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 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 THE EFO '

[0001] This application claims priority to Australian Provisional Patent Application No. 2023903298 entitled "Inhibitors and Uses Therefor" filed 16 October 2023, 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 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) Proc Natl Acad Sci USA, 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 it is a key mediator of neuronal damage following ischaemia (Redd et al. (2021) Circulation, 144: 947-960; Chassagnon et al. (2017) Proc Natl Acad Sci USA, 114(14): 3750-3755).

[0007] A number of conditions are associated with ischaemia, including stroke and myocardial infarction. Ischaemia sets off a biochemical 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) Proc Natl Acad Sci USA, 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) Proc Natl Acad Sci USA, 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) Proc Natl Acad Sci USA, 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 (Chassagnon et al. (2017) Proc Natl Acad Sci USA, 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] Despite a clear need for therapies, there are no approved therapeutics that treat the cellular injury caused by ischaemia during a stroke or a cardiac event, such as myocardial infarction. Accordingly, effective neuroprotective and cardioprotective therapies are desired.SUMMARY OF THE INVENTION

[0011] The present invention is predicated in part on the design of proteinaceous molecules that inhibit ASIC activity, especially ASICla activity. Based on this activity, theinventors 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 and retinal detachment; as well as for minimising damage to an organ during organ transplantation.

[0012] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting of, or consisting essentially of, an amino acid sequence represented by Formula I:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (I) wherein:Xi is absent or is selected from C and penicillamine (Pen);X2 is absent or is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, 3,3-diphenyl-L-alanine (Dip), 4,4'-biphenyl-L-alanine (Bip) or 1-naphthyl-L-alanine (Na I)) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino-4-guanidino- butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. N-methyl-phenylalanine (Me- F));X7 is selected from 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. cyclohexylalanine (Cha)); hydrophobic amino acid residues including V, L, I and modifiedforms thereof (e.g. tert- Leucine (Tie)); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; C and modified forms thereof (e.g. D-Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar)); hydrophobic amino acid residues including V, L, I and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, alpha-methyl-arginine (aMe-R), Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xi6 is selected from C and modified forms thereof (e.g. D-Cys), Pen, 5-aminovaleric acid (Ava) and basic amino acid residues including R, K and modified forms thereof;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; wherein when Xie is other than C or a modified form thereof, Pen or Ava, Xs is C or a modified form thereof; and when Xs is other than C or a modified form thereof, Xie is selected from C and modified forms thereof, Pen and Ava.

[0013] In some embodiments:X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino-4-guanidino- butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar)); hydrophobic amino acid residues including V, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); andX14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof. In some embodiments, Xi, X2, X15 and / or Xis are absent.

[0014] In some embodiments, X3 is Y, W, D-Tyr, Dip, Bip, tBuF or Nal.

[0015] In some embodiments, X4 is selected from R, V, Cit, E, I and K .

[0016] In some embodiments, X5 is selected from A, G, S, T and P .

[0017] In some embodiments, Xe is selected from A, T, L, I and Me-F.

[0018] In particular embodiments, X7 is selected from R, T, I, P, Me-F, Tie andCha.

[0019] In some embodiments, Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, T, C, F, Y and Me-F.

[0020] In some embodiments, X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, I and P.

[0021] In some embodiments, X10 is selected from R, K, Arg(Me), E, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, Sar, L and Y.

[0022] In some embodiments, Xn is R or L.

[0023] In some embodiments, X12 is selected from R, K, A, V, I, Tie, Cha, E and Me-F.

[0024] In some embodiments, X13 is selected from R, K, Me-R, aMe-R, Orn, b- Arg, HArg, Agb, Cit, gArg, A, V, L and F.

[0025] In some embodiments, X14 is selected from R, S, T, A, V, L, I, E and Tie.

[0026] In some embodiments, X16 is C.

[0027] In some embodiments, X17 is absent or is selected from R, K, A, G, S and T.

[0028] In some embodiments, Xis is absent or is selected R, K, A, G, S and T; especially K or A. In alternative embodiments, Xis is absent.

[0029] In some embodiments, at least three of X4, Xs, X9, X10 and X13 are independently a basic amino acid residue, such as R.

[0030] In particular embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by any one of SEQ ID NOs: 1-44 and 47-66:YRPTIRRRRVRICG [SEQ ID NO: 1]YRGLRRKRLVACG [SEQ ID NO: 2]YTRKTFRGWRRCG [SEQ ID NO: 3] yVNRRGRLKRRTCG [SEQ ID NO: 4] yRRLRRPYRKFVCG [SEQ ID NO: 5]yQSKPTIRRRRIRCA [SEQ ID NO: 6]; yLKTRCIKSRVLLRRA [SEQ ID NO: 7];YRSLRHKX19RIVCG [SEQ ID NO: 8];YRRX20X20X20RKRRCG [SEQ ID NO: 9]; yRPTIRRKRX2oCG [SEQ ID NO: 10]; yRTIRKRRKKLSCG [SEQ ID NO: 11];YRPTIRRRRVRIC [SEQ ID NO: 12];YASLRHKX19RIVCG [SEQ ID NO: 13];YRALRHKX19RIVCG [SEQ ID NO: 14];YRSARHKX19RIVCG [SEQ ID NO: 15];YRSLAHKX19RIVCG [SEQ ID NO: 16];YRSLRAKX19RIVCG [SEQ ID NO: 17];YRSLRHAX19RIVCG [SEQ ID NO: 18];YRSLRHKARIVCG [SEQ ID NO: 19];YRSLRHKX19AIVCG [SEQ ID NO: 20];YRSLRHKX19RAVCG [SEQ ID NO: 21];YRSLRHKX19RIACG [SEQ ID NO: 22];YRSLRHKX19RIVC [SEQ ID NO: 23]; yRSLRHKXigRIVCG [SEQ ID NO: 24];YRPTIRRX21RVRICG [SEQ ID NO: 25];YRPTIRRRX21VRICG [SEQ ID NO: 26];YRPTIRRRRVX21ICG [SEQ ID NO: 27];YRPTIRRRRVRICGK [SEQ ID NO: 28];YVPTIRRRRVRICG [SEQ ID NO: 29];YRPTIRRRRRRICG [SEQ ID NO: 30];YRPTIRRRRVRRCG [SEQ ID NO: 31];YRPTIRRRVRICG [SEQ ID NO: 32];WRPTIRRRRVRICG [SEQ ID NO: 33];X22RPTIRRRRVRICG [SEQ ID NO: 34];X23RPTIRRRRVRICG [SEQ ID NO: 35];X24RPTIRRRRVRICG [SEQ ID NO: 36];YRPTX25RRRRVRICG [SEQ ID NO: 37];YRPTX26RRRRVRICG [SEQ ID NO: 38];YRPTIRRRRX25RICG [SEQ ID NO: 39];YRPTIRRRRX26RICG [SEQ ID NO: 40];ARPTIRRRRVRICG [SEQ ID NO: 41];YAPTIRRRRVRICG [SEQ ID NO: 42];YRATIRRRRVRICG [SEQ ID NO: 43];YRPAIRRRRVRICG [SEQ ID NO: 44];YRPTIRARRVRICG [SEQ ID NO: 47];YRPTIRRARVRICG [SEQ ID NO: 48];YRPTIRRRAVRICG [SEQ ID NO: 49];YRPTIRRRRARICG [SEQ ID NO: 50];YRPTIRRRRVAICG [SEQ ID NO: 51];YRPTIRRRRVRACG [SEQ ID NO: 52];CVYVPTIRRRRRRRC [SEQ ID NO: 53];X27VYVPTIRRRRRRRX27 [SEQ ID NO: 54];CTYRATIRRKRRKVC [SEQ ID NO: 55];CYTIPTIRRKRRKVC [SEQ ID NO: 56];CKYRSTIRRKRRRVC [SEQ ID NO: 57];CQYVATIRRKRRKVC [SEQ ID NO: 58];CRKPTIRRKLRC [SEQ ID NO: 59];VYVPTIRRRRRRRC [SEQ ID NO: 60];YRPTIRRRRVRIX28 [SEQ ID NO: 61];YRSLRHKX19RIVX28 [SEQ ID NO: 62];YLRRPYRSCG [SEQ ID NO: 63];YRPTX25RRRX21VRICG [SEQ ID NO: 64];YRPTX26RRRX21VRICG [SEQ ID NO: 65]; andWRPTIRRRX21VRICG [SEQ ID NO: 66] wherein X19 is Sar; X20 is Me-F; X21 is Me-R; X22 is Dip; X23 is Bip; X24 is Nal; X25 is Tie; X26 is Cha; X27 is Pen; and X28 is Ava.

[0031] In particular embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by any one of SEQ ID NOs: 1-12, 53 and 55-59.

[0032] In some embodiments, Xi and X2 are absent and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the Xs or Xie position and the N-terminal amine of the amino acid residue in the X3 position.

[0033] In some embodiments, Xi and X16 are C or Xi and X16 are Pen, and the proteinaceous molecule comprises a disulfide bond between the side chains of Xi and Xie.

[0034] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula II:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (II) wherein :X2-X15 are as defined for Formula I;Xi and Xie are independently C or Pen; and the side chains of Xi and Xie form a linkage represented by Formula III :wherein each sulfur atom is the sulfur atom from X1and X16, and R1is a bond or a divalent linker selected from the group consisting of:C1-6 alkylene,

[0035] In alternative embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IV:X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (IV) wherein :X3-X15, X17 and Xis are as defined for Formula I;Xie is C; andthe side chain of Xi6 forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula V:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xie, and R2is C1-6 alkylene.

[0036] In other embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by Formula VI:X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (VI) wherein:X3-X7 and X9-X18 are as defined for Formula I;Xs is C; and the side chain of Xs forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula VII:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xs, and R3is C1-6 alkylene.

[0037] In particular embodiments, R3is methylene.

[0038] In some embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by Formula VIII:X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (VIII) wherein:X2-X15 are as defined for Formula I;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X2, wherein the thioether linkage is represented by Formula IX:wherein the amine is the N-terminal amine of X2, the sulfur atom is the sulfur atom from X16, and R4is C1-6 alkylene.

[0039] In particular embodiments, R4is methylene or ethylene.

[0040] In some embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by Formula X:X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (X) wherein:X3-Xis are as defined for Formula I;Xie is Ava; and the N-terminal amine of X3 and the C-terminal acid of X16 form an amide bond.

[0041] In particular embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by SEQ ID NO: 61 or 62.

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

[0043] In specific embodiments, the proteinaceous molecule further comprises a cell-penetrating peptide, such as a TAT peptide (TAT), angiopep2 (ANG) or PepH3. In particular embodiments, the cell-penetrating peptide is TAT or angiopep2. In exemplary embodiments, the proteinaceous molecule comprises, consists of, or consists essentially of, an amino acid sequence represented by SEQ ID NO: 67:YRPTIRRRRVRICGX29 [SEQ ID NO: 67]; wherein X29 is:wherein R5is a proteinaceous molecule comprising an amino acid sequence represented by SEQ ID NO: 68 or 69:TFFYGGSRGKRNNFKTEEY [SEQ ID NO: 68];YGRKKRRQRRR [SEQ ID NO: 69].

[0044] Further provided is a composition comprising, consisting of, or consisting essentially of, a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.

[0045] In another aspect, there is provided a proteinaceous molecule of the invention for use in therapy.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In some embodiments, the cancer is a glioblastoma.

[0051] In some embodiments, the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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 or an organ procured for transplantation. In some embodiments, the tissue is a heart, lung or kidney; especially a heart.

[0057] 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

[0058] Figure 1 is a scheme for the synthesis and cyclisation of IB100.

[0059] Figure 2 is a mass spectrum of pure IB100 showing the expected [M + 3H]+3and [M + 2H]+2ions, plus TFA adducts [M + 3H+TFA]+3(a), [M + 3H+2TFA]+3(b), [M + 3H+3TFA]+3(c), [M + 2H+TFA]+2(d), [M + 2H+2TFA]2(e), [M + 2H+3TFA]2(f), and [M + 2H+4TFA]+2(g).

[0060] Figure 3 is a chromatogram from an analytical reverse-phase (RP)-HPLC elution of purified IB100 using a Phenomenex C18 Luna column at 45°C. The peptide was eluted using a gradient of 5 to 43% buffer B (90% acetonitrile in water / 0.05% TFA) in buffer A (0.05% TFA in water) over 13 minutes. The flow rate was 0.5 mL / min. Peptide purity estimated from area under the IB100 peak was 98%.

[0061] Figure 4 shows representative two electrode voltage-clamp current traces demonstrating inhibition of currents from human ASICla (hASICla) heterologously expressed in Xenopus laevis oocytes by various concentrations of IB100. hASICla currents were stimulated by a pH drop from 7.4 to 6.0.

[0062] Figure 5 is a concentration-response curve showing the inhibition of hASICla-mediated sodium currents by IB100. Data are mean of n = 3 experiments. A fit of the Hill equation to the concentration-response data yielded an IC50 of 1.60 nM, with complete inhibition (100% efficacy) observed at an IB100 concentration of 100 nM.

[0063] Figure 6 shows hASICla currents as a fraction of the maximum current during washout of the peptide from X. laevis oocytes expressing hASICla. hASICla currents were maximally inhibited with 1 pM IB100, then recovery of hASICla currents was monitored during washout of the peptide. Currents were fully recovered within 8 minutes, with a half-life for current recovery of about 3 minutes. Data are mean ± SEM, with n = 3.

[0064] Figure 7 is a schematic of the experimental protocol used to test the ability of IB100 to prevent loss of cardiac function in a rat model of myocardial infarction (MI). The ischaemic period, which comprised a 90-minute ligation of the left anterior descending artery (LAD), was followed by removal of the ligature to allow reperfusion of the ischaemic territory.

[0065] Figure 8 is a graph of fractional shortening (a measure of cardiac function) measured 1 week after ischaemia-reperfusion injury (i.e. MI) in sham rats and those treated with vehicle, IB100 or cariporide. Drug delivery was via the external jugular vein. Asterisks indicate statistically significant differences between drug-treated and vehicle- treated cohorts (****, p <0.001).

[0066] Figure 9 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 for 18 hours. Release of lactate dehydrogenase (LDH) was used as a proxy for cell death. Addition of 50 nM IB100 rescued hiPSC-CMs from acidosis-induced cell death at pH 5.0. For reperfusion experiments, the medium was replaced with HBSS pH 7.4 (with or without peptide) after overnight incubation and cultured for 4 hr under normoxic conditions. Data are mean ± SEM. ****p < 0.0001 using one-way ANOVA.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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 alkylenegroups include methylene (-CH2-), ethylene (-CH2CH2-), propylene, including n-propylene (-CH2CH2CH2-), butylene, including n-butylene (-CH2CH2CH2CH2-), and the like.

[0073] 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-).

[0074] 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.

[0075] 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

[0076] 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).

