g. a sensory neuron or a retinal ganglion cell), cardiomyocyte, microglia, astrocyte, oligodendrocyte, macrophage, T cell, dendritic cell, epithelial cell (e.g. renal tubular epithelial cell), endothelial cell (e.g. cardiac endothelial cell, pulmonary arterial endothelial cell), fibroblast, pulmonary arterial smooth muscle cell and osteoblast.

[0294] In particular embodiments, the cell is a cell of the brain, kidney, heart, eye, lung, spinal cord or bone.

[0295] Also provided is a method of antagonising an ASIC, preferably ASICla, comprising, consisting or consisting essentially of contacting the ASIC with a proteinaceous molecule of the invention.

[0296] In another aspect, there is provided a method of treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention. Also provided is a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition.

[0297] In particular embodiments, the ASIC is ASICla.

[0298] In some embodiments, inhibiting an ASIC effects treatment or inhibition of the development of the condition.

[0299] Suitable conditions include, but are not limited to, a neurological condition, neuronal damage (e.g. after a stroke or brain injury, such as traumatic brain injury, or a period of ischaemia), ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, retinal detachment, optic neuritis, autoimmune encephalitis, an inflammatory condition, muscle crush injury, central retinal artery occlusion and chemical brain injury (e.g. via inhalation of toxic gases, smoke or fumes). In particular embodiments, the condition is selected from the group consisting of a neurological condition, neuronal damage (e.g. infarction), ischaemia, pain, ischaemiareperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment; especially a neurological condition, ischaemia, pain or ischaemia-reperfusion injury. In some embodiments, the condition is cardiac damage (e.g. after a myocardial infarction, heart attack or cardiac arrest).

[0300] Representative neurological conditions include stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease; especially stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, traumatic brain injury and Alzheimer's disease; more especially stroke.

[0301] While it is contemplated that the proteinaceous molecules will be useful for the treatment of both ischaemic and hemorrhagic stroke, in particular embodiments, the stroke is an ischaemic stroke.

[0302] In some embodiments, the condition is ischaemia, such as neuronal, ocular (e.g. acute retinal ischaemia), renal or cardiac ischaemia.

[0303] In some embodiments, the ischaemia is neuronal ischaemia, such as ischaemia associated with a stroke, traumatic brain injury or perinatal brain injury. Neuronal ischaemia may have a number of causes, such as systemic hypotension, heart dysfunction (e.g. an arrhythmia), arterial blood flow obstruction (e.g. due to thrombosis or embolism), cervical blood vessel dissection, vasospasm, carotid artery disease, atherosclerosis or an infection.

[0304] In some embodiments, the ischaemia is optical ischaemia, such as acute retinal ischaemia. The ischaemia may be associated with a condition, such as ocular ischaemic syndrome, amaurosis fugax, anterior segment ischaemic syndrome, retinal artery occlusion (e.g. central retinal artery occlusion or branch retinal artery occlusion) and / or may be caused by, for example, arterial blood flow obstruction (e.g. due to thrombosis or embolism) such as of the retinal artery, carotid artery (e.g. common carotid artery, internal carotid artery or external carotid artery) or ophthalmic artery, Takayasu's arteritis, Giant cell arteritis or ocular surgery.

[0305] The ischaemia may, in some embodiments, be renal ischaemia. Renal ischaemia may be associated with nephroangiosclerosis, renal artery stenosis, renal vascular lesions, atherosclerosis, infarction, surgery, transplant or an infection (e.g. sepsis).

[0306] In some embodiments, the ischaemia is cardiac ischaemia, such as cardiac ischaemia associated with a myocardial infarction or cardiac arrest. The ischaemia may result from, for example, atherosclerosis, coronary artery disease, coronary artery spasm, coronary artery dissection, cardiac arrest and / or blood flow obstruction (e.g. due to thrombosis or embolism). The cardiac ischaemia may lead to, for example, a myocardial infarction, heart attack, angina, unstable angina or cardiac arrhythmia. In some embodiments, the cardiac ischaemia is associated with or results from cardiac surgery, such as coronary bypass graft (CABG) surgery or transcatheter aortic valve insertion (TAVI; also known as transcatheter aortic valve replacement).

[0307] Suitable cancers include, but are not limited to, a glioblastoma, glioma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, breast cancer, skin cancer, lung cancer, prostate cancer and chronic myelogenous leukemia; especially a glioblastoma.

[0308] In some embodiments, the condition is ischaemia-reperfusion injury (also known as reperfusion injury), such as renal ischaemia-reperfusion injury, neuronal ischaemia-reperfusion injury, or cardiac ischaemia-reperfusion injury; especially cardiac ischaemia-reperfusion injury.

[0309] In alternative embodiments, the condition is pain. The pain may be nociceptive, inflammatory or neuropathic pain.

[0310] Suitable types of neuropathic pain include, but are not limited to, peripheral neuropathy; diabetic neuropathy; post herpetic neuralgia; trigeminal neuralgia; back pain; HIV neuropathy; cancer neuropathy; phantom limb pain; carpal tunnel syndrome; paroxysmal extreme pain disorder; central post-stroke pain; post-operative pain; erythromelalgia (also known as erythermalgia) such as inherited erythromelalgia; or pain associated with chronic alcoholism, hypothyroidism, uraemia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy or vitamin deficiency.

[0311] In some embodiments, the pain is inflammatory pain, representative examples of which include arthritic pain, including pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid disease, degenerative joint disease, gout or ankylosing spondylitis; or visceral pain, including pain associated with inflammatory bowel disease, functional bowel disorder, gastroesophageal reflux, dyspepsia, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, endometriosis, dysmenorrhea, painful bladder syndrome, prostatitis, cystitis, pancreatitis or pelvic pain.

[0312] Types of nociceptive pain which are contemplated by the invention include, but are not limited to, pain associated with central nervous system trauma, strains, sprains, burns, myocardial infarction or acute pancreatitis; post-operative pain; posttraumatic pain; renal colic; cancer pain including tumour related pain or pain associated with cancer therapy; or back pain, including pain associated with herniated or ruptured intervertebral discs, or pain associated with abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.

[0313] Other types of pain in which administration of the molecules of the invention may be useful include, but are not limited to, pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative arthropathies, non- articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis or pyomyositis; heart or vascular pain, including pain resulting from angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma or skeletal muscle ischaemia; head pain including migraine, cluster headache, tension-type headache, mixed headache or headache associated with vascular disorders; breakthrough pain; or orofacial pain, including dental pain, otic pain, burning mouth syndrome or temporomandibular myofascial pain. In some embodiments, the pain is migraine pain.

[0314] The use of the molecule of the invention for both acute pain (e.g. pain lasting for less than six months) and chronic pain (e.g. pain lasting for at least six months) is contemplated. In particular embodiments, the subject has chronic pain, which has lasted for at least six months.

[0315] In some embodiments, the condition is an inflammatory condition, for example asthma, arthritis (e.g. rheumatoid arthritis or osteoarthritis) or chronic rhinosinusitis.

[0316] In some embodiments, the condition is arthritis, such as rheumatoid arthritis or osteoarthritis.

[0317] In a still further aspect, there is provided a method of treating or at least partially inhibiting the development of a neurological condition in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention. In another aspect, there is provided a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of a neurological condition in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of a neurological condition in a subject, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of a neurological condition in a subject.

[0318] Suitable neurological conditions are as described supra. In some embodiments, the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease; especially stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, traumatic brain injury and Alzheimer's disease; more especially stroke.

[0319] In particular embodiments, the neurological condition is a stroke, especially an ischaemic stroke. The proteinaceous molecule will preferably be administered shortly after the onset of the stroke, such as within 48, 36, 24, 20, 16, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour of the onset of the stroke. The proteinaceous molecule may, in some embodiments, be administered periodically for a duration of, for example, days, weeks, months, or years after stroke onset, as discussed elsewhere herein.

[0320] The onset of stroke may be assessed by the appearance of one or more symptoms of stroke, such as sudden numbness or weakness in the face, arm or leg, confusion, trouble speaking, difficulty understanding speech, trouble seeing in one or both eyes, trouble walking, dizziness, loss of balance, lack of coordination, severe headache, difficulty swallowing and the like. Alternatively, the onset of the stroke may be medically determined, for example, by a computed tomography scan, magnetic resonance imaging, digital subtraction angiography, positron emission tomography, blood test, electrocardiogram and the like.

[0321] In some embodiments, the proteinaceous molecule is administered following a transient ischaemic attack (i.e. a brief stroke-like attack that resolves within minutes to hours).

[0322] Also provided herein is a method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention. The use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of ischaemia in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of ischaemia in a subject and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of ischaemia in a subject is also contemplated herein.

[0323] Suitable types of ischaemia are as discussed supra.

[0324] The inventors have conceived that the proteinaceous molecule will be useful for inhibiting the development of ischaemic damage. As such, in a further aspect, there is provided a method of treating or at least partially inhibiting the development of ischaemic damage in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention, a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of ischaemic damage in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of ischaemic damage in a subject, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of ischaemic damage in a subject.

[0325] In some embodiments, the methods and uses comprise at least partially inhibiting the development of ischaemic damage.

[0326] Ischaemic damage includes tissue damage resulting from the ischaemic cascade, especially cell death via apoptosis, necroptosis or necrosis, including infarction.

[0327] The damage may be a result of any type of ischaemia, such as neuronal, ocular, renal or cardiac ischaemia, suitable embodiments of which are as discussed supra. The ischaemic damage may, in some embodiments, be associated with surgery, e.g. cardiac or brain surgery.

[0328] In some embodiments, the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.

[0329] In particular embodiments, the ischaemic damage is cardiac ischaemic damage; especially ischaemic damage associated with a myocardial infarction, cardiacarrest or heart attack. In specific embodiments, the ischaemic damage is associated with or results from cardiac surgery, such as CABG surgery or TAVI.

[0330] In alternative embodiments, the ischaemic damage is neuronal ischaemic damage; especially ischaemic damage associated with a stroke, traumatic brain injury or perinatal brain injury.

[0331] In particular embodiments, the proteinaceous molecule reduces or minimises the infarct size (i.e. the amount of dead tissue).

[0332] While the proteinaceous molecule may be administered at any time, the proteinaceous molecule will preferably be administered shortly after the commencement of ischaemia, such as within 48, 36, 24, 20, 16, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour of the commencement of ischaemia. The proteinaceous molecule may, in some embodiments, be administered periodically for a duration of, for example, days, weeks, months, or years, as discussed elsewhere herein.

[0333] The proteinaceous molecule is also proposed to be useful for inhibiting ischaemia-reperfusion injury in a tissue, or the progression thereof. Accordingly, also provided herein, in another aspect, is a method of at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue, comprising, consisting or consisting essentially of contacting the tissue with a proteinaceous molecule of the invention, a use of a proteinaceous molecule of the invention for at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue, a proteinaceous molecule of the invention for use in at least partially inhibiting the development of ischaemiareperfusion injury in a tissue, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue.

[0334] The tissue may be any tissue that has undergone a period of ischaemia, followed by return of the blood supply. In some embodiments, the tissue is an organ transplant, a tissue in a subject that has suffered a stroke (e.g. brain tissue), a myocardial infarction (e.g. cardiac tissue), heart attack (e.g. cardiac tissue), cardiac arrest (e.g. cardiac tissue), traumatic brain injury (e.g. brain tissue) or perinatal brain injury (e.g. brain tissue). In some embodiments, the tissue is cardiac tissue that has undergone or is undergoing surgery, such as CABG surgery or TAVI.

[0335] In particular embodiments, the tissue is an organ transplant. The organ may be any organ suitable for transplantation, such as a heart, lung, kidney, liver, pancreas, intestine, thymus, uterus, skin, or a part thereof; especially a heart, lung or kidney. The tissue may be an entire organ that is transplanted (e.g. a heart) or a part thereof (e.g. a heart valve).

[0336] The tissue may be, for example, cardiac, pulmonary, renal, skin, hepatic, pancreatic, intestinal, thymic, uterine, skin, brain or muscle tissue; especially cardiac, pulmonary, renal or brain tissue; more especially cardiac tissue. In particular embodiments, the tissue is a heart, lung or kidney; especially a heart.

[0337] The tissue may be contacted with the proteinaceous molecule by, for example, immersing the tissue in or perfusing the tissue with a liquid comprising the proteinaceous molecule (i.e. in solubilised form). Alternatively or in addition, the proteinaceous molecule may be administered to a subject comprising the tissue, e.g. by intravenous, intranasal intrathecal, intraventricular, intracerebroventricular or intracerebral administration; especially intravenous administration.

[0338] The tissue may be contacted with the proteinaceous molecule prior to the period of ischaemia, after the period of ischaemia but before the return of the blood supply (i.e. before reperfusion), and / or after both the period of ischaemia and reperfusion of the tissue. In particular embodiments, the tissue may be contacted with the proteinaceous molecule prior to the period of ischaemia and may be continued (e.g. continuously or periodically) until after reperfusion of the tissue, or may be contacted with the proteinaceous molecule after the period of ischaemia but prior to reperfusion and may be continued (e.g. continuously or periodically) until after reperfusion of the tissue.

[0339] In particular embodiments, the proteinaceous molecule is administered shortly after the commencement of ischaemia, such as within 48, 36, 24, 20, 16, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour of the commencement of ischaemia.

[0340] The proteinaceous molecule of the invention may also be useful for treating or inhibiting the development of a heart attack, myocardial infarction or cardiac arrest. Accordingly, provided in a further aspect, is a method of treating or at least partially inhibiting the development of a heart attack, myocardial infarction or cardiac arrest in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention. The use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of a heart attack, myocardial infarction or cardiac arrest in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of a heart attack, myocardial infarction or cardiac arrest in a subject and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of a heart attack, myocardial infarction or cardiac arrest in a subject is also contemplated herein.

[0341] The proteinaceous molecules of the invention are also proposed to be useful for inhibiting damage to an organ during organ transplantation, especially ischaemic damage. In another aspect of the present invention, there is provided a method of at leastpartially inhibiting damage to an organ during organ transplantation, comprising, consisting or consisting essentially of contacting the organ with a proteinaceous molecule of the invention. Also provided is a use of a proteinaceous molecule of the invention for at least partially inhibiting damage to an organ during organ transplantation, a proteinaceous molecule of the invention for use in at least partially inhibiting damage to an organ during organ transplantation, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for at least partially inhibiting damage to an organ during organ transplantation.

[0342] The organ may be any organ, or a part thereof, which is suitable for transplantation, such as a heart, lung, kidney, liver, pancreas, intestine, thymus, uterus, skin, or a part thereof; especially a heart, lung or kidney. In preferred embodiments, the organ is a heart.

[0343] The damage is preferably ischaemic damage or reperfusion injury, especially ischaemic damage, such as apoptosis, necroptosis or necrosis resulting from a period of ischaemia. The period of ischaemia may be equivalent to the time from when the organ is removed from the donor subject to when the organ is transplanted into the recipient subject. For example, the period of ischaemia may be a period in the range of from about 1 hour to about 50 hours (and all integer minutes therebetween).

[0344] The organ may be contacted with the proteinaceous molecule by, for example, immersing the tissue in or perfusing the tissue with a liquid comprising the proteinaceous molecule (i.e. in solubilised form). The organ may, in some embodiments, be contacted with the proteinaceous molecule of the invention from when the organ is removed from the donor subject to when the organ is transplanted into the recipient subject. In some embodiments, the organ is contacted with the proteinaceous molecule for a duration in the range of from about 1 hour to about 50 hours (and all integer minutes therebetween); especially about 2 hours to about 36 hours, about 2 hours to about 16 hours, about 4 hours to about 12 hours, about 4 hours to about 8 hours, or about 4 hours to about 6 hours.

[0345] The proteinaceous molecule may also be administered to the recipient subject following transplantation of the organ, e.g. by intravenous, intrathecal, intraventricular, intracerebroventricular, intranasal or intracerebral administration; especially intravenous or intranasal administration; more especially intravenous administration as discussed elsewhere herein.

[0346] Also provided herein is a neuroprotective and / or cardioprotective agent comprising a proteinaceous molecule of the invention, and the use of a proteinaceous molecule of the invention for neuroprotection or cardioprotection.

[0347] In any one of the aspects described above, the ASIC is preferably ASICla. The ASIC is preferably a human channel, such as hASICla.

[0348] Any one of the methods and uses described above may involve administration of an effective amount of the proteinaceous molecule of the invention as described in Section 4 supra. The proteinaceous molecule of the invention may be administered via any suitable route of administration, such as oral, topical, intranasal, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebroventricular, intracerebral, intravesical, intravenous or intraperitoneal administration. In particular embodiments, the proteinaceous molecule is administered via intravenous, intrathecal, intraventricular, intracerebroventricular, intranasal or intracerebral administration; especially intravenous or intranasal administration; more especially intravenous administration.

[0349] The dosage and frequency will depend on the subject, the condition, disease or disorder to be treated and the route of administration. A skilled person will readily be able to determine suitable dosages and frequency of such dosages. For example, the proteinaceous molecule may be administered in an amount in the range of from about 0.25 μg to about 2000 mg (and all one-tenth integer μg therebetween), including from about 1 μg to about 100 mg, about 10 μg to about 10 mg, or about 100 μg to about 10 mg; or about 500 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg; and may be administered at a frequency of, for example, once daily, or twice or three times daily. The treatment may be continued for multiple days, weeks, months or years. The proteinaceous molecule may be administered in an amount relative to the body weight of the subject, such as from about 0.1 μg / kg to about 50 mg / kg body weight of the subject (and all one-tenth integer μg therebetween), including from about 1 μg / kg to about 5 mg / kg, about 10 μg / kg to about 500 μg / kg, or about 50 μg / kg to about 150 μg / kg body weight of the subject; or about 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 μg / kg body weight of the subject. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages and frequency of administration are determined by reference to the usual dose and manner of administration of the said ingredients. In particular embodiments, the peptide is administered to a subject in need of such treatment, although the peptide may be administered prophylactically.

[0350] When used for inhibiting damage to an organ during organ transplantation, the proteinaceous molecule may be in a solution in a concentration of from about 0.1 nM to about 1 pM (and all one-tenth integer nM therebetween), including from about 1 nM to about 100 nM, about 10 nM to about 90 nM, about 20 nM to about 80 nM, about 30 nM to about 70 nM, or about 40 nM to about 60 nM; especially about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 nM.

[0351] Any one of the methods or uses described above may, in some embodiments, involve the administration of one or more further active agents as described in Section 4 supra, such as an anti-inflammatory agent, anticoagulant, thrombolytic agent, antiplatelet agent, antihypertensive agent, diuretic, antihistamine, mast cell stabiliser or a treatment for a neurological condition.

[0352] A skilled person will be well aware of suitable assays used to evaluate the antagonism or inhibition of an activity of ASIC, especially ASICla. For example, the method may include contacting ASIC or a subunit thereof (e.g. immobilised ASIC or a subunit thereof such as the extracellular domain) with a proteinaceous molecule and assessing the binding affinity. Alternatively, the method may include screening for the inhibition of the activity, presence or expression of a downstream cellular target or product, or a downstream effect, such as a sodium ion current, calcium ion current, ERK phosphorylation or ERK activation. Detecting such inhibition may be achieved utilising techniques including, but not limited to, ELISA, a binding assay (e.g. a radioligand binding assay or fluorescence binding assay), surface plasmon resonance, immunofluorescence, Western blots, immunoprecipitation, immunostaining, scintillation proximity assays, competitive inhibition assays, a colorimetric assay, electrophysiology or a membrane potential assay, as described in further detail in the examples herein.