[0077] 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.

[0078] 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, including residues with modified side chains, N-methyl amino acids, o-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 determinedthrough 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 in inhibiting, minimising or reducing the damage or injury, such as cell death.

[0085] As used herein, the phrase "inhibit the development of" 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. In some embodiments, the proteinaceous molecules treat or inhibit the development of (or prevent) any one of the diseases, disorders or conditions recited herein.

[0086] 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 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, RIPK1 phosphorylation and / or ERK phosphorylation.

[0087] 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.

[0088] 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 partof 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, 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.

[0089] 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.

[0090] 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.

[0091] 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 ofcomparison. 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, He, 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.

[0092] "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.

[0093] 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 al. (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) CurrentGenomics, 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.

[0094] 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.

[0095] 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 adverse effect 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.

[0096] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Abbreviations

[0097] 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-arginine HArg =homoarginineAgb =2-amino-4-guanidino-butyric acidCit =citrulline gArg =guanidinyl-alkylated-arginineMe-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-0-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 acidMe-Y =N-methyl-tyrosineMe-L =N-methyl-leucineMe-S =N-methyl-serineMe-C =N-methyl-cysteineCOOHF =p-carboxy-phenylalanineCF3F =4-trifluoromethyl-phenylalanine hiPSC-CMs =human induced pluripotent stem cell-derived card io myocytes LDH =lactate dehydrogenase3. Proteinaceous Molecules

[0098] The present invention is based, in part, on the design of proteinaceous molecules that inhibit ASIC activity. Based on this activity, the inventors conceived that these proteinaceous molecules, including proteinaceous molecules of Formula I, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX, 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, ischaemiareperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment; as well as for at least partially inhibiting damage to an organ during organ transplantation.

[0099] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting of, or consisting essentially of, an amino acid sequence represented by Formula I:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (I) wherein:Xi is absent or is selected from C and penicillamine (Pen);X2 is absent or is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, Dip, Bip, tBuF or Nal) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X? is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; C and modified forms thereof (e.g. D-Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. Sar or D-Ser); hydrophobic amino acid residues including V, L, I and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residuesincluding V, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xi4 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X15 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xi6 is selected from C and modified forms thereof (e.g. D-Cys or Me-C), Pen, Ava and basic amino acid residues including R, K and modified forms thereof;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; wherein when Xie is other than C or a modified form thereof, Pen or Ava, Xs is C or a modified form thereof; and when Xs is other than C or a modified form thereof, Xie is selected from C and modified forms thereof, Pen and Ava.[O1OO] In some embodiments, Xi is absent. In alternative embodiments, Xi is C or Pen. In particular embodiments, Xi is C. In alternative embodiments, Xi is Pen.

[0101] In specific embodiments, when Xi is C, Xie is C, and when Xi is Pen, Xie is Pen.

[0102] X2 is absent or is selected from any amino acid residue. In some embodiments, X2 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; 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; aromatic amino acid residues including Y, W, F and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof.

[0103] In particular embodiments, X2 is absent or is selected from R, K, A, G, S, T, V, L, I, Y, W, F, N and Q; especially absent or is V, T, Y, K, Q or R; more especially absent or is V; most especially absent. In preferred embodiments, when X2 is absent, Xi is also absent.

[0104] In particular embodiments, Xi is C or Pen and X2 is selected from R, K, A, G, S, T, V, L, I, Y, W, F, N and Q. In preferred embodiments, Xi is C or Pen and X2 is V, T, Y, K, Q or R. In some embodiments, Xi is C and X2 is V.

[0105] X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, Dip, Bip or Nal) and small amino acid residues including A, G, S, T and modified forms thereof. In particular embodiments, X3 is absent or is selected from Y, F, W, D-Tyr, Dip, Bip, Nal, A, G, S and T. In specific embodiments, X3 is selected from Y, F, W, D-Tyr, Dip, Bip, Nal, A, G, S and T; especially Y, W, D-Tyr, Dip, Bip, Nal, A or T; more especially Y, W or D-Tyr; most especially Y.

[0106] In particular embodiments, X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, Dip, Bip or Nal). In particular embodiments, X3 is absent or is selected from Y, F, W, D-Tyr, Dip, Bip and Nal. In specific embodiments, X3 is selected from Y, F, W, D-Tyr, Dip, Bip and Nal; especially Y, W, D-Tyr, Dip, Bip and Nal; more especially Y, W or D-Tyr; most especially Y.

[0107] In some embodiments, X3 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, Dip, Bip, tBuF or Nal). In particular embodiments, X3 is selected from Y, F, W, Dip, Bip, tBuF and Nal. In specific embodiments, X3 is selected from Y, W, Dip, Bip, tBuF and Nal; especially Y, Bip or Nal. In some embodiments, X3 is Y.

[0108] In some embodiments, Xi and X2 are absent and X3 is Y.

[0109] In some embodiments, X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, V, L, I, D, E, N and Q; especially R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, T, V, L, Q, K, E or I; more especially R, Cit, V, E, I or K; most especially R or V. In some embodiments, X4 is R, Cit, E or A. In some embodiments, X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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. In particular embodiments, X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, V, L, I, N and Q; especially R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, T, V, L, Q, K or I; more especially R, V, I or K; most especially R or V. In particular embodiments, X4 is R. In some embodiments, X4 is other than Me-R and aMe-R. In some embodiments, X4 is other than A.

[0110] In particular embodiments, X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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. In particularembodiments, X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L, I, N and Q; especially R, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L, Q, K or I; more especially R, V, I or K; most especially R or V. In particular embodiments, X4 is R.

[0111] In some embodiments, X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); and small amino acid residues including A, G, S, T and modified forms thereof; especially R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S or T. In some embodiments, X4 is R, Cit or A; especially R or Cit; most especially R.

[0112] In some embodiments, X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); especially R, K, Orn, b-Arg, HArg, Agb, Cit or gArg; more especially R or K; most especially R.

[0113] In some embodiments, when X3 is absent, X4 is a basic amino acid residue or modified from thereof as described above; especially K.

[0114] In alternative embodiments, X4 is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof; especially V, L or I; more especially V.

[0115] X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof; especially R, K, A, G, S, T, P, N or Q. In some embodiments, X5 is selected from R, A, G, S, T, P and N; especially A, G, S, T or P; more especially P or S; most especially P.

[0116] In some embodiments, X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; especially A, G, S, T or P; more especially S or P. In some embodiments, X5 is A or P, especially P.

[0117] Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); especially R, K, A, G, S, T, V, L, I, Y, W, F or Me-F. In some embodiments, Xe is selected from R, K, T, L, I and Me-F; especially T, L, I or Me-F. In particular embodiments, Xe is T or L; especially T. In some embodiments, Xe is other than A.

[0118] In some embodiments, Xe is selected from small amino acid residues including A, G, S, T and modified forms thereof and hydrophobic amino acid residuesincluding V, L, I and modified forms thereof; especially T, V, L or I; more especially T or L; most especially T.

[0119] X? is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); especially R, K, G, S, T, Cha, V, L, I, Tie, P, Y, W, F or Me-F. In some embodiments, X7 is selected from R, T, I, P, Me-F, Tie and Cha; especially R, Cha or I; especially R, Tie, Cha or I; more especially R or I.

[0120] In some embodiments, X7 is selected from 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. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); especially R, K, G, S, T, Cha, V, L, I or Tie; more especially R, G, S, T, Cha, V, L, I or Tie; most especially R, Cha, V, L, I or Tie. In particular embodiments, X7 is Cha, V, L, I or Tie; especially I, Cha or Tie; especially I or Cha, or I or Tie; most especially I. In some embodiments, X7 is other than A.

[0121] Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; C and modified forms thereof (e.g. D- Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); especially R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, C, D-Cys, Y, W, F or Me-F. In some embodiments, Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, T, C, F, Y and Me-F; especially R or H. In some embodiments, Xs is other than aMe-R, Me-R and / or A.

[0122] In particular embodiments, Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg); especially R, K, H, Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg; more especially R, K or H; most especially R. In some embodiments, Xs is R, HArg or Arg(Me); especially R.

[0123] X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof; especially R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, T, V, L, I or P. In some embodiments, X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, I and P; especially R or K. In some embodiments, X9 is selected from R, K, Orn, Cit, HArg, Arg(Me), aMe-R and Agb; especially R, K, Orn, Cit, HArg or Agb.

[0124] In particular embodiments, X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); especially R, K, Orn, b-Arg, HArg, Agb, Cit or gArg. In exemplary embodiments, X9 is R or K; especially R. In particular embodiments, X9 is other than Me-R and aMe-R.

[0125] In some embodiments, X10 is selected from R, K, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg, K(Ac), G, S, T, D-Ser, Sar, V, L, I, D, E, Y, W and F; such as R, K, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg, E or K(Ac); or R, K, Arg(Me), Orn, HArg, Agb, Cit, E or K(Ac). In some embodiments, X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. Sar); hydrophobic amino acid residues including V, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof; especially R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, Sar, V, L, I, Y, W or F. In some embodiments, X10 is selected from R, K, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg, K(Ac), G, S, T, D-Ser, Sar, V, L, I, Y, W and F; such as R, K, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg or K(Ac); or R, K, Arg(Me), Orn, HArg, Agb, Cit or K(Ac). In particular embodiments, X10 is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, Sar, L and Y; especially R, K or Sar.

[0126] In some embodiments, X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); and small amino acid residues including A, G, S, T and modified forms thereof (e.g. Sar); especially R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T or Sar; more especially R, K, Me-R or Sar; most especially R, K or Me-R. In particular embodiments, X10 is R or K; especially R. In some embodiments, X10 is other than aMe-R and / or A.

[0127] Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof; especially absent or is R, K, Me-R, Orn, b- Arg, HArg, Agb, Cit, gArg, G, S, T, V, L, I, Y, W or F. In particular embodiments, Xn is absent or is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, S, L and W; especially R, L, me-R or HArg; especially R, L or Me-R; more especially R or L; most especially R. In some embodiments, Xn is other than aMe-R and / or A.

[0128] In some embodiments, Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acidresidues including Y, W, F and modified forms thereof; especially R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, V, L, I, Y, W or F. In particular embodiments, Xn is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, S, L and W; especially R, L or Me-R; more especially R or L; most especially R.

[0129] In specific embodiments, Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg) and hydrophobic amino acid residues including V, L, I and modified forms thereof; especially R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L or I; more especially R, K, Me-R or L; most especially R, K or Me-R. In some embodiments, Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); especially R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg; more especially R, K or Me-R. In exemplary embodiments, Xn is R.

[0130] In some embodiments, X12 is absent or is R, K, A, G, S, T, Cha, V, L, I, Tie, D, E, Y, W, F or Me-F; especially R, K, Cha, V, L, I, A, E or Tie. In some embodiments, X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); especially absent or is R, K, Cha, V, L, I, Tie, Y, W, F or Me-F; more especially absent or is R, K, V, I, Tie, Cha or Me-F; most especially R, V or I. In some embodiments, X12 is other than A.

[0131] In some embodiments, X12 is selected from 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. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); especially R, K, Cha, V, L, I, A or Tie; especially R, K, Cha, V, L, I or Tie; more especially R, V, I, Cha or Tie; most especially R, V or I. In some embodiments, X12 is V, Tie, A or R; especially V or Tie. In some embodiments, X12 is R or V; especially V.

[0132] X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof; especially absent or is R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, T, V, L, I, Y, W or F. In particular embodiments, X13 is absent or is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, V, L and F; especially R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A,, L or F; more especially R, K or V. In some embodiments, X13 is R, Me-R, Cit or A; especially R, Cit or Me-R.

[0133] In some embodiments, X13 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg) and hydrophobic amino acid residues including V, L, I and modified forms thereof; especially R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L or I; more especially R, K or V; most especially R or K. In particular embodiments, X13 is R.

[0134] In alternative embodiments, X13 is absent.

[0135] In some embodiments, X14 is absent or is selected from R, K, A, G, S, T, D, E, V, L, I or Tie; especially R, S, T, A, V, L, I, E or Tie; especially I, R, A, E or Tie. X14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); especially absent or is R, K, A, G, S, T, V, L or I; or especially absent or is R, K, A, G, S, T, V, L, I or Tie. In some embodiments, X14 is absent or is selected from R, S, T, V, L and I; especially R, S, T, V, L or I; more especially I, R or V. In some embodiments, X14 is selected from R, S, T, A, V, L, I and Tie; especially R, S, T, A, V, L, I or Tie; especially I, R, A or Tie. In some embodiments, X14 is absent.

[0136] In some embodiments, X14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof and hydrophobic amino acid residues including V, L, I and modified forms thereof; especially absent or is R, K, V, L or I; more especially R, V or I; most especially I. In particular embodiments, X14 is selected from basic amino acid residues including R, K and modified forms thereof and hydrophobic amino acid residues including V, L, I and modified forms thereof; especially R, K, V, L or I; more especially R, V or I; most especially I.

[0137] X15 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof; especially absent or is R, K, V, L or I. In some embodiments, X15 is absent or is selected from R and L; especially is absent.

[0138] Xi6 is selected from C and modified forms thereof (e.g. D-Cys or Me-C), Pen, Ava and basic amino acid residues including R, K and modified forms thereof; especially C, D-Cys, Pen, Ava, R and K. In some embodiments, X16 is C, D-Cys, Me-C, Pen, Ava, R or K. In some embodiments, X16 is selected from C, Pen, Ava and R; especially C, Pen and Ava; more especially C.

[0139] In some embodiments, Xi is absent and X16 is C. In further embodiments, Xi and X2 are absent and Xi6 is C.

[0140] In some embodiments, Xi is absent and Xi6 is Ava. In further embodiments, Xi and X2 are absent and Xi6 is Ava.

[0141] In alternative embodiments, Xs is C and X16 is selected from basic amino acid residues including R, K and modified forms thereof; especially R or K; most especially R.

[0142] X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; especially absent or is selected from R, K, A, G, S and T; more especially is absent or is selected from R, A and G; most especially G.

[0143] In some embodiments, X17 is absent or is selected from small amino acid residues including A, G, S, T and modified forms thereof; especially is absent or is A, G, S or T; more especially absent or is G or A; most especially G or A. In particular embodiments, X17 is G.

[0144] In some embodiments, X17 is absent.

[0145] Xis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; especially absent or is selected from R, K, A, G, S and T; more especially absent or is A or K; most especially absent or K. In particular embodiments, Xis is absent.