[0353] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples.EXAMPLES

[0354] All starting materials, amino acids, reagents and equipment used are commercially available (e.g. from Sigma-Aldrich, Burlington, Massachusetts, USA; Iris Biotech GmbH, Marktredwitz, Germany; Shimadzu Corporation, Kyoto, Japan; Phenomenex, Torrance, California, USA; and the like) and were obtained from commercial sources unless otherwise indicated.EXAMPLE 1 - SYNTHESIS OF THIOETHER-CYCLISED IB212 AND ANALOGUES THEREOFMaterials and Methods

[0355] Linear IB212 (CICH2C(O)NH-YRPTIRRRRVRICGEE-NH2; SEQ ID NO: 140) was prepared via solid-phase peptide synthesis (SPPS) and then cyclised (refer to Figure 1). IB212 was synthetised on a CEM Liberty Blue automated microwave peptide synthesiser (CEM Corporation, Charlotte, North Carolina, USA) using Rink Amide 4- methylbenzhydrylamine (MBHA) resin (CEM) and standard fluorenylmethyloxycarbonyl (Fmoc)-protected amino acid building blocks. During assembly, each amino acid (AA) attachment cycle was performed as following : The resin was treated with a solution of Fmoc-AA-OH (5 eq.), N,N'-diisopropylcarbodiimide (10 eq.) and Oxyma (5 eq.) indimethylformamide (DMF) for 4 minutes at 90 °C (this step was repeated twice for coupling of arginine residues), followed by deprotection with 20% piperidine in DMF for 50 seconds at 90 °C. After full sequence assembly, the resin was removed from the synthesiser and final chloroacetylation was carried out at room temperature by treating the resin with chloroacetic acid (5 eq.), N,N'-diisopropylcarbodiimide (5 eq.) and Oxyma (ethyl 2-cyano- 2-(hydroxyimino)acetate) (5 eq.) in DMF for 20 minutes. After that, the resin was washed with DMF, followed by dichloromethane (DCM) and dried under vacuum.

[0356] The resin was then treated with a solution of TFA:triisopropylsilane: 3,6- dioxa-l,8-octanedithiol:water (9:0.4:0.2:0.4; 20 mL per 0.1 mmol synthesis scale) and agitated at room temperature for 3 hours. The resin was then filtered using a stream of nitrogen to remove all liquid from resin. The filtrate was cooled on ice before adding cold tert-butylmethyl ether (4-5-fold in volume). The precipitate was separated by centrifugation, redissolved in minimum of 50% acetonitrile, diluted with 0.1% TFA so the resulting solution had < 10% acetonitrile content and purified using preparative reversed- phase high-performance liquid chromatography (RP-HPLC).Thioether Cyclisation

[0357] The linear peptide was dissolved in 50% acetonitrile (at 0.5-1 mg / mL concentration) and combined with DIPEA (10 eq.). After 45 minutes, the reaction was quenched by acidification with TFA. The crude product was lyophilised, redissolved in 0.1% TFA, and purified using preparative RP-HPLC.Preparative HPLC

[0358] IB212 (LcH2C(O)NH-YRPTIRRRRVRliGEE-NH2; SEQ ID NO: 141; refer to Figure 1 and Table 6) was purified via RP-HPLC on a Shimadzu LC-20 System (Shimadzu Corporation, Kyoto, Japan) using a Phenomenex C18 Luna column (Phenomenex, Torrance, California, USA) and mobile phase consisting of buffer A (0.1% TFA in water) and buffer B (90% acetonitrile in water / 0.1% TFA).Analytical HPLC

[0359] IB212 purity and identity were evaluated via HPLC-mass spectrometric (LC-MS) analysis on a Shimadzu LCMS-2020 System (Shimadzu Corporation, Kyoto, Japan) using a Phenomenex C18 Luna column (Phenomenex, Torrance, California, USA) and a Shimadzu LCMS-2020 mass spectrometer (Shimadzu Corporation, Kyoto, Japan). The mobile phases were 0.05% TFA in water (buffer A) and 90% acetonitrile in water / 0.05% TFA (buffer B), and the peptide was eluted using a gradient of 10-36% buffer B over 13 minutes at a flow rate of 0.5 mL / min. Under these conditions, the mass spectrum of IB212 displayed a mixture of m / z adduct ions consisting of [M+xH]+x, [M+xH+zTFA]+x.Other analogues

[0360] The other thioether cyclised peptides in Table 6 were prepared using a similar procedure unless otherwise stated. Where the peptide included an N-methyl arginine residue, the coupling of amino acids after this residue was performed by treating the resin twice with a solution of Fmoc-AA-OH (5 eq.) N,N'-diisopropylcarbodiimide (10 eq.) and Oxyma (5 eq .) in DMF for 4 minutes at 90 °C followed by an acetylation step, where the resin treated with 10% acetic anhydride in DMF for 2 min at 65 °C. Purification and cyclisation were performed as described above.

[0361] The C-terminal acid peptides (refer to Table 6) were synthesised using the same microwave-assisted solid-phase synthesis procedure as described above for IB212 but assembled on a preloaded-Wang resin (CEM).Results

[0362] Following synthesis, cyclisation and HPLC purification, 27 mg of IB212 was obtained from a 0.05 mmol scale synthesis (yield = 25%). The mass spectrum of the final product showed the expected ion sizes (Figure 2). Peptide purity estimated from the area under the IB212 peak in the final analytical HPLC chromatogram (Figure 3) was >95%.EXAMPLE 2 - SYNTHESIS OF PEGYLATED THIOETHER-CYCLISED IB324 AND ANALOGUES THEREOFMaterials and Methods

[0363] The unpegylated IB324 precursor, IB320( LC(O)N H-YRPTIRRRRVRICGEEK-NH2; SEQ ID NO: 142; refer to Figure 4 and Table 6), was prepared applying a similar synthetic procedure as IB212.

[0364] Pegylation was carried out by treating IB320 dissolved in DMF at 30 mg / mL concentration with 1. 1-1.3 eq of mPEG37-(N-hydroxysuccinimide) (NHS) ester (Broadpharm) and 10 eq of DIPEA for 20 minutes. mPEG37 is also referred to herein as PEG37. After that, the reaction mixture was acidified with 10% TFA, diluted 20-times with water and IB324 (Table 6) was isolated by purification using preparative RP-HPLC, following the same method as described in Example 1.

[0365] Analytical HPLC of the pegylated product, such as IB324, was carried out on a Shimadzu LCMS-2020 System using a C18 Phenomenex Aeris column (3.6 pm, 100A, 250 x 2.1 mm) eluting at 0.2 miymin at 50°C. The gradient frequently used was 10-45% buffer B in buffer A over 30 min. Buffer A: 0.05% TFA, buffer B: 90% ACN, 0.05% TFA.

[0366] The other thioether cyclized peptides listed in Table 6, which include latestage side-chain modifications (i.e. reactions performed in solution following SPPS) to lysine or ornithine residues, were synthesized following a procedure similar to that of IB324, but using the appropriate activated conjugation reagents, such as NHS-ester forthe various PEG and lipid conjugations and fluorescein isothiocyanate for fluorescein isothiocyanate (FITC) conjugation.Results

[0367] Following synthesis, cyclisation and HPLC purification, 1.5 g of IB324 was obtained from a 3.75 mmol scale synthesis (yield = 10%). The mass spectrum of the final product showed the expected ion sizes (Figure 5). Peptide purity estimated from the area under the IB324 peak in the final analytical HPLC chromatogram (Figure 6) was >95%.EXAMPLE 3 - SYNTHESIS OF IB350, COMPRISING AN ISOGLUTAMIC ACID RESIDUE CONNECTED TO A LYSINE SIDE CHAIN

[0368] The precursor for IB350, IB340( l-C(O)NH-YRPTIRRRRVRICGEE-PEG12-PEG12-K(isoE)-COOH; SEQ ID NO: 143; refer to Table 6), was prepared using Fmoc-Lys(Mtt)-Wang preloaded resin. Firstly, the Mtt group was removed manually by treating the resin with 2% TFA in DCM for 1 min (lOx), followed by washing with DCM ( lx), 5% DIPEA in DMF (lx) and DMF (5x). Next, Boc-Glu-OtBu (5eq) was coupled to the lysine side-chain using N,N'-diisopropylcarbodiimide (10 eq.) and Oxyma (5 eq.) in DMF for 60 minutes at room temperature. The resin was then washed with DMF (5x) and transferred to peptide synthesiser to complete the peptide assembly accordingly to the procedure described for IB212.

[0369] IB340 was lipidated by treatment with 1.5 eq. of octadecanedioic NHS ester (AAblocks) and 10 eq. of DIPEA for 20 minutes. After that, the reaction mixture was acidified with 10% TFA, diluted 10-times with water and the final IB350 (refer to Table 6) was isolated by purification using preparative RP-HPLC.EXAMPLE 4 - SYNTHESIS OF IB554, COMPRISING A DISULFIDE BON D

[0370] Linear IB554 (Acetyl-CYRPTIRRRRVRICGEE-NH2; SEQ ID NO: 380) was prepared via SPPS, cleaved from resin and purified as described in Example 1. The linear peptide fraction from preparative HPLC was diluted to 30 mL with 50% ACN / H2O and submitted to oxidation at room temperature for 5 min, using drop-wise addition of 0.1M h / methanol until the solution turned yellowish-brown, before quenching with ascorbic acid. Quenched reaction sample was diluted to 10% acetonitrile and purified by preparative RP- HPLC as described in Example 1 to form d isulfide-cycl ised IB554 (refer to Table 7). IB664 was prepared in a similar manner (refer to Table 7).EXAMPLE 5 - SYNTHESIS OF BISTHIOETHER-CYCLISED IB721, IB722 AND ANALOGUES THEREOF

[0371] IB554 was prepared via SPPS and cleaved from resin as described in Example 4. IB721 and IB722 were prepared by first reducing IB554 using 10 eq tris(2- carboxyethyl)phosphine in 20% acetonitrile / H2O for 1.5 h followed by lyophilisation. Crudereduced linear IB554 was then submitted to cyclisation with crosslinker a,a'-dibromo- meta-xylene (1 eq.) or cis-l,4-dichloro-2-butene (6 eq.) in 0.1 M NaHCOs / acetonitrile (1: 1) and a small amount of DMF and 10 eq. DIPEA to give IB721 and IB722 respectively (refer to Table 7). Each product was purified by preparative RP-HPLC as described in Example 1.TABLE 6SEQUENCES OF THIOETHER-CYCLISED PEPTIDESRepresentative structure showing thioether cyclisation:wherein: * = C-terminal amide; * = N-terminal acetamide; and each PEG group has the structure provided in Table 4; Orn(PEG37), K(PEG37), K(isoE-C18A), K(isoE-C16), K(C18A), K(albutag), Orn(PEG4-MPA), K(isoE-C14A), K(isoE-C16A), K(isoE-C14), K(isoE-C12), K(isoE-ClO), K(C16), K(C12), K(PEG4-biotin) and K(isoE-albutag) have the structures provided in Table 5; Hey = homocysteine; aMePro = alpha-methylproline; F(4-MeOH) = 4-hydroxymethyl-L-phenylalanine; F(4-COOH) = 4-carboxy-L-phenylalanine; F(4-NH2) = 4-amino-L-phenylalanine; Y(iodo) = 3-iodo-tyrosine; Y(diiodo) = 3,5-diiodo-tyrosine; other abbreviations are as defined herein and Orn(C18A), K(isoE) and Dopa have the following structures:5 TABLE 7SEQUENCES OF DISULFIDE- OR BISTHIOETHER-CYCLISED PEPTIDESRepresentative structure showing disulfide cyclisation:wherein: * = C-terminal amide; * = N-terminal acetamide.EXAMPLE 6 - INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) BY SYNTHETIC IB212Materials and Methods

[0372] The ability of IB212 to inhibit the activity of hASICla was assessed using two-electrode voltage-clamp electrophysiology performed on Xenopus laevis oocytes expressing hASICla. Xenopus laevis stage V-VI oocytes were removed and treated with collagenase (Sigma type I) for defolliculation. cRNA encoding hASICla was synthesised using an mMessage mMachine cRNA transcription kit (Ambion Inc., Austin, Texas, USA) and healthy stage V-VI oocytes were injected with 0.5-5 ng cRNA per oocyte. Oocytes were kept at 17 °C in 0.6X Leibovitz's L-15 medium supplemented with 50 μg / mL gentamicin, 50 μg / mL streptomycin and 2.5% fetal horse serum.

[0373] Experiments were performed at room temperature (22-23 °C) 1-4 days after cRNA injection in calcium-free ND96 solution (96 mM NaCI, 2 mM KCI, 2 mM MgCH, 5 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES); pH 7.45). IB212 serial dilutions were made in regular ND96 solution (96 mM NaCI, 2 mM KCI, 1.8 mM CaCH, 2 mM MgCI?, 5 mM HEPES; pH 7.45), with 0.05% fatty acid free bovine serum albumin (BSA) added to prevent adsorptive losses to plasticware and tubing. The corresponding control conditions also contained 0.05% fatty acid free-BSA as a vehicle control. HEPES in ND96 solutions was replaced by 4-(2-sulfonatoethyl)morpholin-4-ium (MES) to buffer solutions at pH 6.0.

[0374] Oocytes were clamped at -60 mV (Axoclamp 900A; Molecular Devices, San Jose, CA, USA) using microelectrodes filled with 3 M KCI solution (0.5-1.0 M resistance). Data acquisition (sampled at 2 kHz and filtered at 0.01 kHz) was performed using pCIamp 10 software (Molecular Devices, LLC, San Jose, CA, USA). Concentrationresponse data were obtained using serial dilutions of IB212 (prepared in accordance with Example 1) applied at pH 7.45 directly to the oocyte bath for 6 min. Channels were stimulated by a pH drop to 6.0 applied for 10 seconds (no peptide present in the pH stimulus) with an interval of 120 seconds between stimuli.

[0375] Data were analysed using Prism 9 (GraphPad Software, Boston, MA, USA). The Hill equation (specifically the "sigmoidal dose-response (variable slope)" in Prism 9) was fit to the data with no constraints. Data are expressed as mean ± SEM.Results

[0376] IB212 potently inhibited proton-gated sodium currents mediated by hASICla. A fit of the Hill equation to concentration-response data yielded an IC50 (i.e., the concentration required for 50% inhibition of channel currents) of 0.5 ± 0.07 nM, with complete inhibition (100% efficacy) observed at an IB212 concentration of 10 nM (Figure 7).

[0377] The inhibitory effect of IB212 was fully reversed (i.e., hASICla currents recovered to control levels) within six minutes of peptide wash out. The half-life for current recovery was about 3 minutes.EXAMPLE 7 - CARDIOPROTECTIVE EFFICACY IN A RAT MODEL OF SEVERE MYOCARDIAL INFARCTIONMaterials and Methods

[0378] The cardioprotective efficacy of IB212 and IB324 (prepared in accordance with Examples 1 and 2) was assessed by examining their ability to protect heart structure and function following severe ischaemia-reperfusion injury (myocardial infarction, MI) in Sprague Dawley rats, over two separate studies. The activity was compared to a control peptide, IB100 ( CH2C(O)NH-YRPTIRRRRVRICG-NH2; SEQ ID NO: 261), which does not contain acidic amino acid residues at the C-terminus.

[0379] Rats were randomly assigned to treatment groups to achieve similar group mean weight. Rats were anaesthetised with 1-3% isoflurane and connected to a ventilator. The animals were secured and held in a supine position. The chest hair was removed and wiped with iodophor. The chest was opened by a left lateral thoracotomy and ischaemia was induced by ligating the left anterior descending (LAD) coronary artery about 2 mm distal to its origin. A small piece of polyethylene tubing (PE50) was placed on top of the vessel just prior to the occlusion and secured with a triple-loop knot. Regional myocardial ischaemia was confirmed by epicardial cyanosis and hypokinesia. Jugular vein cannulation was performed to administer saline to prevent evaporation and dehydration during the 90-minute occlusion period. Reperfusion of the LAD was achieved by removing the polyethylene tube.

[0380] A schematic of the experimental design used for the MI experiments is shown in Figure 8.

[0381] For all animals, the test article was delivered via intravenous (i.v.) administration via the external jugular vein by infusion that started 7 min prior to reperfusion and continued until 3 minutes post reperfusion. Heart function was compared between cohorts treated with IB100 (0.3 mg / kg), IB212 (0.3 mg / kg) or vehicle (saline) in study 1 (Figure 9) : or with IB212 (0.3 mg / kg or 143 nmols / kg), IB324 (0.56 mg / kg or 143 nmols / kg), or vehicle (saline) in study 2 (Figure 10). Sham animals received the full surgical procedure as outlined above without occlusion of the LAD and without administration of drug or vehicle. After the operation, the wound was sutured and gentamicin (40 mg / kg, i.m.) was injected to prevent infection and tolfedine (20 mg / kg, i.m.) was injected twice daily to relieve pain.

[0382] After one week, the chest was shaved and M-mode echocardiography(ECG) was performed under 1-3% isoflurane with heart rate maintained in the range of - Ill -330-420 beats / minute. Long-axis parasternal views of the left ventricle at mid-papillary level and parasternal views of the left ventricle were obtained using a Visual Sonics Vevo 3100 ultrasound system. Left ventricle internal dimensions were measured in systole and diastole using leading-edge methods based on guidelines provided by the American Society of Echocardiography.Results

[0383] Fractional shortening (FS) was used as a measure of cardiac function. FS is the percentage change in ventricular diameter during systole, and it can be measured from the parasternal long-axis view using M-mode ECG. The experimental protocol employed (Figure 8) caused a substantial loss in cardiac pump performance as evidenced by the large reduction in FS in vehicle-treated rats compared to the sham cohort (Figures 9 and 10). Relative to vehicle-treated animals, there was a statistically significant improvement in FS levels in the animals that received 0.3 mg / kg IB212 over the cohort receiving 0.3 mg / kg IB100 in study 1 (Figure 9); and also an improvement in FS decline in the animals that received 0.56 mg / kg IB324 over those receiving 0.3 mg / kg IB212 in study 2 (Figure 10).

[0384] IB100 is highly cardioprotective in the context of myocardial ischaemiareperfusion injury and as efficacious as cariporide, which was shown to be cardioprotective in human clinical trials in patients with acute anterior MI that received percutaneous transluminal coronary angioplasty [Ruppecht et al. (2000) Circulation, 101: 2902-2908]. Here, IB212 and IB324, containing acidic residues at the C-terminus displayed enhanced cardioprotective efficacy compared to IB100.EXAMPLE 8 - INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) BY SYNTHETIC PEPTIDESMaterials and Methods

[0385] Peptides were synthesised in accordance with Examples 1-5. The ability of the peptides to inhibit the activity of hASICla was assessed using two-electrode voltageclamp electrophysiology performed on Xenopus laevis oocytes expressing hASICla in accordance with Example 6.

[0386] Peptide inhibition of hASICla was also measured using electrophysiology in CHO cells using an automated SyncroPatch 384 PE platform (Nanion Inc., Germany) in 384-well plates (referred to as SyncroPatch in Table 8). Patch-clamp electrophysiology experiments were carried out using hASICla (human ACCN2 gene)-transfected CHO cells, with hASICla over-expression was induced using tetracycline (Charles River Laboratories, USA). Cells were held at -50 mV throughout recordings. Positive controls for activation of hASICla channels were performed at pH 7.0, pH 6.5, pH 6.0 and pH 5.5. Benzamil was used as a control antagonist. Eight serial dilutions of peptide (prepared in accordance withExamples 1-5) were tested covering up to a 2,000-fold dilution from the maximal concentration with between 2-4 replicates each. BSA (0.05%) was included in serial dilutions to prevent adsorptive losses to plasticware. Peptides were tested for agonism upon immediate application to the cells as well as antagonism upon acidic stimulation. The peptides were applied in extracellular solution at pH 7.4 followed by an acid stimulation using extracellular solution at pH 6.5 four minutes later. Currents were recorded by onboard patch clamp amplifiers. Data acquisitions were performed via the Syncropatch 384PE software (Nanion Inc., Germany) and analysed using Microsoft Excel (Microsoft Corp., Redmond, WA, USA) and XLfit 5.5.0.5 (IDBS 2016 add-on for Excel). Nonlinear least squares fits were made assuming a simple binding model. ICso, or EC50, the concentration of test article producing either half-maximal inhibition or activation, and Hill slope were determined from the resulting curves.