[0146] In some embodiments:Xi is absent or is C or Pen;X2 is absent or is selected from R, K, A, G, S, T, V, L, I, Y, W, F, N and Q;X3 is absent or is selected from Y, F, W, D-Tyr, Dip, Bip and Nal; or X3 is selected from Y, W, Dip, Bip, tBuF and Nal;X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, T, V, L, I, N and Q; or X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, T, V, L, I, N, Q, D, E, A, G, S and T;X5 is selected from R, K, A, G, S, T, P, N and Q;X6is selected from R, K, G, S, T, V, L, I, Y, W, F and Me-F;X7is selected from R, K, G, S, T, Cha, V, L, I, Tie, P, Y, W, F and Me-F;Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, C, D-Cys, Y, W, F and Me-F; or Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, Arg(Me), gArg, G, S, T, C, D-Cys, Y, W, F and Me-F;X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, T, V, L, I and P; or X9 is selected from R, K, Orn, b-Arg, HArg, Cit, gArg, Arg(Me), aMe-R, Agb A, G, S, T, V, L, I and P;X10 is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, Sar, V, L, I, Y, W and F; or X10 is selected from R, K, Me-R, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg, K(Ac), G, S, T, D-Ser, Sar, V, L, I, Y, W, D, E and F;Xn is absent or is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, T, V, L, I, Y, W and F;X12 is absent or is selected from R, K, Cha, V, L, I, Tie, Y, W, F and Me-F; or X12 is selected from R, K, Cha, V, L, I, Tie, A, Y, W, F, D, E and Me-F;X13 is absent or is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, T, V, L, I, Y, W and F;X14 is absent or is selected from R, K, A, G, S, T, V, L and I; or X14 is absent or is selected from R, K, A, G, S, T, V, L, I, D, E and Tie;X15 is absent or is selected from R, K, V, L and I;X16 is selected from C, D-Cys, Pen, Ava, R and K; or X16 is selected from C, D-Cys, Me-C, Pen, Ava, R and KX17 is absent or is selected from R, K, A, G, S and T; andXis is absent or is selected from R, K, A, G, S and T.

[0147] In some embodiments:Xi is absent or is C or Pen;X2 is absent or is selected from V, T, Y, K, Q and R;X3 is absent or is selected from Y, W, D-Tyr, Dip, Bip and Nal; or X3 is selected from Y, W, Dip, Bip, tBuF and Nal;X4 is selected from R, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L, Q, K and I; or X4 is selected from R, Cit, E and A;X5 is selected from R, A, G, S, T, P and N;Xe is selected from R, K, T, L, I and Me-F;X7 is selected from R, T, I, P, Me-F, Tie and Cha;Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, T, C, F, Y and Me-F; or Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, Arg(Me), gArg, G, T, C, F, Y and Me- F;X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, I and P;Xio is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, G, S, Sar, L and Y; or Xio is selected from R, K, Me-R, Arg(Me), Orn, b-Arg, HArg, Agb, Cit, gArg, K(Ac), G, S, Sar, L, E and Y;Xn is absent or is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, S, L and W; or Xn is absent or is selected from R, K, Me-R, Orn, HArg, Agb, Cit, S, L and W;X12 is absent or is R, K, V, I, Tie, Cha or Me-F; or X12 is R, V, A, E or Tie, such as R, V, E or Tie;X13 is absent or is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, V, L and F;X14 is absent or is selected from R, S, T, V, L and I; or X14 is absent or is selected from R, S, T, A, V, L, I, E and Tie;X15 is absent or is selected from R and L;X16 is selected from C, Pen, Ava and R;X17 is absent or is selected from R, A and G; andXis is absent or is A or K.

[0148] In some embodiments:Xi is absent or is C;X2 is absent or is V;X3 is Y or W;X4 is R or V; or X4 is R or Cit;X5 is P or S;Xe is T or L;X7 is R, Cha or I; or X7 is Cha, Tie or I;Xs is R or H; or Xs is R, HArg or Arg(Me); especially R;X9 is R or K;Xio is R, K or Sar; or Xio is R, K, Arg(Me), Orn, HArg, Agb, Cit, K(Ac), E or Sar;Xn is R, L or Me-R; or Xn is R, L, HArg or Me-R;X12 is R, V or I; or X12 is R, V or Tie, such as V or Tie;X13 is R, K or V; or X13 is R, Me-R or Cit;X14 is absent or is I, R or V; or X14 is absent or is I, R, V, E or Tie;X15 is absent;Xi6 is C or Ava;X17 is absent or is G; andXis is absent or is K.

[0149] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-44, 47-66 and 296-336:YRPTIRRRRVRICG [SEQ ID NO: 1];YRGLRRKRLVACG [SEQ ID NO: 2];YTRKTFRGWRRCG [SEQ ID NO: 3]; yVNRRGRLKRRTCG [SEQ ID NO: 4]; yRRLRRPYRKFVCG [SEQ ID NO: 5]; yQSKPTIRRRRIRCA [SEQ ID NO: 6]; yLKTRCIKSRVLLRRA [SEQ ID NO: 7];YRSLRHKX19RIVCG [SEQ ID NO: 8];YRRX20X20X20RKRRCG [SEQ ID NO: 9]; yRPTIRRKRX2oCG [SEQ ID NO: 10] yRTIRKRRKKLSCG [SEQ ID NO: 11]YRPTIRRRRVRIC [SEQ ID NO: 12]YASLRHKX19RIVCG [SEQ ID NO: 13]YRALRHKX19RIVCG [SEQ ID NO: 14]YRSARHKX19RIVCG [SEQ ID NO: 15]YRSLAHKX19RIVCG [SEQ ID NO: 16]YRSLRAKX19RIVCG [SEQ ID NO: 17]YRSLRHAX19RIVCG [SEQ ID NO: 18]YRSLRHKARIVCG [SEQ ID NO: 19]YRSLRHKX19AIVCG [SEQ ID NO: 20]YRSLRHKX19RAVCG [SEQ ID NO: 21]YRSLRHKX19RIACG [SEQ ID NO: 22]YRSLRHKX19RIVC [SEQ ID NO: 23] yRSLRHKXigRIVCG [SEQ ID NO: 24]YRPTIRRX21RVRICG [SEQ ID NO: 25];YRPTIRRRX21VRICG [SEQ ID NO: 26];YRPTIRRRRVX21ICG [SEQ ID NO: 27];YRPTIRRRRVRICGK [SEQ ID NO: 28];YVPTIRRRRVRICG [SEQ ID NO: 29];YRPTIRRRRRRICG [SEQ ID NO: 30];YRPTIRRRRVRRCG [SEQ ID NO: 31];YRPTIRRRVRICG [SEQ ID NO: 32];WRPTIRRRRVRICG [SEQ ID NO: 33];X22RPTIRRRRVRICG [SEQ ID NO: 34];X23RPTIRRRRVRICG [SEQ ID NO: 35];X24RPTIRRRRVRICG [SEQ ID NO: 36];YRPTX25RRRRVRICG [SEQ ID NO: 37];YRPTX26RRRRVRICG [SEQ ID NO: 38];YRPTIRRRRX25RICG [SEQ ID NO: 39];YRPTIRRRRX26RICG [SEQ ID NO: 40];ARPTIRRRRVRICG [SEQ ID NO: 41];YAPTIRRRRVRICG [SEQ ID NO: 42];YRATIRRRRVRICG [SEQ ID NO: 43];YRPAIRRRRVRICG [SEQ ID NO: 44];YRPTIRARRVRICG [SEQ ID NO: 47];YRPTIRRARVRICG [SEQ ID NO: 48];YRPTIRRRAVRICG [SEQ ID NO: 49];YRPTIRRRRARICG [SEQ ID NO: 50];YRPTIRRRRVAICG [SEQ ID NO: 51];YRPTIRRRRVRACG [SEQ ID NO: 52];CVYVPTIRRRRRRRC [SEQ ID NO: 53];X27VYVPTIRRRRRRRX27 [SEQ ID NO: 54];CTYRATIRRKRRKVC [SEQ ID NO: 55];CYTIPTIRRKRRKVC [SEQ ID NO: 56];CKYRSTIRRKRRRVC [SEQ ID NO: 57];CQYVATIRRKRRKVC [SEQ ID NO: 58];CRKPTIRRKLRC [SEQ ID NO: 59];VYVPTIRRRRRRRC [SEQ ID NO: 60];YRPTIRRRRVRIX28 [SEQ ID NO: 61];YRSLRHKX19RIVX28 [SEQ ID NO: 62];YLRRPYRSCG [SEQ ID NO: 63];YRPTX25RRRX21VRICG [SEQ ID NO: 64];YRPTX26RRRX21VRICG [SEQ ID NO: 65];WRPTIRRRX21VRICG [SEQ ID NO: 66];YLRRPYRACG [SEQ ID NO: 296];YLRRPYRSC [SEQ ID NO: 297];X30RPTIRRRRVRICG [SEQ ID NO: 298];YRPTIRKRRVRICG [SEQ ID NO: 299];YRPTIRX31RRVRICG [SEQ ID NO: 300];YRPTIRX32RRVRICG [SEQ ID NO: 301];YRPTIRX33RRVRICG [SEQ ID NO: 302];YRPTIRX34RRVRICG [SEQ ID NO: 303];YRPTIX33RRRVRICG [SEQ ID NO: 304];YRPTIRRKRVRICG [SEQ ID NO: 305];YRPTIRRX31RVRICG [SEQ ID NO: 306];YRPTIRRX32RVRICG [SEQ ID NO: 307];YRPTIRRX33RVRICG [SEQ ID NO: 308];YRPTIRRX34RVRICG [SEQ ID NO: 309];YRPTIRRRKVRICG [SEQ ID NO: 310];YRPTIRRRX31VRICG [SEQ ID NO: 311];YRPTIRRRX33VRICG [SEQ ID NO: 312];YRPTIRRRX34VRICG [SEQ ID NO: 313];YX32PTIRRRX21VRICG [SEQ ID NO: 314];YRPTIRRRX21VX32ICG [SEQ ID NO: 315];YRPTIRX35RX21VRICG [SEQ ID NO: 316];YRPTIRRX36RVRICG [SEQ ID NO: 317];YRPTIRRRRVRX25CG [SEQ ID NO: 318];YEPTIRRRRVRICG [SEQ ID NO: 319];YRPTIRRRRERICG [SEQ ID NO: 320];WEPTIRRRRVRICG [SEQ ID NO: 321];YEPTX26RRRRVRICG [SEQ ID NO: 322];YEPTIRRRX21VRICG [SEQ ID NO: 323];YEPTX26RRRX21VRICG [SEQ ID NO: 324];YRPTIRRERVRICG [SEQ ID NO: 325];YRPTIRX37RRVRICG [SEQ ID NO: 326];YRPTIX37RRRVRICG [SEQ ID NO: 327];YRPTIRRX37RVRICG [SEQ ID NO: 328];YRPTIRRRX37VRICG [SEQ ID NO: 329];YRPTIRRRRVRECG [SEQ ID NO: 330];YRPTIRX38RRVRICG [SEQ ID NO: 331];SLRRPYRSCG [SEQ ID NO: 332];FLRRPYRSCG [SEQ ID NO: 333];YLRRPYRSX39G [SEQ ID NO: 334];YLRRPYRsCG [SEQ ID NO: 335]; andX30LRRPYRSCG [SEQ ID NO: 336], wherein X19 is Sar; X20 is Me-F; X21 is Me-R; X22 is Dip; X23 is Bip; X24 is Nal; X25 is Tie; X26 is Cha; X27 is Pen; X28 is Ava; X30 is tBuF; X31 is Orn; X32 is Cit; X33 is HArg; X34 is Agb; X35 is b-Arg; X36 is K(Ac); X37 is Arg(Me); X38 is aMe-R; and X39 is Me-C.

[0150] 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- 12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330. In specific embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 1 or 12.

[0151] 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- 44 and 47-66. In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-12, 53 and 55-59.

[0152] 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- 12, 14, 18, 22, 23, 25-31, 33-45 and 47-66; especially any one of SEQ ID NOs: 1-12, 53 and 55-59. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66.

[0153] In some embodiments, the proteinaceous molecule is other than a proteinaceous molecule comprising SEQ ID NOs: 45 or 46:YRPTARRRRVRICG [SEQ ID NO: 45]; orYRPTIARRRVRICG [SEQ ID NO: 46].

[0154] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XI:X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (XI) wherein:X2 is absent or is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof;X3 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dip, Bip or Nal) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof and P and modified forms thereof;Xe is selected from small amino acid residues including A, G, S, T and modified forms thereof;X? is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. Cha) and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg) and small amino acid residues including A, G, S, T and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg); acidic amino acid residues including D, E and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof;Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg) and small amino acid residues including A, G, S, T and modified forms thereof;X12 is selected from 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. Cha); acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X13 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg); and small amino acid residues including A, G, S, T and modified forms thereof;X14 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X15 is absent;X16 is selected from C and modified forms thereof (e.g. D-Cys) and Ava;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof.

[0155] In some embodiments:X2 is absent or is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof;X3 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dip, Bip or Nal) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof and P and modified forms thereof;Xe is selected from small amino acid residues including A, G, S, T and modified forms thereof;X7 is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. Cha) and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg) and small amino acid residues including A, G, S, T and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg) and small amino acid residues including A, G, S, T and modified forms thereof;Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg) and small amino acid residues including A, G, S, T and modified forms thereof;X12 is selected from 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. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X13 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg); and small amino acid residues including A, G, S, T and modified forms thereof;Xi4 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X15 is absent;Xi6 is selected from C and modified forms thereof (e.g. D-Cys) and Ava;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof.

[0156] In some embodiments:X2 is absent or is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof;X3 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dip, Bip, tBuF or Nal);X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); and hydrophobic amino acid residues including V, L, I and modified forms thereof; or X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X5is P;Xe is selected from small amino acid residues including A, G, S, T and modified forms thereof;X7 is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit, Arg(Me) or gArg);Xio is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit, K(Ac), Arg(Me) or gArg); or Xio is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b- Arg, HArg, Agb, Cit, K(Ac), Arg(Me) or gArg); and acidic amino acid residues including D, E and modified forms thereof;Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg);X12 is selected from 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. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); or X12 is selected from 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. Cha); acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X13 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg);Xi4 is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); or Xi4 is selected from basic amino acid residues including R, K and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);X15 is absent;Xi6 is selected from C and modified forms thereof (e.g. D-Cys) and Ava;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof.

[0157] In some embodiments:X2 is absent or is selected from hydrophobic amino acid residues including V, L, I and modified forms thereof;X3 is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dip, Bip, tBuF or Nal);X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); and hydrophobic amino acid residues including V, L, I and modified forms thereof; or X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X5is P;Xe is selected from small amino acid residues including A, G, S, T and modified forms thereof;X7 is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. Cha) and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);Xs is R;X9is R;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit, K(Ac), Me(Arg) or gArg); or X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b- Arg, HArg, Agb, Cit, K(Ac), Me(Arg) or gArg); and acidic amino acid residues including D, E and modified forms thereof;Xn is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg);X12 is selected from 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. Cha); and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); or X12 is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and acidic amino acid residues including D, E and modified forms thereof;X13 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit or gArg);X14 is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); or X14 is selected from basic amino acid residues including R, K and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie);Xis is absent;Xi6 is selected from C and Ava;X17 is absent or is selected from small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof.

[0158] In some embodiments:X2 is absent or is V, L or I; especially absent or V; more especially absent;X3 is selected from Y, W, F, Dip, Bip and Nal; or X3 is selected from Y, W, Dip, Bip, tBuF and Nal; especially Y or W; or Y;X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L and I; or X4 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, V, L, I, D, E, A, G, S and T; especially R, Cit, A, E or V; especially R or Cit; more especially R;X5is P;Xe is selected from A, G, S and T; especially T;X7 is selected from G, S, T, Cha, V, L, I and Tie; especially I, Tie or Cha;Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit and gArg; or Xs is R, HArg or Arg(Me); most especially R;X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit and gArg; or X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit and Arg(Me); especially R or K; most especially R;X10 is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit and gArg; or X10 is selected from R, K, Me-R, Arg(Me), Orn, HArg, Agb, K(Ac), D, E and Cit; especially R, K, E or Me- R; more especially R or Me-R; most especially R;Xn is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit and gArg; especially R, K, HArg or Me-R; especially R, K or Me-R; especially R, HArg or Me-R; more especially R or Me-R; most especially R;X12 is selected from R, K, A, G, S, T, Cha, V, L, I and Tie; especially V, R, A, D, E, Tie or Cha; especially V, R, A, E or Tie; especially V, R or Tie; especially V or R; especially V;X13 is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit and gArg; especially R, Me-R or Cit; especially R or Me-R; more especially R;X14 is selected from R, K, V, L and I; or X14 is selected from R, K, V, L, Tie, D, E and I; especially I, R or Tie; more especially I;X15 is absent;Xi6 is C or Ava; especially C;X17 is absent or is selected from small amino acid residues including A, G, S, T and modified forms thereof; especially absent or is G; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; especially absent or is K.

[0159] 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, 12, 25-31, 33-44, 47-52, 60, 61 and 64-66; especially any one of SEQ ID NOs: 1, 12, 26, 28, 29, 65 and 66. In specific embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 1 or 12.

[0160] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XII:YRX5LRHX9X10RIVX16X17 (XII) wherein:X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof;X9 is selected from basic amino acid residues including R, K and modified forms thereof and small amino acid residues including A, G, S, T and modified forms thereof;Xie is selected from C and modified forms thereof (e.g. D-Cys) and Ava; andX17 is absent or is selected from small amino acid residues including A, G, S, T and modified forms thereof.

[0161] In some embodiments:X5 is selected from A, G, S and T; especially A or S;X9 is selected from R, K, A, G, S and T; especially K or A;Xie is C or Ava; especially C; andX17 is absent or is A, G, S or T; more especially absent or is G.

[0162] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 8, 14, 18, 22, 23 and 62; especially SEQ ID NO: 8, 22 or 23.

[0163] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XIII:X1X2X3X4X5TIRRX10X11RX13X14X16 (XIII) wherein:Xi is selected from C and Pen;X2 is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof and hydrophobic amino acid residues including V, L, I and modified forms thereof;X5 is selected from small amino acid residues including A, G, S, T and modified forms thereof and P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof;Xn is selected from basic amino acid residues including R, K and modified forms thereof and hydrophobic amino acid residues including V, L, I and modified forms thereof;X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof;X14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof and hydrophobic amino acid residues including V, L, I and modified forms thereof; andX16 is selected from C and modified forms thereof and Pen; wherein when Xi is Pen, X16 is Pen and when Xi is C or a modified form thereof, X16 is C or a modified form thereof.

[0164] In some embodiments:Xi is C or Pen; especially C;X2 is selected from basic amino acid residues including R, K and modified forms thereof; 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; aromatic amino acid residues including Y, W, F and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof; especially R, K, A, G, S, T, V, L, I, Y, W, F, N or Q; more especially V, T, Y, K, Q or R; most especially V or R;X3 is absent or is Y, W, F, A, G, S or T; especially absent or is Y or T; more especially Y;X4 is R, K, V, L or I; especially V, R, I or K;Xs is A, G, S, T or P; especially A, S or P; more especially P;X10 is R or K;Xn is R, K, V, L or I; especially R or L;X13 is absent or is R or K; especially R or K;X14 is absent or is R, K, V, L or I; especially absent or R or V; more especially R or V; andXi6 is C or Pen; especially C; wherein when Xi is Pen, X16 is Pen and when Xi is C, X16 is C.

[0165] In some embodiments:Xi is C or Pen; especially C;X2 is selected from basic amino acid residues including R, K and modified forms thereof; 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; aromatic amino acid residues including Y, W, F and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof; especially R, K, A, G, S, T, V, L, I, Y, W, F, N or Q; more especially V, T, Y, K, Q or R; most especially V;X3 is Y, W, F, A, G, S or T; especially Y or T; more especially Y;X4 is R, V, L or I; especially V, R or I; more especially V;Xs is A, G, S, T or P; especially A, S or P; more especially P;X10 is R or K; especially R;Xn is R or K; especially R;X13 is R or K; especially R;X14 is R, K, V, L or I; especially R or V; more especially R; andXi6 is C or Pen; especially C; wherein when Xi is Pen, X16 is Pen and when Xi is C, X16 is C.

[0166] In some embodiments:Xi is C or Pen; especially C;X2 is selected from basic amino acid residues including R, K and modified forms thereof; especially R or K; most especially R;X3 is absent;X4 is R or K; especially K;X5is P;Xio is R or K; especially K;Xn is V, L or I; especially L;X13 is absent;X is absent; andXi6 is C or Pen; especially C; wherein when Xi is Pen, Xi6 is Pen and when Xi is C, Xi6 is C.

[0167] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 53- 59.

[0168] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XIV:Z1X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18Z2 (XIV) wherein:Xi-Xis 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.

[0169] 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.

[0170] 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 in between); 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.

[0171] In particular embodiments, Zi and Z2 are absent.

[0172] Suitable embodiments of Xi-Xis are as discussed supra.

[0173] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XV:Z1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18Z2 (XV) wherein:X2-X18 are as defined for Formula XI 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.

[0174] Suitable embodiments of Zi, Z2 and X2-X18 are discussed supra.

[0175] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XVI:Z1YRX5LRHX9X10RIVX16X17Z2 (XVI) wherein:X5, X9, X10, Xie and X17 are as defined for Formula XII 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.

[0176] Suitable embodiments of Zi, Z2, X5, X9, X10, X16 and X17 are discussed supra.

[0177] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XVII:Z1X1X2X3X4X5TIRRX10X11RX13X14X16Z2 (XVII) wherein:X1-X5, X10, Xn, X13, X14 and Xie are as defined for Formula XIII 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.

[0178] Suitable embodiments of Zi, Z2, X1-X5, X10, Xn, X13, X14 and X16 are discussed supra.

[0179] In some embodiments of any of the aspects described herein, at least three of X4, Xs, X9, X10 and X13 are independently a basic amino acid residue, especially R or K, more especially R.

[0180] 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.

[0181] In particular embodiments (e.g. of Formula I or XIV), Xs is C and the proteinaceous molecule comprises an intramolecular linkage between the side chain of the cysteine residue in the Xs position and the N-terminal amine of the N-terminal amino acid residue, such as a thioether bond. In specific embodiments, Xi and X2 are absent, Xs is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the Xs position and the N-terminal amine of the amino acid residue in the X3 position.

[0182] In alternative embodiments (e.g. of Formula I, XI, XII, XIV, XV or XVI), Xie is C and the proteinaceous molecule comprises an intramolecular linkage between the side chain of the cysteine residue in the X16 position and the N-terminal amine of the N- terminal amino acid residue, such as a thioether bond. In specific embodiments, Xi and X2 are absent, Xie is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X16 position and the N-terminal amine of the amino acid residue in the X3 position.

[0183] In some embodiments (e.g. of Formula I, XIII, XIV or XVII), Xi and X16 are C or Xi and X16 are Pen, and the proteinaceous molecule comprises a disulfide bond between the side chains of Xi and Xi6.

[0184] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula II:X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (II) wherein:X2-X15 are as defined for Formula I;Xi and Xie are independently C or Pen; and the side chains of Xi and Xie form a linkage represented by Formula III:wherein each sulfur atom is the sulfur atom from Xi and X16, and R1is 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-Ci-6 alkylene-.

[0185] In some embodiments, R1is 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, R1isa bond or a divalent linker selected from the group consisting of: methylene, ethylene,

[0186] Such linkage may also be present in a proteinaceous molecule of Formula XIII. Accordingly, in some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XVIII:X1X2X3X4X5TIRRX10X11RX13X14X16 (XVIII) wherein:X2-X5, X10, Xn, X13 and X14 are as defined for Formula XIII;Xi and X16 are independently C or Pen; and the side chains of Xi and Xi6 form a linkage represented by Formula III as defined for Formula II supra.

[0187] In alternative embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IV:X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (IV) wherein:X3-X15, X17 and Xis are as defined for Formula I;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula V:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xie, and R2is C1-6 alkylene.

[0188] In some embodiments, R2is methylene or ethylene, especially methylene.

[0189] Such linkage may also be present in a proteinaceous molecule of Formula XL Accordingly, in some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XIX:X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (XIX)wherein:X2 is absent;X3-X15, X17 and Xis are as defined for Formula I;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula V as defined for Formula IV supra.

[0190] In other embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VI:X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (VI) wherein:X3-X7 and X9-X18 are as defined for Formula I;Xs is C; and the side chain of Xs forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula VII:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xs, and R3is C1-6 alkylene.

[0191] In particular embodiments, R3is methylene or ethylene, especially methylene.

[0192] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VIII:X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (VIII) wherein:X2-X15 are as defined for Formula I;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X2, wherein the thioether linkage is represented by Formula IX:wherein the amine is the N-terminal amine of X2, the sulfur atom is the sulfur atom from X16, and R4is C1-6 alkylene.

[0193] In particular embodiments, R4is methylene or ethylene, especially methylene.

[0194] Such linkage may also be present in a proteinaceous molecule of Formula XI. Accordingly, in some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula XX:X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (XX) wherein:X2-X15, X17 and Xis are as defined for Formula XI;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X2, wherein the thioether linkage is represented by Formula IX as defined for Formula VIII supra.

[0195] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula X:X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (X) wherein:X3-Xis are as defined for Formula I;Xie is Ava; and the N-terminal amine of X3 and the C-terminal acid of X16 form an amide bond.

[0196] Such bonds may also be present in proteinaceous molecules represented by Formula XI and XII, wherein X16 is Ava, and the N-terminal amine of X2 or X3 and the C-terminal acid of X16 form an amide bond.

[0197] In particular embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 61 or 62.

[0198] In some embodiments, the proteinaceous molecule is cyclised through N- to-C cyclisation (head to tail cyclisation), preferably 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 aC-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.

[0199] 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.

[0200] 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 at the C-terminus and a primary amine at the N-terminus. In some embodiments, the proteinaceous molecule comprises a C-terminal amide or a C-terminal methyl group.

[0201] The proteinaceous molecule of the invention may be between 10 amino acid residues and 50 amino acid residues in length (and all integer amino acid residues therebetween); especially between 10 amino acid residues and 40 amino acid residues in length, between 10 amino acid residues and 30 amino acid residues in length or between 10 amino acid residues and 20 amino acid residues in length; more especially between about 12 amino acid residues and 18 amino acid residues in length; including about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid residues in length.

[0202] 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.

[0203] In some embodiments, the proteinaceous molecule of Formula I, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX or XX 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: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50,52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66. In some embodiments, the proteinaceous molecule of Formula I, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX or XX 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: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25- 31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66. In such molecules, the variance occurs at one or more of Xi to Xis, Zi and Z2 when present in the subject Formula.

[0204] The present invention also contemplates proteinaceous molecules that are variants of any one of SEQ ID NOs: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33- 36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66. Such "variant" proteinaceous molecules include proteinaceous molecules derived from any one of SEQ ID NOs: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52,53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305- 309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, 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 acidstherebetween) 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.

[0205] 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.

[0206] The proteinaceous molecules of any one of SEQ ID NOs: 1-44, 47-66 and 296-336 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: 1-44, 47-66 and 296-336 may be prepared by mutagenesis of nucleic acids encoding the amino acid sequence of any one of SEQ ID NOs: 1-44, 47-66 and 296-336. 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.

[0207] Conservative substitutions, such as exchanging one amino acid with another having similar properties, may be particularly desirable. Variant proteinaceous molecules 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: 1-44, 47-66 and 296- 336.

[0208] 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: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1- 12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66. A "conservative amino acidsubstitution" 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] Amide-containing: The residues contain an amide in their side chain, such as glutamine and asparagine.

[0215] Aromatic: The residues contain an aromatic group in their side chain and include phenylalanine, tyrosine and tryptophan.

[0216] 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 andthreonine. 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 o-amino group, as well as the o-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.

[0217] 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.

[0218] 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 sidechain 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.

[0219] 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 moleculeat 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

[0220] 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).

[0221] 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.

[0222] Accordingly, the present invention also contemplates variants of the proteinaceous molecules of any one of SEQ ID NOs: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305- 309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, 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- 44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305- 309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, 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: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298- 302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, as determined by sequence alignment programs described herein using default parameters. Variants of any one of SEQ ID NOs: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26- 29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, 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: 1-44, 47-66 and 296-336, especially any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305- 309, 312, 314, 315, 318, 320-327 and 330; more especially any one of SEQ ID NOs: 1, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330, including any one of SEQ ID NOs: 1-12, 14, 18, 22, 23, 25-31, 33-44 and 47-66, and any one of SEQ ID NOs: 1, 3, 5, 8, 11, 12, 22, 23, 26, 28, 29, 65 and 66, 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, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX or XX. In particular embodiments, the variant proteinaceous molecule of the invention inhibits an activity of ASICla.

[0223] 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.

[0224] In some embodiments, calculations of sequence similarity or sequence identity between sequences are performed as follows:

[0225] 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.

[0226] 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.

[0227] 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).

[0228] 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, o-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0229] 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 tetra nitromethane to form a 3-nitrotyrosine derivative.

[0230] Suitable modified arginine residues include, but are not limited to, Nm- carboxymethyl-L-arginine, No-carboxyethyl-L-arginine, Na-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)] and guanidinyl-alkylated- arginine (gArg).

[0231] 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, Ne- allyloxycarbonyl-L-lysine, N-methyllysine, o-methyllysine, 0-lysine, Na-acetyl-L-lysine, Ne- acetyl-L- lysine [K(Ac)], Ne-methyl-L-lysine, Ne-dimethyl-L-lysine and Ne-formyl-L-lysine.

[0232] Representative modified histidine residues include, but are not limited to, Nl-methyl-L-histidine, N3-methyl-L-histidine, N-methyl-L-histidine, o-methylhistidine, homohistidine and p-histidine.