[0387] A third method to evaluate the inhibitory activity of the peptides to hASICla was by Fluorescence Imaging Plate Reader (FLIPR) calcium influx assay on a FLIPR Penta (Molecular Devices, USA). Experiments were carried out using human ASICla acid-sensing ion channel (human ACCN2 gene) transfected CHO cells where overexpression was induced using tetracycline (Charles River Laboratories, USA). The complete growth medium for the cells was as follows, Ham's F12 with the addition of 10% Foetal Bovine Serum (FBS) Tetracycline-screened, 100 units / mL of Penicillin-Streptomycin, 0.01 mg / mL of Blasticidin and 0.4 mg / mL of Zeocin. Cells were passaged and seeded (at 10,000 cells per well) a day prior to the FLIPR assay. After 18 hrs of tetracycline-induced ASICla overexpression, the cells were loaded with Calcium 6 dye (Molecular Devices, USA) diluted in Hank's balanced salt solution (HBSS) (+Ca and Mg) + 20 mM HEPES, pH 7.4. Serial dilutions of the peptides (prepared in accordance with Examples 1-5) were made in HBSS (+Ca and Mg) + 20 mM HEPES, + 0.1% BSA, pH 7.4. Ten 1:2 serial dilutions were prepared from a top concentration of 1 pM. Cells were exposed to the peptide 10 minutes before ASICla stimulation with low pH buffer. Fluorescence recording was initiated immediately prior to stimulation and a minimum of three replicates was collected for each concentration. Results were analysed using Prism 10 (GraphPad Software, Boston, MA, USA). Non-linear regression, specifically the log(inhibitor) vs normalized response-variable slope was fitted to the data for calculation of the concentration required for half-maximal inhibition (IC50).Results

[0388] The results are presented in Table 8 in comparison to IB100.EXAMPLE 9 - PEPTIDE STABILITY IN HUMAN SERUMMaterials and Methods

[0389] The stability of the peptides to human serum proteases was assessed after incubation with human serum for 1 hr. Peptides (prepared in accordance with Examples 1- 5) were mixed with human serum (100%) to a final concentration of 50 pM and incubated at 37°C. Aliquots were taken after 0 and 60 min, mixed with 3% TFA / acetonitrile and incubated on ice for serum protein precipitation. After centrifugation to separate the pellet, samples were analysed by LC-MS. Each peptide stability test was performed at least in duplicate. The data is reported as the percentage of intact peptide after 1 hr incubation in human serum at 37°C.Results

[0390] The results are presented in Table 9.EXAMPLE 10 - ACTIVATION OF THE HUMAN MAS-RELATED G-PROTEIN COUPLED RECEPTOR X2 (MRGPRX2)Materials and Methods

[0391] The agonist activity of the peptides was measured using FluorescenceImaging Plate Reader (FLIPR) calcium mobilisation assay on a FLIPR Penta (Molecular Devices, USA). The stable cell line of Human CHO-K1 / MRGPRX2 was sourced fromGenScript. The complete growth medium for the cells was as follows, Ham's F12 (Kaighn's) medium with the addition of 10% Foetal Bovine Serum (FBS), 100 units / mL of Penicillin- Streptomyocin, and 0.2mg / mL of Zeocin. Cells were seeded at 10,000 cells per well a day prior to the FLIPR assay. After 18 hrs, cells were loaded with Calcium 6 dye (Molecular Devices, USA) diluted in HBSS (- Ca, Mg) + 20 mM HEPES, pH 7.4. Serial dilutions of the peptides (prepared in accordance with Examples 1-5) were made in HBSS (-Ca, Mg) + 20mM HEPES, + 0.1% BSA, pH 7.4. Ten 1:3 serial dilutions were prepared from a top concentration of 1 mM. Fluorescence recording was initiated prior to peptide addition and a minimum of three replicates was collected for each concentration. Results were analysed using Prism 10 (GraphPad Software, Boston, MA, USA). Non-linear regression, specifically the log(agonist) vs response -variable slope (four parameters) was fitted to the data for calculation of the concentration required for half-maximal activation (EC50).Results

[0392] The ability of the peptides comprising C-terminal acidic amino acid residues to activate human MRGPRX2 was assessed. The results are presented in Table 10.

[0393] The peptides comprising C-terminal acidic amino acid residues have reduced agonist activity at MRGPRX2 compared to the comparison peptide without C- terminal acidic amino acid residues.TABLE 10AGONIST ACTIVITY AT MRGPRX2EXAMPLE 11 - MAST CELL DEGRANULATION ACTIVATION IN HUMAN LAD-2 CELLSMaterials and Methods

[0394] Human LAD-2 cells were obtained from the National Institutes of Health (NIH) under Licensing Agreement and cultured following NIH's instructions in a controlled atmosphere of 5% CO2 at 37°C in StemPro-34 serum-free medium (Thermo Fisher Scientific, Waltham, MA, USA; Catalogue No. 10639011) with Stem Pro-34 nutrient supplement, Penicillin (100 U / mL) / Streptomycin (100 μg / mL), 2 mM L-glutamine, and stem cell factor (hSCF, 100 ng / mL). The cell medium was changed by twice a week hemidepletion, and cells were maintained at a concentration below 0.5xl06cells / mL. The day before the assay, cells were incubated overnight in fresh medium (hemi-depletion). On the day of the assay, cells were counted, centrifuged to eliminate culture media and cell debris (200Xg, 5 min), washed once with Assay Buffer containing 1 mg / mL (0.1%) of BSA, 10 mM HEPES Buffer in Hanks' Balanced Salt Solution (HBSS), at final pH 7.4), centrifuged again and resuspended in pre-warmed Assay Buffer at 500,000 cells / mL.

[0395] Peptides (prepared in accordance with Examples 1-5) were dissolved in PBS pH 7.4 to a final concentration of 20 mM. A concentrated 900 pM stock solution in Assay Buffer was prepared and 9 serial 1:2 dilutions in Assay Buffer were made to have final concentrations in assay ranging from 300 pM to 0.59 pM. Substance P and 48 / 80 were used as positive control with final concentrations in assay ranging from 10 pM to 0.02 pM. On the day of the assay, 10 pL / well of peptide dilutions were added to the cell suspension (10,000 cells / well for 384-well plate) in a final assay volume of 30 pL and the plates were incubated at 37°C, 5% CO2 for 30 minutes.

[0396] β-Hexosaminidase activity was measured by addition of the fluorogenic substrate 4-methylumbelliferyl-N-acetyl-b-D-glucosaminide for 30 minutes at 37°C. The reaction was terminated by adding quenching buffer, and fluorescence was measured using a Tecan "Safire2" with excitation and emission wavelength of 360 nm and 460 nm, respectively. Potency (EC50) was calculated by nonlinear regression using XLfit 4.2 (IDBS Ltd), applying the 4-parameter logistic model to dose-response curves.Results

[0397] In light of the results in Example 10, the ability of the peptides comprising C-terminal acidic amino acid residues to cause activation of mast cell degranulation was assessed. The results are presented in Table 11. The peptides comprising C-terminal acidic amino acid residues caused reduced mast cell degranulation activation compared to IB100.

[0398] A clear correlation between overall net charge and LAD-2 mast cell degranulation and MRGPRX2 activation (refer to Example 10) was found after analysing a large set of analogues (Figure 11).TABLE 11 LAD 2 MAST CELL DEGRANULATION (MCD) ACTIVATIONEXAMPLE 12 - PHARMACOLOGICAL SAFETY

[0399] To assess potential pharmacological safety liabilities, IB100 and IB212 were tested at a concentration of 10 pM using the industry-standard SafetyScreen 44 assay (Eurofins, France), which evaluates various receptors, transporters, enzymes, and ion channels. As illustrated in Figure 12, IB212 demonstrated a more favourable safety profile compared to IB100, emphasising its potential for further development.

[0400] To evaluate the potential proarrhythmic risk, the effect of IB324 on a panel of six cardiac ion channels (hERG, Cav1.2, Navi.5, Kv4.3, Kir2.1 and Kv7.1) was assessed using electrophysiological screening conducted by Eurofins (USA). This Comprehensive in Vitro Proarrhythmia Assay (CiPA) is a critical component in assessing cardiac toxicity and ensuring safety during drug development. Notably, IB324 demonstrated no significant effects on any of the cardiac profiler channels at concentrations up to 10 pM (Table 12).TABLE 12COMPREHENSIVE IN VITRO PROARRHYTHMIA ASSAY RESULTSEXAMPLE 13 - HIPSC-DERIVED CARDIOMYOCYTE IN VITRO ISCHAEMIA-REPERFUSION INJURY MODELMaterials and Methods

[0401] The cardioprotective efficacy of IB212 was examined using an in vitro ischaemia-reperfusion injury model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Human iPSCs were differentiated using high density monolayer differentiation. On day -1 of differentiation, hiPSCs were plated onto vitronectin-coated plates and cultured overnight in mTeSRl medium (Stem Cell Technologies, Australia) supplemented with 10 pM Y-27632 (Stem Cell Technologies). Differentiation was induced on day 0 by first washing with PBS, then changing the culture medium to RPMI (ThermoFisher, Catalogue No. 11875119) containing 3 pM CHIR99021 (Stem Cell Technologies), 500 μg / mL BSA and 213 μg / mL ascorbic acid. After 3 days of culture, the medium was replaced with RPMI containing 500 μg / mL BSA, 213 μg / mL ascorbic acid and 5 pM Xav-939 (Stem Cell Technologies). On day 5, the medium was exchanged for RPMI containing 500 μg / mL BSA and 213 μg / mL ascorbic acid without supplemental cytokines. From day 7 onwards, the culture medium was replaced every 2 days with RPMI plus lx B27 supplement containing insulin.

[0402] After 15 or 17 days of culturing, hiPSC-CMs were re-plated for in vitro ischaemia-reperfusion assays. At the time of re-plating, a subset of cells (~500,000) was set aside for flow cytometry analysis of cardiomyocyte purity. For all experiments, only cell preparations with >80% sarcomeric a-actinin-positive cardiomyocytes were used. After replating, the cells were maintained for an additional 7 days in RPMI + B27. To prepare media for ischaemia-reperfusion injury, lOx HBSS without sodium bicarbonate was diluted to lx concentration in sterile tissue culture-grade water. Solutions were buffered witheither 12 mM HEPES (for pH 7.4 media) or 12 mM MES (for pH 5) and the pH adjusted with 1 M NaOH. The medium was sterile filtered using a 0.22 pm syringe filters. The replated cells were treated overnight (18 hr) in HBSS with or without 50 nM IB212 (prepared in accordance with Example 1) under either normoxic (~18.5% O2; 5% CO2) or hypoxic (0.5% O2; 5% CO2) culture conditions. For reperfusion experiments, following the overnight incubation, the medium was replaced with HBSS pH 7.4 [with or without 50 nM IB212 (prepared in accordance with Example 1)] and cells incubated for an additional 4 hours under normoxic conditions. To assess cell death, the supernatant was collected and LDH levels were measured using a cytotoxicity detection kit (Roche). For all cell culture experiments, the percent cell death was calculated using low and high controls where cardiomyocytes were cultured overnight in standard culture medium (RPMI + B27) or RPMI + B27 containing 1% Triton X-100, respectively.Results

[0403] IB212 at 50 nM concentration significantly protected hiPSC-CMs from acidosis-induced death, as depicted in Figure 13.