[0233] Suitable modified alanine residues include, but are not limited to, N- methylalanine, o-methylalanine (2-aminoisobutyric acid), 0-alanine, Na-acetyl-L-alanine, o-aminobutyric acid (or 2-aminobutyric acid, Abu), homoalanine, cyclohexylalanine (Cha) and p-homoalanine.

[0234] Suitable modified leucine residues include, but are not limited to, o- methylleucine, N-methylleucine, 0-leucine, t-butylglycine, homoleucine, Na-acetyl-L- leucine, tert-leucine (Tie) and p-homoleucine.

[0235] Suitable modified glutamine residues include, but are not limited to, o- methylglutamine, Na-methylglutamine, NY-methylglutamine, p-glutamine, homoglutamine, Na-acetyl-L-glutamine and p-homoglutamine.

[0236] Exemplary modified asparagine residues include Np-methyl-Np-methoxy- asparagine, o-methylasparagine, Na-methylasparagine, Np-methylasparagine, p- asparagine, homoasparagine, Na-acetyl-L-asparagine and p-homoasparagine.

[0237] Modified glycine residues include, but are not limited to, N-methylglycine, P-homoglycine, sarcosine (Sar) and Na-acetyl-L-glycine.

[0238] Modified serine residues may include N-methylserine, o-methylserine, p- serine, Na-acetyl-L-serine, isoserine, O-methylserine, homoserine and p-homoserine.

[0239] Exemplary modified threonine residues include N-methylthreonine, o- methylthreonine, p-threonine, Na-acetyl-L-threonine, O-methylthreonine, homothreonine and p-homothreonine.

[0240] Exemplary modified proline residues include o-methylproline, p-proline, Na-acetyl-L-proline, 4-phenoxy-pyrrolidine-2-carboxylic acid, 5,5-dimethylpyrrolidine-2- carboxylic acid, 5-methylpyrrolidine-2-carboxylic acid, homoproline and p-homoproline.

[0241] Suitable modified isoleucine residues include, but are not limited to, o- methylisoleucine, N-methylisoleucine, p-isoleucine, homoisoleucine, Na-acetyl-L- isoleucine, p-methylisoleucine and p-homoisoleucine.

[0242] Modified valine residues may include, but are not limited to, norvaline, o- methylvaline, N-methylvaline, p-valine, p-homovaline and Na-acetyl-L-valine.

[0243] Suitable modified phenylalanine residues include, but are not limited to, o-methylphenylalanine, N-methyl-phenylalanine (Me-F), p-phenylalanine, p- methylphenylalanine, P,p-dimethylphenylalanine, p-hydroxyphenylalanine, homophenylalanine, Na-acetyl-L-phenylalanine, p-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) and 4-tert-butyl- phenylalanine (tBuF).

[0244] Exemplary modified tyrosine residues include D-tyrosine, o- methyltyrosine, N-methyltyrosine, p-tyrosine, p-methyltyrosine, p,p-dimethyltyrosine, p- hydroxytyrosine, homotyrosine, O-methylhomotyrosine, Na-acetyl-L-tyrosine, O- methyltyrosine, O-ethyltyrosine, m-tyrosine and p-homotyrosine.

[0245] Suitable modified tryptophan residues include, but are not limited to, o- methyltryptophan, N-methyltryptophan, p-tryptophan, p-methyltryptophan, homotryptophan, N-formyl-tryptophan, 2-methyltryptophan, Na-acetyl-L-tryptophan and P-homotryptophan.

[0246] Suitable modified cysteine residues include, but are not limited to, N- methylcysteine (Me-C), o-methylcysteine, N-acetylcysteine, p-cysteine, p-methylcysteine, D-Cys and homocysteine.

[0247] Suitable modified glutamic acid residues include, but are not limited to, N-methylglutamic acid, o-methylglutamic acid, p-glutamic acid, Na-acetyl-L-glutamic acid, glutamic acid y-methyl ester, y-carboxy glutamic acid, homoglutamic acid and p- homoglutamic acid.

[0248] Suitable modified aspartic acid residues include, but are not limited to, N- methylaspartic acid, o-methylaspartic acid, p-aspartic acid, Na-acetyl-L-aspartic acid, aspartic acid p-methyl ester and p-homoaspartic acid.

[0249] 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.

[0250] 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- butyl glycine, norleucine, norvaline, phenylglycine, 2-aminobutyric acid, ornithine, / Vs-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 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

[0251] 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.

[0252] 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, for example, when the proteinaceous molecule is acyclic. 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 0 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, 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; or a capping moiety, including an acetyl group, pyroglutamate or an amino group.

[0253] 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. 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, 100, 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 kDa.

[0254] In some embodiments, the PEG has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 oxyethylene units; especially 2, 3, 4, 5, or 6 oxyethylene units.

[0255] 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.

[0256] When present, the PEG may be, for example, conjugated to the N- terminal or C-terminal amino acid residue of the proteinaceous molecule or through a sidechain of an amino acid residue, including through the amine of a lysine side-chain. In particular embodiments, the PEG is attached through the C-terminal amino acid residue, such as through the o-amino group, or 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 (e.g. wherein Xis is K), with a PEG conjugated to the side chain of the lysine residue.

[0257] 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.

[0258] The proteinaceous molecule may comprise a cell-penetrating 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: 69), TFFYGGSRGKRNNFKTEEY [Angiopep2 (ANG); SEQ ID NO: 68]; RRWRRWWRRWWRRWRR (W / R; SEQ ID NO: 70), CWKis (AlkCWKis; SEQ ID NO: 71), KI8WCCWKI8 (Di-CWKis; SEQ ID NO: 72), WTLNSAGYLLGKINLKALAALAKKIL (Transportan; SEQ ID NO: 73), GLFEALEELWEAK (DipaLytic; SEQ ID NO: 74), KieGGCRGDMFGCAKieRGD (KieRGD; SEQ ID NO: 75), KieGGCMFGCGG (Pl; SEQ ID NO: 76), KielCRRARGDNPDDRCT (P2; SEQ ID NO: 77), KKWKMRRNQFWVKVQRbAK (B) bA (P3; SEQ ID NO: 78), VAYISRGGVSTYYSDTVKGRFTRQKYNKRA (P3a; SEQ ID NO: 79),IGRIDPANGKTKYAPKFQDKATRSNYYGNSPS (P9.3; SEQ ID NO: 80),KETWWETWWTEWSQPKKKRKV (Pep-1; SEQ ID NO: 81), PLAEIDGIELTY (Plae; SEQ ID NO: 82), KieGGPLAEIDGIELGA (Kplae; SEQ ID NO: 83), KieGGPLAEIDGIELCA (cKplae; SEQ ID NO: 84), GALFLGFLGGAAGSTMGAWSQPKSKRKV (MGP; SEQ ID NO: 85), WEAK(LAKA)2- LAKH(LAKA)2LKAC (HA2; SEQ ID NO: 86), (LARL)6NHCH3(LARL46; SEQ ID NO: 87), KLLKLLLKLWLLKLLL (Hel-11-7; SEQ ID NO: 88), (KKKK)2GGC (KK; SEQ ID NO: 89), (KWKK)2GCC (KWK; SEQ ID NO: 90), (RWRR)2GGC (RWR; SEQ ID NO: 91), PKKKRKV (SV40 NLS7; SEQ ID NO: 92), PEVKKKRKPEYP (NLS12; SEQ ID NO: 93), TPPKKKRKVEDP (NLS12a; SEQ ID NO: 94), GGGGPKKKRKVGG (SV40 NLS13; SEQ ID NO: 95), GGGFSTSLRARKA (AV NLS13; SEQ ID NO: 96), CKKKKKKSEDEYPYVPN (AV RME NLS17; SEQ ID NO: 97), CKKKKKKKSEDEYPYVPNFSTSLRARKA (AV FP NLS28; SEQ ID NO: 98), LVRKKRKTEEESPLKDKDAKKSKQE (SV40 N1 NLS24; SEQ ID NO: 99), and K9K2K4K8GGK5(Loligomer; SEQ ID NO: 100); 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: 101); the Drosophila melanogaster Antennapedia domain Antp (amino acids 43-58), RQIKIWFQNRRMKWKK (SEQ ID NO: 102); Buforin II, TRSSRAGLQFPVGRVHRLLRK (SEQ ID NO: 103); hClock-(amino acids 35- 47) (human Clock protein DNA-binding peptide), KRVSRNKSEKKRR (SEQ ID NO: 104); MAP (model amphipathic peptide), KLALKLALKALKAALKLA (SEQ ID NO: 105); K-FGF, AAVALLPAVLLALLAP (SEQ ID NO: 106); Ku70-derived peptide, comprising a peptide selected from the group comprising VPMLKE (SEQ ID NO: 107), VPMLK (SEQ ID NO: 108), PMLKE (SEQ ID NO: 109) or PMLK (SEQ ID NO: 110); Prion, Mouse Prpe (amino acids 1- 28), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO: 111); pVEC, LLIILRRRIRKQAHAHSK (SEQ ID NO: 112); Pep-I, KETWWETWWTEWSQPKKKRKV (SEQ ID NO: 113); SynBI, RGGRLSYSRRRFSTSTGR (SEQ ID NO: 114); Transportan, GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 115); Transportan-10, AGYLLGKINLKALAALAKKIL (SEQ ID NO: 116); CADY, Ac-GLWRALWRLLRSLWRLLWRA-cysteamide (SEQ ID NO: 117); Pep-7, SDLWEMMMVSLACQY (SEQ ID NO: 118); HN-1, TSPLNIHNGQKL (SEQ ID NO: 119); VT5, DPKGDPKGVTVTVTVTVTGKGDPKPD (SEQ ID NO: 120); pISL, RVIRVWFQNKRCKDKK (SEQ ID NO: 121); 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: 122), KLFMALVAFLRFLT (PepH2; SEQ ID NO: 123), AGILKRW (PepH3; SEQ ID NO: 124) or KSKAINVLRGFRKEIGRMLNILN (PepH4; SEQ ID NO: 125); RKKRRRESRKKRRRES (DPV3; SEQ ID NO: 126); GRPRESGKKRKRKRLKP (DPV6; SEQ ID NO: 127); RQIKIWFQNRRMKWKK (penetratin; SEQ ID NO: 128); GRRRRRRRRRPPQ (R9-TAT; SEQ ID NO: 129); RVRVFVVHIPRLT (ARF 19-31; SEQ ID NO: 130); VSALK (Bip4; SEQ ID NO: 131); GIGAVLKVLTTGLPALISWIKRKRQQ (Melittin; SEQ ID NO: 132); or HGLASTLTRWAHYNALIRAF (gH625; SEQ ID NO: 133); especially a TAT peptide, angiopep2 or PepH3.

[0259] 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, glutamine and asparagine or other suitable modified side chain; especially through the amino group of a lysine sidechain (i.e. the e-amino group). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue (e.g. wherein Xis is K), with a cell-penetrating peptide conjugated to the side chain of the lysine residue.

[0260] 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.

[0261] In specific embodiments, the proteinaceous molecule further comprises a cell-penetrating peptide, such as a TAT peptide (TAT), angiopep2 (ANG) or PepH3; especially TAT or angiopep2. In exemplary embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 67:YRPTIRRRRVRICGX29 [SEQ ID NO: 67]; wherein X29 is:wherein R5is a proteinaceous molecule comprising an amino acid sequence represented by SEQ ID NO: 68 or 69:TFFYGGSRGKRNNFKTEEY [SEQ ID NO: 68];YGRKKRRQRRR [SEQ ID NO: 69].

[0262] 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.

[0263] 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.

[0264] 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.

[0265] In some embodiments, the proteinaceous molecule is other than a proteinaceous molecule consisting of SEQ ID NO: 1 or 135.

[0266] 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 of, or consisting essentially of, a sequence represented by Formula I, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX or XX or any one of SEQ ID NOs: 1-44, 47-66 and 296-336 as described herein.

[0267] 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.

[0268] Although the nucleic acid molecules are typically isolated, in some embodiments the nucleic acid molecules may be integrated into, ligated to, or otherwisefused 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 of, or consisting essentially of, a sequence represented by Formula I, II, IV, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX or XX or any one of SEQ ID NOs: 1-44, 47-66 and 296-336 as described herein.

[0269] 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.

[0270] 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).

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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).

[0276] 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, disulfide bonds may be formed using oxidation. Suitable conditions for oxidation of the peptide will be readily determined by a person skilled in the art.

[0277] 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 phosphoniumhexafluorophosphate), 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-tetramethylene 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.

[0278] 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 bond formation 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

[0279] The proteinaceous molecules are also useful in compositions for treating or inhibiting the development of a condition associated with ASIC activity, such as aneurological 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.

[0280] The proteinaceous molecule may be formulated into the pharmaceutical composition as a neutral or salt form.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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 mayinclude, 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.

[0285] 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.

[0286] 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.

[0287] 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 be formulated 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.

[0288] 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 syntheticfatty 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.

[0289] 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.

[0290] 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, hydroxypropyl methylcellulose, 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.

[0291] 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.

[0292] 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 fillersuch 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.

[0293] 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).

[0294] The proteinaceous molecules may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations.

[0295] 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.

[0296] 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.

[0297] 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 ofdisease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] Representative thrombolytic agents include tissue plasminogen activator (e.g. alteplase, reteplase, tenecteplase and anistreplase), streptokinase and urokinase.

[0303] Suitable antiplatelet agents include acetylsalicylic acid, clopidogrel, dipyridamole, cangrelor, prasugrel, ticagrelor, ticlopidine, apciximab, eptifibatide, tirofiban, triflusal, cilostazol, vorapaxar, terutroban, ifetroban, naproxen and picotamide.

[0304] Suitable antihypertensive agents include, but are not limited to, diuretics (e.g. indapamide, bendroflumethiazide, amiloride and spironolactone), angiotensin-converting 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).

[0305] 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.

[0306] 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, istradefylline, 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.

[0307] Ranolazine may also be administered concurrently with the proteinaceous molecule of the invention.

[0308] 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).

[0309] 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 pg to about 2000 mg. The proteinaceous molecule may be present in an amount of from about 0.25 pg to about 2000 mg / mL of carrier. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, thedosages are determined by reference to the usual dose and manner of administration of the said ingredients.

[0310] 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.

[0311] 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 Jing et al. (2018) Acta Pharmacologica Sinica, 39: 845-857.

[0312] In some embodiments, the composition has a temperature in the range of from 0-4 °C.5. Methods of Use

[0313] 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 organduring organ transplantation. Accordingly, a proteinaceous molecule of the invention for use in therapy is contemplated.

[0314] In another aspect, there is provided a method of inhibiting an activity of an ASIC, comprising, consisting of, 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.

[0315] In particular embodiments, the ASIC is ASICla.

[0316] 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.

[0317] 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), card io myocyte, 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.

[0318] In particular embodiments, the cell is a cell of the brain, kidney, heart, eye, lung, spinal cord or bone.

[0319] Also provided is a method of antagonising an ASIC, preferably ASICla, comprising, consisting of, or consisting essentially of, contacting the ASIC with a proteinaceous molecule of the invention.

[0320] 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 of, 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 whichinhibiting 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.

[0321] In particular embodiments, the ASIC is ASICla.

[0322] In some embodiments, inhibiting an ASIC effects treatment or inhibition of the development of the condition.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] In some embodiments, the condition is ischaemia, such as neuronal, ocular (e.g. acute retinal ischaemia), renal or cardiac ischaemia.

[0327] 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.

[0328] 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.

[0329] 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).

[0330] 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).

[0331] 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.

[0332] 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.

[0333] In alternative embodiments, the condition is pain. The pain may be nociceptive, inflammatory or neuropathic pain.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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 ortemporomandibular myofascial pain. In some embodiments, the pain is migraine pain.

[0338] 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.

[0339] In some embodiments, the condition is an inflammatory condition, for example asthma, rheumatoid arthritis or chronic rhinosinusitis.

[0340] 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 of, 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 useof 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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).

[0345] Also provided herein is a method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising, consisting of, 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.

[0346] Suitable types of ischaemia are as discussed supra.

[0347] 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 of, 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.

[0348] In some embodiments, the methods and uses comprise at least partially inhibiting the development of ischaemic damage.

[0349] Ischaemic damage includes tissue damage resulting from the ischaemic cascade, especially cell death via apoptosis, necroptosis or necrosis, including infarction.

[0350] 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.

[0351] In some embodiments, the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.

[0352] In particular embodiments, the ischaemic damage is cardiac ischaemic damage; especially ischaemic damage associated with a myocardial infarction, cardiac arrest or heart attack. In specific embodiments, the ischaemic damage is associated with or results from cardiac surgery, such as CABG surgery or TAVI.

[0353] In alternative embodiments, the ischaemic damage is neuronal ischaemic damage; especially ischaemic damage associated with a stroke, traumatic brain injury or perinatal brain injury.

[0354] In particular embodiments, the proteinaceous molecule reduces or minimises the infarct size (i.e. the amount of dead tissue).

[0355] 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.

[0356] 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 of, 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.

[0357] 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.

[0358] 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).

[0359] 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.

[0360] 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.

[0361] 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 proteinaceousmolecule 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.

[0362] 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.

[0363] 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 least partially inhibiting damage to an organ during organ transplantation, comprising, consisting of, 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.

[0364] 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.

[0365] 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).

[0366] 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 16hours, about 4 hours to about 12 hours, about 4 hours to about 8 hours, or about 4 hours to about 6 hours.

[0367] 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.

[0368] 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.

[0369] In any one of the aspects described above, the ASIC is preferably ASICla. The ASIC is preferably a human channel, such as hASICla.

[0370] 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.

[0371] 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 pg to about 2000 mg (and all one-tenth integer pg therebetween), including from about 1 pg to about 100 mg, about 10 pg to about 10 mg, or about 100 pg to about 10 mg; or about 500 pg, 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 pg / kg to about 50 mg / kg body weight of the subject (and all one-tenth integer pg therebetween), including from about 1 pg / kg to about 5 mg / kg, about 10 pg / kg to about 500 pg / kg, or about 50 pg / kg to about 150 pg / kg body weight of the subject; or about 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 pg / kg body weight of the subject. In embodiments where the pharmaceutical compositioncomprises 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.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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

[0376] 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 - PRODUCTION OF THIOETHER-CYCLISED IB100 AND ANALOGUES THEREOFMaterials and MethodsSynthesis of IB100

[0377] Linear IB100 (CICH2C(O)NH-YRPTIRRRRVRICG-NH2; SEQ ID NO: 134) was prepared via solid-phase peptide synthesis (SPPS) and then cyclised (refer to Figure 1). IB100 was synthetised on a CEM Liberty Blue automated microwave peptide synthesiser (CEM Corporation, Charlotte, North Carolina, USA) using Rink Amide 4- methylbenzhydrylamine (MBHA) resin 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.) in dimethylformamide (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.

[0378] The resin was then treated with a solution of trifluoroacetic acid (TFA) :triisopropylsilane: 3,6-dioxa-l,8-octanedithiol :water (10:0.4: 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, washed with small amounts of TFA, and the filtrate was concentrated to no less than 15 mL (when at 0.1 mmol scale) under a stream of nitrogen before addition of 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

[0379] The linear peptide was dissolved in 50% acetonitrile (at 2-3 mg / mL concentration) and combined with N,N-diisopropylethylamine (10 eq.). After 30 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

[0380] IB100 (LC(O)N H-YRPTIRRRRVRICG-NH2; SEQ ID NO: 135; refer to Figure 1 and Table 4) 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

[0381] IB100 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 5-43% buffer B over 13 minutes at a flow rate of 0.5 mL / min. Under these conditions, the mass spectrum of IB100 displayed a mixture of m / z adduct ions consisting of [M+xH]+x, [M+xH+zTFA]+x.

[0382] The other thioether cyclised peptides in Table 4 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 dimethylformamide (DMF) for 4 minutes at 90 °C followed by an acetylation step, where the resin treated with 10% acetic anhydride in DMF for 2 minutes at 65 °C. Purification and cyclisation were performed as described above.

[0383] The conjugates IB116 and IB117 (refer to Table 4) were fully assembled on Rink Amide resin using the same microwave-assisted solid-phase synthesis procedure as described above for IB100. First, the TAT (YGRKKRRQRRR; SEQ ID NO: 69) or angiopep2 (TFFYGGSRGKRNNFKTEEY; SEQ ID NO: 68) sequences were assembled on the solid support, followed by incorporation of a PEG2 linker to the N-terminus using Fmoc- NH-PEG2-COOH, and by final assembly of the IB100 sequence. Resin cleavage, cyclisation and purification steps were performed as described above for IB100.

[0384] The thioether IB152 (refer to Table 7) was prepared using a similar synthetic procedure to IB100. The thioether IB153 (refer to Table 7) was prepared using a similar synthetic procedure as IB100 but using acrylic acid instead of chloroacetic acid as the reagent during the final modification step of the linear sequence. Resin cleavage, cyclisation and purification steps were performed as described above for IB100.Results

[0385] Following synthesis, cyclisation and HPLC purification, 630 mg of IB100 was obtained from a 1 mmol scale synthesis (yield = 33%). The mass spectrum of the final product showed the expected ion sizes (Figure 2). Peptide purity estimated from the area under the IB100 peak in the final analytical HPLC chromatogram (Figure 3) was 98%.EXAMPLE 2 - SYNTHESIS OF HEAD-TO-TAIL CYCLISED IB133

[0386] Linear IB133 (NH2-YRPTIRRRRVRI[Ava]-COOH; SEQ ID NO: 61) was prepared via solid-phase peptide synthesis (SPPS) and then cyclised in solution. IB133 was synthetised on a CEM Liberty Blue automated microwave peptide synthesiser (CEM Corporation, Charlotte, North Carolina, USA) using 2-chlorotrityl resin 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.), Oxyma (5 eq.) and N,N-diisopropylethylamine (0.1 eq.) in dimethylformamide (DMF) for 10 minutes at 60 °C, followed by deprotection with 20% piperidine in DMF for 50 seconds at 90 °C. After full sequence assembly and keeping the N-terminus Fmoc- protected, the resin was removed from the synthesiser and the fully protected peptide was released by treating the resin with a solution of 30% trifluoroethanol in dichloromethane for 1.5 hr. The resin was then filtered, washed with dichloromethane and the resulting filtrate was concentrated under a stream of nitrogen before addition of cold tert-butylmethyl ether (4- 5-fold in volume). The precipitate was separated by centrifugation, redissolved in 50% acetonitrile and freeze-dried.

[0387] Cyclisation was carried out at room temperature by combining the crude fully-protected linear IB133 peptide with benzotriazol-l-yloxytripyrrolidinophosphonium hexafluoro-phosphatechloroacetic acid (2 eq.), N,N-diisopropylethylamine (4 eq.) in DMF for 50 minutes. The reaction solution was then diluted lOx with a mixture of acetonitrile and 0.1% TFA and purified by preparative RP-HPLC as described in Example 1 to form head-to-tail cyclised IB133 (refer to Table 5).EXAMPLE 3 - SYNTHESIS OF DISULFIDE-CYCLISED IB146 AND ANALOGUES THEREOF

[0388] Linear IB146 (CVYVPTIRRRRRRRC-NH2; SEQ ID NO: 234) was prepared via SPPS and cleaved from resin as described in Example 1. The crude linear peptide was then submitted to oxidation in 0.1 M NH4HCO3 buffer pH 8.4 at room temperature for 24 h, and purified by preparative RP-HPLC as described in Example 1 to form disulfide-cyclised IB146 (refer to Table 6). Disulfide-bridged analogues listed in Table 6 were also prepared using this method, including the penicillamine derivative, IB149.EXAMPLE 4 - SYNTHESIS OF BIOTHIOETHER-CYCLISED IB148 AND ANALOGUES THEREOF

[0389] Linear IB146 (CVYVPTIRRRRRRRC-NH2; SEQ ID NO: 234) was prepared via SPPS and cleaved from resin as described in Example 1. The crude linear peptide was then submitted to cyclisation in 0.1 M NaHCOs / DMF (1 : 1) at room temperature with 1.2 eq. of the following crosslinker: a,a'-dibromo-meta-xylene,a,a’- dibromo-ortho-xylene or cis-l,4-dichloro-2-butene, to give IB148, IB150 or IB151 respectively (refer to Table 6).IB191 was prepared by alkylating IB146 with CH2I2 (20 eq.) in 0.1M NF COsiacetonitrile (1 : 1) for 18 hours. Each product was purified by preparative RP-HPLC as described in Example 1.

[0390] The crude linear Kll (CRKPTIRRKLRC-NH2; SEQ ID NO: 349) was cyclised with trans-dibromobut-2-ene (1.5 eq.) in the presence of 1.1 eq. of tris(2- carboxyethyl)phosphine in 0.1 M NH4CO3 overnight. The final product was purified by preparative RP-HPLC as described in Example 1.TABLE 4SEQUENCES OF THIOETHER-CYCLISED PEPTIDESO'Representative structure showing thioether cyclisation:wherein: * = C-terminal amide;PEG2-ANG = , wherein R5is a proteinaceous molecule comprising an amino acid sequence represented by SEQ IDNO: 68 : TFFYGGSRGKRNNFKTEEY; andPEG2-TAT =, wherein R5is a proteinaceous molecule comprising an amino acid sequence represented by SEQ ID NO:69 : YGRKKRRQRRR.TABLE 5SEQUENCE OF HEAD-TO-TAIL CYCLISED PEPTIDE, IB133Representative structure:TABLE 6SEQUENCES OF DISULFIDE- OR BlSTHIOETHER-CYCLISED PEPTIDESRepresentative structure showing disulfide cyclisation:wherein: * = C-terminal amideTABLE 7SEQUENCES OF THIOETHER CYCLISED PEPTIDES WITH A LINKERRepresentative structure showing thioether cyclisation with a linker:wherein: * = C-terminal amideEXAMPLE 5 - INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) BY SYNTHETIC IB100Materials and Methods

[0391] The ability of IB100 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 pg / mL gentamicin, 50 pg / mL streptomycin and 2.5% fetal horse serum.

[0392] 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 MgClz, 5 mM N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid (HEPES); pH 7.45). IB100 serial dilutions were made in regular ND96 solution (96 mM NaCI, 2 mM KCI, 1.8 mM CaCl2, 2 mM MgCh, 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.

[0393] 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 MQ resistance). Data acquisition (sampled at 2 kHz and filtered at 0.01 kHz) was performed using pCIamp 10 software (Molecular Devices). Concentration-response data were obtained using serial dilutions of IB100 (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.

[0394] To gain an indication of the duration of the inhibitory effect of IB100, hASICla currents were maximally inhibited with 1 pM IB100, then the recovery of hASICla currents was monitored during washout of the peptide.

[0395] 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

[0396] IB100 potently inhibited proton-gated sodium currents mediated by hASICla, with current inhibition observed at concentrations as low as 0.1 nM (Figure 4). 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 1.60 nM, with complete inhibition (100% efficacy) observed at an IB100 concentration of 100 nM (Figure 5).

[0397] The inhibitory effect of IB100 was fully reversed (i.e., hASICla currents recovered to control levels) within eight minutes of peptide wash out (Figure 6). The halflife for current recovery was about 3 minutes.EXAMPLE 6 - CARDIOPROTECTIVE EFFICACY OF IB100 IN A RAT MODEL OF SEVERE MYOCARDIAL INFARCTIONMaterials and Methods

[0398] The cardioprotective efficacy of IB100 (prepared in accordance with Example 1) was assessed by examining its ability to protect heart structure and function following severe ischaemia-reperfusion injury (myocardial infarction, MI) in Sprague Dawley rats.

[0399] 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.

[0400] For all animals, the test article was delivered via bolus intravenous (i.v.) administration via the external jugular vein 5 minutes prior to reperfusion. Heart function was compared between cohorts treated with IB100 (1 mg / kg), the sodium hydrogen exchange (NHE) inhibitor cariporide (1 mg / kg), or vehicle (saline). In addition, one cohort received bolus i.v. IB100 (1 mg / kg) followed by an additional dose of IB100 (1 mg / kg) infused via the external jugular vein over a period of 5 minutes beginning immediately after the bolus injection. 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.

[0401] 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 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.

[0402] A schematic of the experimental design used for the MI experiments is shown in Figure 7.Results

[0403] 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 7) 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 (Figure 8). In contrast, there was a much smaller reduction in FS in rats that received a 1 mg / kg i.v. dose of IB100 5 minutes prior to reperfusion. Relative to vehicle-treated animals, there was a statistically significant 15% improvement in FS in the animals that received 1 mg / kg IB100. The sparing of cardiac function as measured by FS was similar in rats that received cariporide (1 mg / kg i.v.) and those that received a bolus i.v. dose of IB100 (1 mg / kg) followed by a second dose (1 mg / kg) infused over a 10-minute period.

[0404] It is evident that IB100 is highly cardioprotective in the context of myocardial ischaemia-reperfusion injury. Moreover, in the rodent model of MI described herein, IB100 is 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].EXAMPLE 7 - BINDING AND INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) BY SYNTHETIC PEPTIDESMaterials and Methods

[0405] Peptides were synthesised in accordance with Examples 1-4. 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 5.

[0406] For Chinese Hamster Ovary (CHO) cell electrophysiology, peptide activity was assessed using whole-cell patch-clamp electrophysiology on CHO cells stably transfected with human ASICla for constitutive over-expression (B'SYS GmbH,Switzerland). Experiments were conducted at ambient room temperature on a QPatch 48 (Sophion, Denmark) automated electrophysiology platform for gigaseal ion channel recordings.