[0404] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0405] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0406] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.EMBODIMENTS

[0407] Exemplary embodiments include, but are not limited to:1. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (I) wherein:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal), homotyrosine, levodopa (Dopa), Phe(4-MeOH), Phe(4-C00H), Phe(4-NH2), 3-iodo-tyrosine (Tyr(iodo)) or 3,5-diiodo-tyrosine(Tyr(diiodo))); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit), canavanine (Cav) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze) or a-methylproline);X4 is T or a modified form thereof; or S or a modified form thereof;X5 is selected from cyclohexylalanine (Cha); cyclohexylglycine (Chg); and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is R;X? is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg or 2-aminobutyric acid (Abu)); X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg, 2-aminoisobutyric acid (Aib) or Abu); and amide containing amino acid residues including N, Q and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi) or homocysteine), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (isoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, Kand modified forms thereof (e.g. D-lysine (D-Lys) or Orn); a poly(ethylene glycol) (PEG); and amide containing amino acid residues including N, Q and modified forms thereof;X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X17 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys, Orn or Orn(Ac)); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. IsoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.2. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (I) wherein:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal)) ;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp));X4 is T or a modified form thereof;Xs is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. cyclohexylalanine (Cha) or cyclohexylglycine (Chg)); hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof;X? is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and basic amino acid residues including R, K and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi)), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (IsoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-lysine (D-Lys) or Orn); and a poly(ethylene glycol) (PEG);X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X17 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.3. The proteinaceous molecule according to embodiment 1, wherein X1 is selected from Y, W, Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-COOH), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, V and Q.4. The proteinaceous molecule according to embodiment 1 or 2, wherein X1 is selected from Y, W and Nal.5. The proteinaceous molecule according to embodiment 1 or 2, wherein X1 is Y.6. The proteinaceous molecule according to any one of embodiments 1-5, wherein X2 is selected from R, Orn, K(me2), Cit, Cav, Orn(Ac), A, V, L and Q.7. The proteinaceous molecule according to any one of embodiments 1-5, wherein X2 is selected from R, K, Orn, K(me2), Cit, Orn(Ac), A, G, S, T, V, L, I, N and Q.8. The proteinaceous molecule according to any one of embodiments 1-5, wherein X2 is selected from R, Orn, K(me2), Cit, Orn(Ac), A, V, L and Q.9. The proteinaceous molecule according to any one of embodiments 1-5, wherein X2is R.10. The proteinaceous molecule according to any one of embodiments 1-9, wherein X3 is P, Aze, Hyp or a-methylproline.11. The proteinaceous molecule according to any one of embodiments 1-9, wherein X3 is P or Hyp.12. The proteinaceous molecule according to any one of embodiments 1-9, wherein X3is P.13. The proteinaceous molecule according to any one of embodiments 1-12, wherein X4 is T or S.14. The proteinaceous molecule according to any one of embodiments 1-12, wherein X4is T.15. The proteinaceous molecule according to any one of embodiments 1-14, wherein X5 is selected from A, G, S, T, Cha, Chg, V, L and I.16. The proteinaceous molecule according to any one of embodiments 1-14, wherein X5 is Cha, Chg or I.17. The proteinaceous molecule according to any one of embodiments 1-11, wherein X5is I.18. The proteinaceous molecule according to any one of embodiments 2-17, whereinXs is R.19. The proteinaceous molecule according to any one of embodiments 1-18, wherein X? is R or K.20. The proteinaceous molecule according to any one of embodiments 1-18, wherein X7is R.21. The proteinaceous molecule according to any one of embodiments 1-20, whereinX8 is R, K, D or E.22. The proteinaceous molecule according to any one of embodiments 1-20, wherein Xs is R, K or E.23. The proteinaceous molecule according to any one of embodiments 1-20, wherein Xs is R.24. The proteinaceous molecule according to any one of embodiments 1-23, wherein X9is R, K or Me-R.25. The proteinaceous molecule according to any one of embodiments 1-23, wherein X9 is R or Me-R.26. The proteinaceous molecule according to any one of embodiments 1-25, wherein X10 is V, Tie, A, L, Abu or Chg.27. The proteinaceous molecule according to any one of embodiments 1-25, wherein X10 is selected from V, L, I and Tie.28. The proteinaceous molecule according to any one of embodiments 1-25, wherein X10 is V or Tie.29. The proteinaceous molecule according to any one of embodiments 1-28, wherein X11 is selected from R, K and Cit.30. The proteinaceous molecule according to any one of embodiments 1-28, wherein X11 is R or Cit.31. The proteinaceous molecule according to any one of embodiments 1-30, wherein X12 is I, Tie, L, A, Abu, Aib, Chg, Q or K.32. The proteinaceous molecule according to any one of embodiments 1-30, wherein X12 is selected from V, L, I, Tie, R and K.33. The proteinaceous molecule according to any one of embodiments 1-30, wherein X12 is I, Tie, L or K.34. The proteinaceous molecule according to any one of embodiments 1-30, wherein X12 is I.35. The proteinaceous molecule according to any one of embodiments 1-34, wherein X13 is C.36. The proteinaceous molecule according to any one of embodiments 1-35, wherein X14 is selected from D, E, isoE, D-Glu, A, G, S, T, R, K, D-Lys and Orn.37. The proteinaceous molecule according to any one of embodiments 1-35, wherein X14 is E, G, Q or K.38. The proteinaceous molecule according to any one of embodiments 1-35, whereinX14 is E, G or K.39. The proteinaceous molecule according to any one of embodiments 1-38, wherein X15 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a poly(ethylene glycol).40. The proteinaceous molecule according to any one of embodiments 1-38, wherein X15 is absent or is E, D, isoE, D-Glu or a PEG.41. The proteinaceous molecule according to any one of embodiments 1-38, wherein X15 is absent or is E, isoE, D-Glu or a PEG.42. The proteinaceous molecule according to any one of embodiments 1-41, wherein X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.43. The proteinaceous molecule according to any one of embodiments 1-41, wherein X16 is absent or is E, D, isoE or D-Glu.44. The proteinaceous molecule according to any one of embodiments 1-41, wherein X16 is absent or is E, isoE or D-Glu.45. The proteinaceous molecule according to any one of embodiments 1-44, wherein X17 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.46. The proteinaceous molecule according to any one of embodiments 1-44, wherein X17 is absent or is E, K, D-Lys, Orn, Orn(Ac) or a PEG.47. The proteinaceous molecule according to any one of embodiments 1-44, wherein X17 is absent or is E, K, D-Lys, Orn or a PEG.48. The proteinaceous molecule according to embodiment 47, wherein X17 is a PEG.49. The proteinaceous molecule according to embodiment 48, wherein X17 is PEG12.50. The proteinaceous molecule according to any one of embodiments 1-49, wherein X16 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.51. The proteinaceous molecule according to any one of embodiments 1-49, wherein X16 is absent or is E, K or a PEG.52. The proteinaceous molecule according to any one of embodiments 1-51, wherein X19 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.53. The proteinaceous molecule according to any one of embodiments 1-51, wherein X19 is absent or is E, K or a PEG.54. The proteinaceous molecule according to any one of embodiments 1-53, wherein X20 is absent or is D, E, isoE, D-Glu, R, K, D-Lys, Orn or a PEG.55. The proteinaceous molecule according to any one of embodiments 1-53, wherein X20 is absent or is E or a PEG.56. The proteinaceous molecule according to any one of embodiments 1-53, wherein X20 is absent or is E.57. The proteinaceous molecule according to any one of embodiments 1-56, wherein X16, X19 and X20 are absent.58. The proteinaceous molecule according to any one of embodiments 1-57, wherein X14 is E and X15 to X20 are absent.59. The proteinaceous molecule according to any one of embodiments 1-57, wherein X15 and X16 are E and X17 to X20 are absent.60. The proteinaceous molecule according to any one of embodiments 1-57, wherein X15 and X16 are E, X17 is E, K or Orn and X16 to X20 are absent.61. The proteinaceous molecule according to any one of embodiments 1-41, wherein X15 is a PEG and X16 and X17 are acidic amino acid residues.62. The proteinaceous molecule according to embodiment 61, wherein X15 is PEG2.63. The proteinaceous molecule according to embodiments 1 or 2, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73 and 262-315.64. The proteinaceous molecule according to embodiment 2, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73.65. The proteinaceous molecule according to embodiment 64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-26, 28, 30-38, 41-43, 47, 48, 51, 53, 55, 56, 59, 61-65 and 68-73.66. The proteinaceous molecule according to embodiment 64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-4, 6, 7-12, 14, 18-20, 22-25, 28, 30, 33, 34, 36, 41, 43, 47, 61, 63, 65, 69, 71 and 73.67. The proteinaceous molecule according to any one of embodiments 1-56, further comprising a stabilising moiety.68. The proteinaceous molecule according to embodiment 67, wherein the stabilising moiety is a PEG.69. The proteinaceous molecule according to embodiment 68, wherein the PEG comprises between 2 and 50 ethylene glycol units.70. The proteinaceous molecule according to embodiment 68, wherein the PEG comprises 4, 12 or 37 ethylene glycol units.71. The proteinaceous molecule according to embodiment 68, wherein the PEG has a molecular weight of from about 1 kDa to about 50 kDa.72. The proteinaceous molecule according to any one of embodiments 68-71, wherein one of X12 and X15 to X20 is a basic amino acid residue (e.g. K or Orn) and the stabilising moiety is attached to the side chain of the basic amino acid residue.73. The proteinaceous molecule according to any one of embodiments 68-71, wherein X17 is a basic amino acid residue (e.g. K or Orn) and the stabilising moiety is attached to the side chain of the basic amino acid residue.74. The proteinaceous molecule according to any one of embodiments 1-73, wherein X13 is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X13 position and the N-terminal amine of the amino acid residue in the X1 position.75. The proteinaceous molecule according to any one of embodiments 1-73, wherein X13 is C and the side chain of the cysteine residue in the X13 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the X1 position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X13, and R1is C1-6 alkylene.76. The proteinaceous molecule according to embodiment 75, wherein R1is methylene.77. The proteinaceous molecule according to any one of embodiments 1-76, wherein the proteinaceous molecule comprises a C-terminal amide.78. A composition comprising, consisting or consisting essentially of a proteinaceous molecule according to any one of embodiments 1-77 and a pharmaceutically acceptable carrier or diluent.79. A proteinaceous molecule according to any one of embodiments 1-77 for use in therapy.80. A method of inhibiting an activity of an acid-sensing ion channel (ASIC), comprising contacting the ASIC with a proteinaceous molecule according to any one of embodiments 1-77.81. The method according to embodiment 80, wherein the ASIC is ASICla.82. A method of treating, inhibiting or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, comprising administering a proteinaceous molecule according to any one of embodiments 1-77.83. The method according to embodiment 82, wherein the condition is selected from the group consisting of a neurological condition, neuronal damage, ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, an inflammatory condition (e.g. rheumatoid arthritis or osteoarthritis) and retinal detachment.84. The method according to embodiment 83, wherein the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease.85. The method according to embodiment 84, wherein the neurological condition is stroke.86. The method according to embodiment 83, wherein the ischaemia is neuronal, ocular, renal or cardiac ischaemia.87. The method according to embodiment 86, wherein the ocular ischaemia is acute retinal ischaemia.88. The method according to embodiment 83, wherein the cancer is a glioblastoma.89. The method according to embodiment 683, wherein the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.90. A method of treating, inhibiting or at least partially inhibiting the development of a neurological condition in a subject, comprising administering a proteinaceous molecule according to any one of embodiments 1-77.91. The method according to embodiment 90, wherein the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease.92. The method according to embodiment 91, wherein the neurological condition is stroke.93. A method of treating, inhibiting or at least partially inhibiting the development of ischaemia in a subject, comprising administering a proteinaceous molecule according to any one of embodiments 1-77.94. A method of treating, inhibiting or at least partially inhibiting the development of ischaemic damage in a subject, comprising administering a proteinaceous molecule according to any one of embodiments 1-77.95. The method according to embodiment 94, wherein the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.96. The method according to embodiment 95, wherein the ischaemic damage is cardiac ischaemic damage.97. The method according to embodiment 96, wherein the ischaemic damage is associated with a myocardial infarction.98. The method according to embodiment 95, wherein the ischaemic damage is neuronal ischaemic damage.99. The method according to embodiment 94, wherein the ischaemic damage is associated with a stroke, traumatic brain injury or perinatal brain injury.100. A method of inhibiting or at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue, comprising contacting the tissue with a proteinaceous molecule according to any one of embodiments 1-77.101. The method according to embodiment 100, wherein the tissue is an organ transplant.102. The method according to embodiment 100 or embodiment 101, wherein the tissue is a heart, lung or kidney.103. The method according to embodiment 102, wherein the tissue is a heart.104. A method of inhibiting or at least partially inhibiting damage to an organ during organ transplantation, comprising contacting the organ with a proteinaceous molecule according to any one of embodiments 1-77.105. The method according to embodiment 104, wherein the organ is a heart, lung or kidney.106. The method according to embodiment 105, wherein the organ is a heart.107. The method according to any one of embodiments 104-106, wherein the damage is ischaemic damage.108. A proteinaceous molecule according to any one of embodiments 1-77 for use in inhibiting an activity of an acid-sensing ion channel (ASIC).109. A proteinaceous molecule according to any one of embodiments 1-77 for use in treating, inhibiting or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition.110. A proteinaceous molecule according to any one of embodiments 1-77 for use in treating, inhibiting or at least partially inhibiting the development of a neurological condition in a subject.111. A proteinaceous molecule according to any one of embodiments 1-77 for use in treating, inhibiting or at least partially inhibiting the development of ischaemia in a subject.112. A proteinaceous molecule according to any one of embodiments 1-77 for use in treating, inhibiting or at least partially inhibiting the development of ischaemic damage in a subject.113. A proteinaceous molecule according to any one of embodiments 1-77 for use in inhibiting or at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue.114. A proteinaceous molecule according to any one of embodiments 1-77 for use in inhibiting or at least partially inhibiting damage to an organ during organ transplantation.115. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for inhibiting an activity of an acid-sensing ion channel (ASIC).116. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for treating, inhibiting or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition.117. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for treating, inhibiting or at least partially inhibiting the development of a neurological condition in a subject.118. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for treating, inhibiting or at least partially inhibiting the development of ischaemia in a subject.119. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for treating, inhibiting or at least partially inhibiting the development of ischaemic damage in a subject.120. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for inhibiting or at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue.121. Use of a proteinaceous molecule according to any one of embodiments 1-77 in the manufacture of a medicament for inhibiting or at least partially inhibiting damage to an organ during organ transplantation.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20 (I) wherein:X1 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. 1-naphthyl-L-alanine (Nal), homotyrosine, levodopa (Dopa), Phe(4- MeOH), Phe(4-COOH), Phe(4-NH2), 3-iodo-tyrosine (Tyr(iodo)), or 3,5-diiodo- tyrosine (Tyr(diiodo))); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X2 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), Ne-dimethyl-L-lysine [K(me2)], citrulline (Cit), canavanine (Cav) or N5-acetyl-ornithine [Orn(Ac)]); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including V, L, I and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X3 is P or a modified form thereof (e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze) or a-methylproline);X4 is T or a modified form thereof; or S or a modified form thereof;X5 is selected from cyclohexylalanine (Cha); cyclohexylglycine (Chg); and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xs is R;X7 is selected from basic amino acid residues including R, K and modified forms thereof;Xs is selected from basic amino acid residues including R, K and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R));X10 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); and small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg or 2-aminobutyric acid (Abu));X11 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Cit);X12 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof (e.g. Chg, 2-aminoisobutyric acid (Alb) or Abu); and amide containing amino acid residues including N, Q and modified forms thereof;X13 is selected from C and modified forms thereof (e.g. C(oxi) or homocysteine), Pen and 5-aminovaleric acid (Ava);X14 is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoglutamic acid (isoE) or D-glutamic acid (D-Glu)); small amino acid residues including A, G, S, T and modified forms thereof; basic amino acid residues including R, K and modified forms thereof (e.g. D-lysine (D-Lys) or Orn); a poly(ethylene glycol) (PEG); and amide containing amino acid residues including N, Q and modified forms thereof;X15 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X17 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys, Orn or Orn(Ac)); and a PEG; X16 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG;X19 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; andX20 is absent or is selected from acidic amino acid residues including D, E and modified forms thereof (e.g. isoE or D-Glu); basic amino acid residues including R, K and modified forms thereof (e.g. D-Lys or Orn); and a PEG; wherein at least one of X14, X15 and X16 is independently an acidic amino acid residue.