[0407] After acquisition of the whole-cell configuration, the cell membrane was clamped at -60 mV. Human ASICla currents were elicited by an exchange of extracellular solution from pH 7.4 to pH 6.5 for 3 seconds, with a recovery time of at least two minutes between successive stimulations. Five or six concentrations of each peptide were evaluated using the cumulative concentration-response assay (where each increasing concentration of peptide is applied to the same cell after each stimulation in a series of successive applications). Peptides were applied during both the conditioning pH 7.4 and stimulating pH 6.5 extracellular solutions. All extracellular solutions (vehicle and peptide) contained 0.1% BSA to prevent adsorptive losses to plasticware. A minimum of three replicates (n > 3) was collected for each concentration of each peptide.

[0408] The peak inward current amplitude was determined for each application of extracellular solution, compared to control (vehicle only) currents for characterisation of antagonist activity. The inhibition produced by each concentration of peptide was calculated relative to control currents recorded on the associated cell during the stimulation prior to application of the lowest peptide concentration. The mean (± S.D.) data was plotted against Log[compound] and fit with a concentration-response function to yield the half-maximal inhibition concentration (IC50) and Hill slope values.

[0409] 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 SynP in Table 8). Patch-clamp electrophysiology experiments were carried out using hASICla (human ACCN2 gene)-transfected CHO cells, with hASICla expression 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 with Examples 1-4) were tested covering up to a 2,000-fold dilution from the maximal concentration with 2-4 replicates each. BSA (0.05%) was included in serial dilutions to prevent adsorptive loses 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 on-board patch clamp amplifiers. Data acquisitions were performed via 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. IC50, or ECso, the concentration of test article producingeither half-maximal inhibition or activation, and Hill slope were determined from the resulting curves.

[0410] A third method used to evaluate the ability of peptides to inhibit hASICla was a calcium influx assay performed using a Fluorescence Imaging Plate Reader (FLIPR) (FLIPR-Penta; Molecular Devices). Experiments were carried out using hASICla- transfected CHO cells, with hASICla expression induced using tetracycline (Charles River Laboratories). The 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- Streptomyocin, 0.01 mg / mL blasticidin and 0.4 mg / mL zeocin. Cells were passaged and seeded (at 10,000 cells per well) a day prior to the FLIPR assay. After 18 hours of tetracycline-induced hASICla expression, the cells were loaded with Calcium 6 dye (Molecular Devices) 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 1-4) 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 hASICla stimulation with low pH buffer. Fluorescence recordings were initiated immediately prior to stimulation and a minimum of three replicates were collected for each concentration. Results were analysed using Prism 10 (GraphPad Software). Non-linear regression, specifically the log(inhibitor) vs normalised responsevariable slope, was fitted to the data for calculation of the concentration required for half- maximal inhibition (IC50).

[0411] Surface plasmon resonance (SPR) experiments were performed as follows. Baculoviruses incorporating constructs encoding truncated versions of hASICla (residues 12-463) with a C-terminal Hise tag were used to individually transfect Spodoptera frugiperda Sf9 insect cells. Large-scale cultures were grown at 27°C and harvested at 48 hours post-infection for each protein construct. Cells were disrupted by sonication at 4°C and the insoluble membrane lysate solubilised in 50 mM Tris-HCI pH 8.0, 150 mM NaCI with 40 mM of n-dodecyl-0-D-maltoside (DDM) (Anagrade, Anatrace Products LLC, Maumee, OH, USA). The solubilised trimer was isolated by ultracentrifugation at 40,000 rpm for 1 hour at 4°C, then the hASICla channel was purified from the supernatant using TALON-Co2+metal affinity resin (Clontech, Takara Bio USA, Inc., San Jose, CA, USA). The isolated protein was further purified via size-exclusion chromatography using a Superdex S200 10 / 30GL column (Cytiva, Marlborough, USA) in a buffer containing 50 mM Tris (pH 8.0), 150 mM NaCI and 1 mM DDM. Fractions containing trimeric hASICla protein were checked for purity using SDS-PAGE, concentrated to 2-3 mg / mL, and used for biochemical studies. The interaction between selected cyclic peptides and hASICla was assessed using a BIACORE T200 instrument (GE Healthcare Technologies, Inc., Chicago, IL, USA) equipped with a research-grade nitrilotriacetic acid (NTA) sensor chip. Hise-taggedhASICla was immobilised at a surface density of approximate 1,000 response units (RU) using standard immobilisation protocols (GE Healthcare Technologies). All experiments were conducted at 25 °C using the following buffer: 50 mM Tris-HCI (pH 8.0), 150 mM NaCI and 1 mM DDM. The binding affinity of each peptide was tested by individually injecting increasing peptide concentrations (0.625 nM to 10 nM) at a flow rate of 60 pL / min and measured by a single cycle kinetics method. Raw data were analysed using BIACORE T200 evaluation software 2.01 and fitted to a 1: 1 interaction model.Results

[0412] The results are presented in Table 8.TABLE 8HUMAN ACID-SENSING ION CHANNEL 1A BINDING AND INHIBITION OF ACTIVITYEXAMPLE 8 - PEPTIDE STABILITY IN HUMAN SERUMMaterials and Methods

[0413] The susceptibility of the peptides to degradation by human serum proteases was assessed by incubation in human serum for 1 hour at 37°C. Peptides (prepared in accordance with Examples 1-4) 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, then incubated on ice for serum protein precipitation. After centrifugation to separate the pellet, samples were analysed using LC-MS. Each peptide stability test was performed at least in duplicate. The data are reported as the percentage of intact peptide after 1 hour incubation in human serum at 37°C.Results

[0414] The results are presented in Table 9.TABLE 9STABILITY IN HUMAN SERUMEXAMPLE 9 - HIPSC-DERIVED CARDIOMYOCYTE IN VITRO ISCHAEMIA-REPERFUSION INJURY MODELMaterials and Methods

[0415] The cardioprotective efficacy of IB100 was examined using an in vitro ischaemia-reperfusion injury model using human induced pluripotent stem cell-derived card io myocytes (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 pg / mL BSA and 213 pg / mL ascorbic acid. After 3 days of culture, the medium was replaced with RPMI containing 500 pg / mL BSA, 213 pg / mL ascorbic acid and 5 pM Xav-939 (Stem Cell Technologies). On day 5, the medium was exchanged for RPMI containing 500 pg / mL BSA and 213 pg / 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.

[0416] 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 o-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 with either 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 filter. The replated cells were treated overnight (18 hr) in HBSS with or without 50 nM IB100 (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 nMIB100 (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 card io myocytes were cultured overnight in standard culture medium (RPMI + B27) or RPMI + B27 containing 1% Triton X-100, respectively.Results

[0417] IB100 at 50 nM concentration significantly protected hiPSC-CMs from acidosis-induced death, as depicted in Figure 9.

[0418] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0419] 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.