2. The proteinaceous molecule according to claim 1, wherein X1 is selected from Y, W, Nal, homotyrosine, Dopa, Phe(4-MeOH), Phe(4-COOH), Phe(4-NH2), Tyr(iodo), Tyr(diiodo), A, V and Q.

3. The proteinaceous molecule according to claim 1, wherein X1 is Y, W or Nal.

4. The proteinaceous molecule according to any one of claims 1-3, wherein X2 is selected from R, Orn, K(me2), Cit, Cav, Orn(Ac), A, V, L and Q.

5. The proteinaceous molecule according to any one of claims 1-4, wherein X3 is P, Aze, Hyp or a-methylproline.

6. The proteinaceous molecule according to any one of claims 1-5, wherein X4is T or S.

7. The proteinaceous molecule according to any one of claims 1-6, wherein X4is T.

8. The proteinaceous molecule according to any one of claims 1-7, wherein X5 is Cha, Chg or I.

9. The proteinaceous molecule according to any one of claims 1-8, wherein X? is R or K.

10. The proteinaceous molecule according to any one of claims 1-9, whereinX8 is R, K or E.

11. The proteinaceous molecule according to any one of claims 1-10, wherein X9is R, K or Me-R.

12. The proteinaceous molecule according to any one of claims 1-11, wherein X10 is V, Tie, A, L, Abu or Chg.

13. The proteinaceous molecule according to any one of claims 1-12, wherein X10 is V or Tie.

14. The proteinaceous molecule according to any one of claims 1-13, wherein X11 is selected from R, K and Cit.

15. The proteinaceous molecule according to any one of claims 1-14, wherein X12 is selected from L, I, Tie and K.

16. The proteinaceous molecule according to any one of claims 1-14, wherein X12 is I, Tie, L, A, Abu, Aib, Chg, Q or K.

17. The proteinaceous molecule according to any one of claims 1-16, wherein X13 is C.

18. The proteinaceous molecule according to any one of claims 1-17, wherein X14 is E, G, Q or K.

19. The proteinaceous molecule according to any one of claims 1-18, wherein X14 is E, G or K.

20. The proteinaceous molecule according to any one of claims 1-19, wherein X15 is absent or is E, D, isoE, D-Glu or a PEG.

21. The proteinaceous molecule according to any one of claims 1-20, wherein X16 is absent or is E, D, isoE or D-Glu.

22. The proteinaceous molecule according to any one of claims 1-21, wherein X17 is absent or is E, K, D-Lys, Orn, Orn(Ac) or a PEG.

23. The proteinaceous molecule according to any one of claims 1-22, wherein X16 is absent or is E, K or a PEG.

24. The proteinaceous molecule according to any one of claims 1-23, wherein X19 is absent or is E, K or a PEG.

25. The proteinaceous molecule according to any one of claims 1-24, wherein X20 is absent or is E or a PEG.

26. The proteinaceous molecule according to claim 1, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73 and 262-315:YRPTIRRRRVRICGEE [SEQ ID NO: 1];YRPTIRRRRVRICGX21EE [SEQ ID NO: 2];YRPTIRRRRVRICE [SEQ ID NO: 3];YRPTIRRRRVRICGEEE [SEQ ID NO: 4];YRPTIRRRRVRICGX21EEE [SEQ ID NO: 5];YRPTIRRRRVRICGX21EEEE [SEQ ID NO: 6];YRPTIRRRX22VRICGX21EE [SEQ ID NO: 7];WRPTIRRRX22VRICGX21EE [SEQ ID NO: 8];WRPTX23RRRX22VRICGX21EE [SEQ ID NO: 9];YRPTIRRRRVRICEEE [SEQ ID NO: 10];YRPTIRRRRVRICGee [SEQ ID NO: 11];YRPTIRRRX22VRICGEE [SEQ ID NO: 12];YX24PTIRRRRVRICGEE [SEQ ID NO: 13];YAPTIRRRRVRICGEE [SEQ ID NO: 14];YRPTIRRRRVX24ICGEE [SEQ ID NO: 15];YX24PTIRRRRVRICGEEE [SEQ ID NO: 16];YRX25TIRRRRVRICGEEE [SEQ ID NO: 17];YRPTIRRRRVRICEE [SEQ ID NO: 18];YRPTIRRRRVRICGEEEE [SEQ ID NO: 19];YRPTIRRRRVRICGEEEEE [SEQ ID NO: 20];YRPTIRRRRVRICGEEEEEE [SEQ ID NO: 21];YRPTIRRRRVRICEEEE [SEQ ID NO: 22];YRPTIRRRRVRICGEEX26 [SEQ ID NO: 23];YRPTIRRRRVRICGEEX26X26 [SEQ ID NO 24];YRPTIRRRX22VRICGEEE [SEQ ID NO 25];YX24PTIRRRX22VRICGEE [SEQ ID NO 26];YX24PTIRRRX22VRICGEEE [SEQ ID NO 27];YX24PTIRRRRX27RICGEE [SEQ ID NO 28];YQPTIRRRX22VRICGEE [SEQ ID NO 29];YX28PTIRRRX22VRICGEE [SEQ ID NO 30];YLPTIRRRX22VRICGEE [SEQ ID NO 31];YVPTIRRRX22VRICGEE [SEQ ID NO 32];YRPTIRRRX22VRICGEX29 [SEQ ID NO 33];YRPTIRRRX22VRICGX29X29 [SEQ ID NO 34];YRPTIRRRRVRICGEEK [SEQ ID NO 35];YRPTIRRRRVRICGEEX30 [SEQ ID NO 36];YRPTIRRRRVRICKEE [SEQ ID NO 37];YRPTIRRRRVRICX30EE [SEQ ID NO 38];YRPTIRRRRVRKCGEE [SEQ ID NO 39];YRPTIRRRRVRX30CGEE [SEQ ID NO 40];YX31PTIRRRRVRICGEE [SEQ ID NO 41];YX32PTIRRRX22VRICGEE [SEQ ID NO 42];YRPTIRRRX22VRICEE [SEQ ID NO 43];YRPTIRRRRVRICGEEX26X26K [SEQ ID NO 44];YRPTIRRRRVRICGEEX26X26X33 [SEQ ID NO 45];YRPTIRRRRVRICGEEX26X26X34 [SEQ ID NO 46];YRPTIRRRRVRICGEEX35 [SEQ ID NO 47];YRPTIRRRRVRICGEEX36 [SEQ ID NO 48];YRPTIRRRRVRICGEEX37 [SEQ ID NO 49];YRPTIRRRRVRICGEEX38 [SEQ ID NO 50];YRPTIRRRRX27RICGEE [SEQ ID NO 51];X39RPTIRRRRX27RICGEE [SEQ ID NO 52];YRPTIRKRRX27RICGEE [SEQ ID NO 53];YRPTIRRERX27RICE [SEQ ID NO 54];YRPTIRRRRX27RX27CGEE [SEQ ID NO 55];YRPTX40RRRRX27RICGEE [SEQ ID NO 56];YRPTIRRRRVRIX41GEE [SEQ ID NO 57];YRPTIRRRRVRICGEEX42 [SEQ ID NO 58];YRPTIRRRRVRICGEEX26X43 [SEQ ID NO 59];YRPTIRRRRVRICX42EE [SEQ ID NO 60];YRPTIRRRRVRICGEEX26X26X43 [SEQ ID NO 61];YX53PTIRRRRVRICGEE [SEQ ID NO 282];YRPTIRRRRX4ORICGEE [SEQ ID NO 283];YRPTX40RRRRVRICGEE [SEQ ID NO 284];YRPTIRRRRVRX40CGEE [SEQ ID NO 285];YRX25TIRRRRVRICGEE [SEQ ID NO 286];YRX54TIRRRRVRICGEE [SEQ ID NO 287];YRX55TIRRRRVRICGEE [SEQ ID NO 288];XssRPTIRRRRVRICGEE [SEQ ID NO 289];X57RPTIRRRRVRICGEE [SEQ ID NO 290];XssRPTIRRRRVRICGEE [SEQ ID NO 291];X59RPTIRRRRVRICGEE [SEQ ID NO 292];YRPTIRRRRVRACGEE [SEQ ID NO 293];YRPTIRRRRVRXeoCGEE [SEQ ID NO 294];YRPTIRRRRVRXeiCGEE [SEQ ID NO 295];YRPTIRRRRXeoRICGEE [SEQ ID NO 296];X62RPTIRRRRVRICGEE [SEQ ID NO 297];YRPTIRRRRVRICGEEX32 [SEQ ID NO 298];YRPTIRRRRVRICGEEX26X33 [SEQ ID NO 299];YRPTIRRRRVRICGEEX26X26X63 [SEQ ID NO 300];YRPTIRRRRVRICGEEX26X26X64 [SEQ ID NO 301];YRPTIRRRRVRICGEEX26X26X65 [SEQ ID NO 302];YRPTIRRRRVRICGEEX26X26X66 [SEQ ID NO 303];YRPTIRRRRVRICGEEX26X26X67 [SEQ ID NO 304];YRPTIRRRRVRICGEEX26X34 [SEQ ID NO 305];YRPTIRRRRVRICGEEXes [SEQ ID NO 306];YRPTIRRRRVRICGEEEEXes [SEQ ID NO 307];YRPTIRRRRVRICGEEEXes [SEQ ID NO 308];YRPTIRRRRVRICGEEXesEE [SEQ ID NO 309];YRPTIRRRRVRICGEEX44X69 [SEQ ID NO 310];YRPTIRRRRVRICGEEX48X70 [SEQ ID NO: 311];YRPTIRRRRVRICGEEX48X71 [SEQ ID NO: 312];YRPTIRRRRVRICGEEX48X48X71 [SEQ ID NO: 313];YRPTIRRRRVRICGEEX72X71 [SEQ ID NO: 314];YRPTIRRRRVRICGEEX73 [SEQ ID NO: 315], wherein :X21 is PEG2;X22 is Me-R;X23 is Cha ;X24 is Cit;X25 is Hyp;X26 is PEG12;X27 is Tie;X28 is Orn;X29 is isoE;X30 is K(PEG37) ;X31 is K(me2) ;X32 is Orn(Ac);X33 is K(isoE-C18A) ;X34 is K(isoE-C16);X35 is K(PEG 5kDa);X36 is K(PEG lOkDa);X37 is K(PEG 20kDa);X38 is K(PEG 40kDa);X39 is Nal ;X40 is Chg ;X41 is C(oxi);X42 is K(albutag);X43 is K(isoE-albutag) ;X44 is Orn(PEG37);X45 is k(PEG37);X48 is PEG4;X49 is Tyr(iodo);X50 is Tyr(diiodo) ;X51 is Pen;X52 is homocysteine;X53 is canavanine;X54 is Aze;X55 is a-methylproline;X56 is homotyrosine;X57 is Dopa;X58 is Phe(4-MeOH);X59 is Phe(4-COOH);X60 is Abu;X61 is Aib;X62 is Phe(4-NH2);X63 is K(isoE-C14A);X64 is K(isoE-C14);X65 is K(isoE-C12);X66 is K(isoE-ClO);X67 is K(isoE-C16A);X69 is K(C16);X&9 is K(PEG4-biotin);X70 is K(C12);X71 is K(C18A);X72 is PEG24; andX73 is Orn(PEG4-MPA).

27. The proteinaceous molecule according to claim 26, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-73.

28. The proteinaceous molecule according to any one of claims 1-27, wherein X13 is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X13 position and the N-terminal amine of the amino acid residue in the X1 position.

29. A composition comprising, consisting or consisting essentially of a proteinaceous molecule according to any one of claims 1-28 and a pharmaceutically acceptable carrier or diluent.

30. A proteinaceous molecule according to any one of claims 1-28 for use in therapy.

31. A method of inhibiting an activity of an acid-sensing ion channel (ASIC), comprising contacting the ASIC with a proteinaceous molecule according to any one of claims 1-28.

32. A method of treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effectivetreatment or inhibition of the development of the condition, comprising administering a proteinaceous molecule according to any one of claims 1-28.

33. A method of treating or at least partially inhibiting the development of a neurological condition in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-28.

34. The method according to claim 33, wherein the neurological condition is selected from the group consisting of stroke, ischaemia, multiple sclerosis, Huntington's disease, Parkinson's disease, spinal cord injury, neuroinflammation, perinatal brain injury, traumatic brain injury and Alzheimer's disease.

35. The method according to claim 34, wherein the neurological condition is stroke.

36. A method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-28.

37. A method of treating or at least partially inhibiting the development of ischaemic damage in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-28.

38. The method according to claim 37, wherein the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.

39. The method according to claim 38, wherein the ischaemic damage is cardiac ischaemic damage.

40. The method according to claim 39, wherein the ischaemic damage is associated with a myocardial infarction.

41. The method according to claim 38, wherein the ischaemic damage is neuronal ischaemic damage.

42. A method of at least partially inhibiting the development of ischaemiareperfusion injury in a tissue, comprising contacting the tissue with a proteinaceous molecule according to any one of claims 1-28.

43. The method according to claim 42, wherein the tissue is an organ transplant.

44. The method according to claim 42 or claim 43, wherein the tissue is a heart, lung or kidney.

45. A method of at least partially inhibiting damage to an organ during organ transplantation, comprising contacting the organ with a proteinaceous molecule according to any one of claims 1-28.

46. The method according to claim 45, wherein the organ is a heart, lung or kidney.

47. The method according to claim 45 or claim 46, wherein the damage is ischaemic damage.

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