[0420] 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

[0421] Exemplary embodiments include, but are not limited to:1. A proteinaceous molecule comprising, consisting of, or consisting essentially of, an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (I) wherein:Xi is absent or is selected from C and penicillamine (Pen);X2 is absent or is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, 3,3-diphenyl-L-alanine (Dip), 4,4'-biphenyl-L-alanine (Bip) or 1-naphthyl-L-alanine (Nal)) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino-4-guanidino-butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. N-methyl-phenylalanine (Me- F));X7 is selected from 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. cyclohexylalanine (Cha)); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert- Leucine (Tie)); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; C and modified forms thereof (e.g. D-Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar)); hydrophobic amino acid residues including V, L, I and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; hydrophobic amino acid residues including, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, alpha-methyl-arginine (aMe-R), Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;Xi4 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X15 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xi6 is selected from C and modified forms thereof (e.g. D-Cys), Pen, 5-aminovaleric acid (Ava) and basic amino acid residues including R, K and modified forms thereof;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; wherein when Xie is other than C or a modified form thereof, Pen or Ava, Xs is C or a modified form thereof; and when Xs is other than C or a modified form thereof, Xie is selected from C and modified forms thereof, Pen and Ava.2. A proteinaceous molecule comprising, consisting of, or consisting essentially of, of an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (I) wherein:Xi is absent or is selected from C and penicillamine (Pen);X2 is absent or is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, 3,3-diphenyl-L-alanine (Dip), 4,4'-biphenyl-L-alanine (Bip) or 1-naphthyl-L-alanine (Nal)) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino-4-guanidino- butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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;X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. N-methyl-phenylalanine (Me- F));X7 is selected from 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. cyclohexylalanine (Cha)); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert- Leucine (Tie)); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof; C and modified forms thereof (e.g. D-Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar));hydrophobic amino acid residues including V, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, alpha-methyl-arginine (aMe-R), Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;Xi4 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X15 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xi6 is selected from C and modified forms thereof (e.g. D-Cys), Pen, 5-aminovaleric acid (Ava) and basic amino acid residues including R, K and modified forms thereof;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; wherein when Xie is other than C or a modified form thereof, Pen or Ava, Xs is C or a modified form thereof; and when Xs is other than C or a modified form thereof, Xie is selected from C and modified forms thereof, Pen and Ava.3. The proteinaceous molecule according to embodiment 1 or 2, wherein Xi is absent.4. The proteinaceous molecule according to embodiment 1 or 2, wherein Xi is C or Pen.5. The proteinaceous molecule according to any one of embodiments 1-4, wherein X2 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; 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; aromatic amino acid residues including Y, W, F and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof.6. The proteinaceous molecule according to any one of embodiments 1-3, wherein X2 is absent or is V, T, Y, K, Q or R.7. The proteinaceous molecule according to embodiment 5, wherein X2 is absent or is V.8. The proteinaceous molecule according to embodiment 6, wherein X2 is absent.9. The proteinaceous molecule according to embodiment 1, wherein Xi is C or Pen and X2is V, T, Y, K, Q or R.10. The proteinaceous molecule according to embodiment 9, wherein Xi is C and X2is V.11. The proteinaceous molecule according to any one of embodiments 1-10, wherein X3 is Y, W, D-Tyr, Dip, Bip, Nal or A.12. The proteinaceous molecule according to any one of embodiments 1-10, wherein X3 is Y, W, D-Tyr, Dip, Bip, tBuF or Nal.13. The proteinaceous molecule according to embodiment 11 or 12, wherein X3 is Y, W or D-Tyr.14. The proteinaceous molecule according to embodiment 13, wherein X3 is Y.15. The proteinaceous molecule according to any one of embodiments 1-14, wherein X4 is selected from R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, T, V, L, Q, K and I.16. The proteinaceous molecule according to embodiment 15, wherein X4 is selected from R, V, I and K.17. The proteinaceous molecule according to any one of embodiments 1 and 3- 16, wherein X4 is selected from R, V, Cit, E, I and K.18. The proteinaceous molecule according to embodiment 17, wherein X4 is R, E or Cit; such as R.19. The proteinaceous molecule according to any one of embodiments 1-18, wherein X5 is selected from R, A, G, S, T, P and N.20. The proteinaceous molecule according to embodiment 19, wherein X5 is selected from A, G, S, T and P; such as P.21. The proteinaceous molecule according to any one of embodiments 1-20, wherein Xe is selected from R, K, A, T, L, I and Me-F.22. The proteinaceous molecule according to embodiment 21, wherein Xe is selected from A, T, L, I and Me-F; such as T.23. The proteinaceous molecule according to any one of embodiments 1-22, wherein X? is selected from R, T, I, P, Me-F, Tie and Cha.24. The proteinaceous molecule according to embodiment 23, wherein X? is selected from R and I.25. The proteinaceous molecule according to embodiment 23, wherein X? is selected from I, Tie and Cha; such as I.26. The proteinaceous molecule according to any one of embodiments 1-25, wherein Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, T, C, F, Y and Me- F.27. The proteinaceous molecule according to embodiment 26, wherein Xs is selected from R and H, such as R.28. The proteinaceous molecule according to any one of embodiments 1-27, wherein X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, I and P.29. The proteinaceous molecule according to embodiment 28, wherein X9 is selected from R and K; such as R.30. The proteinaceous molecule according to any one of embodiments 1-29, wherein X10 is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, Sar, L and Y.31. The proteinaceous molecule according to embodiment 30, wherein X10 is selected from R, K and Sar.32. The proteinaceous molecule according to any one of embodiments 1 and 3- 29, wherein X10 is selected from R, K, Arg(Me), E, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, Sar, L and Y; such as R, K, E, Arg(Me), Orn, HArg, Agb or Cit; such as R.33. The proteinaceous molecule according to any one of embodiments 1-32, wherein Xn is absent or is selected from R, K, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, S, L and W.34. The proteinaceous molecule according to embodiment 33, wherein Xn is R or L; such as R.35. The proteinaceous molecule according to any one of embodiments 1-34, wherein X12 is absent or is selected from R, K, A, V, I, Tie, Cha and Me-F.36. The proteinaceous molecule according to embodiment 35, wherein X12 is selected from R, V and I.37. The proteinaceous molecule according to any one of embodiments 1 and 3- 34, wherein X12 is selected from R, K, A, V, I, Tie, Cha, E and Me-F; such as V, A, Tie or E.38. The proteinaceous molecule according to any one of embodiments 1-37, wherein X13 is absent or is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, V, L and F.39. The proteinaceous molecule according to embodiment 38, wherein X13 is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, V, L and F.40. The proteinaceous molecule according to embodiment 39, wherein X13 is selected from R, K and V.41. The proteinaceous molecule according to embodiment 39, wherein X13 is R or Cit.42. The proteinaceous molecule according to embodiment 38, wherein X13 is absent.43. The proteinaceous molecule according to any one of embodiments 1-42, wherein X14 is absent or is selected from R, S, T, V, L and I.44. The proteinaceous molecule according to embodiment 43, wherein X14 is selected from R, S, T, V, L and I.45. The proteinaceous molecule according to embodiment 44, wherein X14 is I, R or V.46. The proteinaceous molecule according to embodiment 43, wherein X14 is absent.47. The proteinaceous molecule according to any one of embodiments 1 and 3- 42, wherein X14 is selected from R, S, T, A, V, L, I, E and Tie; such as I, Tie or E, or I or Tie.48. The proteinaceous molecule according to any one of embodiments 1-47, wherein X15 is absent or is selected from R and L.49. The proteinaceous molecule according to embodiment 48, wherein X15 is absent.50. The proteinaceous molecule according to any one of embodiments 1-49, wherein X16 is selected from C, Pen, Ava and R.51. The proteinaceous molecule according to embodiment 50, wherein X16 is C.52. The proteinaceous molecule according to embodiment 50, wherein Xi is absent and Xi6 is Ava.53. The proteinaceous molecule according to any one of embodiments 1-52, wherein X17 is absent or is selected from R, K, A, G, S and T.54. The proteinaceous molecule according to embodiment 53, wherein X17 is absent or is selected from R, A and G.55. The proteinaceous molecule according to embodiment 54, wherein X17 is G.56. The proteinaceous molecule according to embodiment 53, wherein X17 is absent.57. The proteinaceous molecule according to any one of embodiments 1-56, wherein Xis is absent or is selected from R, K, A, G, S and T.58. The proteinaceous molecule according to embodiment 57, wherein Xis is absent or is selected from K and A.59. The proteinaceous molecule according to embodiment 58, wherein Xis is absent.60. The proteinaceous molecule according to embodiment 1 or embodiment 2, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-44 and 47-66.61. The proteinaceous molecule according to embodiment 60, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-12, 53 and 55-59.62. The proteinaceous molecule according to embodiment 1 or embodiment 2, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-44, 47-66 and 296-336.63. The proteinaceous molecule according to embodiment 1 or embodiment 2, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-12, 26-29, 33-36, 39, 50, 52, 53, 55-59, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330.64. The proteinaceous molecule according to embodiment 1 or 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, 12, 26-29, 33-36, 39, 50, 52, 65, 66, 298-302, 305-309, 312, 314, 315, 318, 320-327 and 330.65. The proteinaceous molecule according to any one of embodiments 1-64, wherein Xi and X2 are absent and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the Xs or X16 position and the N-terminal amine of the amino acid residue in the X3 position.66. The proteinaceous molecule according to any one of embodiments 1-64, wherein Xi and X16 are C or Xi and X16 are Pen, and the proteinaceous molecule comprises a disulfide bond between the side chains of Xi and Xie.67. The proteinaceous molecule according to any one of embodiments 1-64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula II: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (II) wherein:X2-X15 are as defined in any one of the preceding embodiments;Xi and Xie are independently C or Pen; and the side chains of Xi and Xie form a linkage represented by Formula III:wherein each sulfur atom is the sulfur atom from X1and X16, and R1is a bond or a divalent linker selected from the group consisting of:68. The proteinaceous molecule according to any one of embodiments 1-64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IV: X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (IV) wherein:X3-X15, X17 and Xis are as defined in any one of the preceding embodiments;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula V:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xie, and R2is C1-6 alkylene.69. The proteinaceous molecule according to any one of embodiments 1-64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VI: X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (VI) wherein:X3-X7 and X9-X18 are as defined in any one of the preceding embodiments;Xs is C; and the side chain of Xs forms a thioether linkage with the N-terminal amine of X3, wherein the thioether linkage is represented by Formula VII:wherein the amine is the N-terminal amine of X3, the sulfur atom is the sulfur atom from Xs, and R3is C1-6 alkylene.70. The proteinaceous molecule according to embodiment 68 or embodiment 69, wherein R2and / or R3is methylene.71. The proteinaceous molecule according to any one of embodiments 1-64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VIII: X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (VIII) wherein:X2-X15 are as defined in any one of the preceding embodiments;Xie is C; and the side chain of Xie forms a thioether linkage with the N-terminal amine of X2, wherein the thioether linkage is represented by Formula IX:wherein the amine is the N-terminal amine of X2, the sulfur atom is the sulfur atom from Xie, and R4is C1-6 alkylene.72. The proteinaceous molecule according to embodiment 71, wherein R4is methylene or ethylene.73. The proteinaceous molecule according to any one of embodiments 1-64, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula X: X3X4X5X6X7X8X9X10X11X12X13X14X15X16 (X) wherein:X3-Xis are as defined in any one of the preceding embodiments;Xie is Ava; and the N-terminal amine of X3 and the C-terminal acid of X16 form an amide bond.74. The proteinaceous molecule according to embodiment 73, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 61 or 62.75. The proteinaceous molecule according to any one of embodiments 1-74, wherein the proteinaceous molecule comprises a C-terminal amide.76. The proteinaceous molecule according to any one of embodiments 1-74, wherein the proteinaceous molecule comprises a C-terminal methyl group.77. The proteinaceous molecule according to any one of embodiments 1-74, wherein the proteinaceous molecule comprises a C-terminal acid.78. The proteinaceous molecule according to any one of embodiments 1-77, further comprising a cell-penetrating peptide.79. The proteinaceous molecule according to embodiment 78, wherein the cellpenetrating peptide is a TAT peptide (TAT), angiopep2 (ANG) or PepH3.80. The proteinaceous molecule according to embodiment 79, wherein the cellpenetrating peptide is TAT or angiopep2.81. The proteinaceous molecule according to embodiment 79, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by SEQ ID NO: 67:YRPTIRRRRVRICGX29 [SEQ ID NO: 67]; wherein X29 is:wherein R5is a proteinaceous molecule comprising an amino acid sequence represented by SEQ ID NO: 68 or 69:TFFYGGSRGKRNNFKTEEY [SEQ ID NO: 68];YGRKKRRQRRR [SEQ ID NO: 69].82. The proteinaceous molecule according to any one of embodiments 1-81, wherein at least three of X4, Xs, X9, X10 and X13 are independently a basic amino acid residue.83. A composition comprising, consisting of, or consisting essentially of, a proteinaceous molecule according to any one of embodiments 1-82 and a pharmaceutically acceptable carrier or diluent.84. A proteinaceous molecule according to any one of embodiments 1-82 for use in therapy.85. 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 1-82.86. The method according to embodiment 85, wherein the ASIC is ASICla.87. 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 according to any one of embodiments 1-82.88. The method according to embodiment 87, 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 and retinal detachment.89. The method according to embodiment 88, 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.90. The method according to embodiment 89, wherein the neurological condition is stroke.91. The method according to embodiment 89, wherein the ischaemia is neuronal, ocular, renal or cardiac ischaemia.92. The method according to embodiment 91, wherein the ocular ischaemia is acute retinal ischaemia.93. The method according to embodiment 88, wherein the cancer is a glioblastoma.94. The method according to embodiment 88, wherein the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.95. 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 embodiments 1-82.96. The method according to embodiment 95, 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.97. The method according to embodiment 96, wherein the neurological condition is stroke.98. 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 embodiments 1-82.99. 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 embodiments 1-82.100. The method according to embodiment 99, wherein the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.101. The method according to embodiment 100, wherein the ischaemic damage is cardiac ischaemic damage.102. The method according to embodiment 101, wherein the ischaemic damage is associated with a myocardial infarction.103. The method according to embodiment 100, wherein the ischaemic damage is neuronal ischaemic damage.104. The method according to embodiment 99, wherein the ischaemic damage is associated with a stroke, traumatic brain injury or perinatal brain injury.105. 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 embodiments 1-82.106. The method according to embodiment 105, wherein the tissue is an organ transplant.107. The method according to embodiment 105 or embodiment 106, wherein the tissue is a heart, lung or kidney.108. The method according to embodiment 107, wherein the tissue is a heart.109. 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 embodiments 1-82.110. The method according to embodiment 109, wherein the organ is a heart, lung or kidney.111. The method according to embodiment 110, wherein the organ is a heart.112. The method according to any one of embodiments 109-111, wherein the damage is ischaemic damage.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A proteinaceous molecule comprising, consisting of, or consisting essentially of, an amino acid sequence represented by Formula I: X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18 (I) wherein:Xi is absent or is selected from C and penicillamine (Pen);X2 is absent or is selected from any amino acid residue;X3 is absent or is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. D-Tyr, 3,3-diphenyl-L-alanine (Dip), 4,4'-biphenyl-L- alanine (Bip) or 1-naphthyl-L-alanine (Nal)) and small amino acid residues including A, G, S, T and modified forms thereof;X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino- 4-guanidino-butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X5 is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;Xe is selected from basic amino acid residues including R, K and modified forms thereof; 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 aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. N- methyl-phenylalanine (Me-F));X7 is selected from 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. cyclohexylalanine (Cha)); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. tert-Leucine (Tie)); P and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me- F);Xs is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including / , G, S, T and modified forms thereof; C and modified forms thereof (e.g. D-Cys); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X9 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Orn, b-Arg, HArg, Agb, Cit or gArg); 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 P and modified forms thereof;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar)); hydrophobic amino acid residues including V, L, I and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;Xn is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); acidic amino acid residues including D, E and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F);X13 is absent or is selected from basic amino acid residues including R, K and modified forms thereof (e.g. Me-R, alpha-methyl-arginine (aMe-R), Orn, b-Arg, HArg, Agb, Cit or gArg); 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 aromatic amino acid residues including Y, W, F and modified forms thereof;X14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;X15 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof;Xi6 is selected from C and modified forms thereof (e.g. D-Cys), Pen, 5-aminovaleric acid (Ava) and basic amino acid residues including R, K and modified forms thereof;X17 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; andXis is absent or is selected from basic amino acid residues including R, K and modified forms thereof; and small amino acid residues including A, G, S, T and modified forms thereof; wherein when Xie is other than C or a modified form thereof, Pen or Ava, Xs is C or a modified form thereof; and when Xs is other than C or a modified form thereof, Xie is selected from C and modified forms thereof, Pen and Ava.

2. The proteinaceous molecule according to claim 1, wherein:X4 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. ornithine (Orn), beta-arginine (b-Arg), homoarginine (HArg), 2-amino- 4-guanidino-butyric acid (Agb), citrulline (Cit), or guanidinyl-alkylated-arginine (gArg)); 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;X10 is selected from basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine (Me-R), Orn, b-Arg, HArg, Agb, Cit or gArg); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine (Sar)); hydrophobic amino acid residues including V, L, I and modified forms thereof; and aromatic amino acid residues including Y, W, F and modified forms thereof;X12 is absent or is selected from 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. Cha); hydrophobic amino acid residues including V, L, I and modified forms thereof (e.g. Tie); and aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Me-F); andX14 is absent or is selected from basic amino acid residues including R, K and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; and hydrophobic amino acid residues including V, L, I and modified forms thereof.

3. The proteinaceous molecule according to claim 1 or claim 2, wherein Xi, X2, X15 and / or Xis are absent.

4. The proteinaceous molecule according to any one of claims 1-3, wherein X3 is Y, W, D-Tyr, Dip, Bip, tBuF or Nal.

5. The proteinaceous molecule according to any one of claims 1-4, wherein X4 is selected from R, V, Cit, E, I and K.

6. The proteinaceous molecule according to any one of claims 1-5, wherein X5 is selected from A, G, S, T and P.

7. The proteinaceous molecule according to any one of claims 1-6, wherein Xe is selected from A, T, L, I and Me-F.

8. The proteinaceous molecule according to any one of claims 1-7, wherein X7 is selected from R, T, I, P, Me-F, Tie and Cha.

9. The proteinaceous molecule according to any one of claims 1-8, wherein Xs is selected from R, K, H, Orn, b-Arg, HArg, Agb, Cit, gArg, G, T, C, F, Y and Me-F.

10. The proteinaceous molecule according to any one of claims 1-9, wherein X9 is selected from R, K, Orn, b-Arg, HArg, Agb, Cit, gArg, A, I and P.

11. The proteinaceous molecule according to any one of claims 1-10, wherein X10 is selected from R, K, Arg(Me), E, Me-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, G, S, Sar, L and Y.

12. The proteinaceous molecule according to any one of claims 1-11, wherein Xn is R or L.

13. The proteinaceous molecule according to any one of claims 1-12, wherein X12 is selected from R, K, A, V, I, Tie, Cha, E and Me-F.

14. The proteinaceous molecule according to any one of claims 1-13, wherein X13 is selected from R, K, Me-R, aMe-R, Orn, b-Arg, HArg, Agb, Cit, gArg, A, V, L and F.

15. The proteinaceous molecule according to any one of claims 1-14, wherein X14 is selected from R, S, T, A, V, L, I, E and Tie.

16. The proteinaceous molecule according to any one of claims 1-15, wherein X16 is C.

17. The proteinaceous molecule according to any one of claims 1-16, wherein X17 is absent or is selected from R, K, A, G, S and T.

18. The proteinaceous molecule according to any one of claims 1-17, wherein at least three of X4, Xs, X9, X10 and X13 are independently a basic amino acid residue.

19. 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: 1-44 and 47-66: YRPTIRRRRVRICG [SEQ ID NO: 1];YRGLRRKRLVACG [SEQ ID NO: 2];YTRKTFRGWRRCG [SEQ ID NO: 3];yVNRRGRLKRRTCG [SEQ ID NO: 4]; yRRLRRPYRKFVCG [SEQ ID NO: 5]; yQSKPTIRRRRIRCA [SEQ ID NO: 6]; yLKTRCIKSRVLLRRA [SEQ ID NO: 7];YRSLRHKX19RIVCG [SEQ ID NO: 8];YRRX20X20X20RKRRCG [SEQ ID NO: 9]; yRPTIRRKRX2oCG [SEQ ID NO: 10]; yRTIRKRRKKLSCG [SEQ ID NO: 11];YRPTIRRRRVRIC [SEQ ID NO: 12];YASLRHKX19RIVCG [SEQ ID NO: 13];YRALRHKX19RIVCG [SEQ ID NO: 14];YRSARHKX19RIVCG [SEQ ID NO: 15];YRSLAHKX19RIVCG [SEQ ID NO: 16];YRSLRAKX19RIVCG [SEQ ID NO: 17];YRSLRHAX19RIVCG [SEQ ID NO: 18];YRSLRHKARIVCG [SEQ ID NO: 19];YRSLRHKX19AIVCG [SEQ ID NO: 20];YRSLRHKX19RAVCG [SEQ ID NO: 21];YRSLRHKX19RIACG [SEQ ID NO: 22];YRSLRHKX19RIVC [SEQ ID NO: 23]; yRSLRHKXigRIVCG [SEQ ID NO: 24];YRPTIRRX21RVRICG [SEQ ID NO: 25];YRPTIRRRX21VRICG [SEQ ID NO: 26];YRPTIRRRRVX21ICG [SEQ ID NO: 27];YRPTIRRRRVRICGK [SEQ ID NO: 28];YVPTIRRRRVRICG [SEQ ID NO: 29];YRPTIRRRRRRICG [SEQ ID NO: 30];YRPTIRRRRVRRCG [SEQ ID NO: 31];YRPTIRRRVRICG [SEQ ID NO: 32];WRPTIRRRRVRICG [SEQ ID NO: 33];X22RPTIRRRRVRICG [SEQ ID NO: 34];X23RPTIRRRRVRICG [SEQ ID NO: 35];X24RPTIRRRRVRICG [SEQ ID NO: 36];YRPTX25RRRRVRICG [SEQ ID NO: 37];YRPTX26RRRRVRICG [SEQ ID NO: 38];YRPTIRRRRX25RICG [SEQ ID NO: 39];YRPTIRRRRX26RICG [SEQ ID NO: 40];ARPTIRRRRVRICG [SEQ ID NO: 41];YAPTIRRRRVRICG [SEQ ID NO: 42];YRATIRRRRVRICG [SEQ ID NO: 43];YRPAIRRRRVRICG [SEQ ID NO: 44];YRPTIRARRVRICG [SEQ ID NO: 47];YRPTIRRARVRICG [SEQ ID NO: 48];YRPTIRRRAVRICG [SEQ ID NO: 49];YRPTIRRRRARICG [SEQ ID NO: 50];YRPTIRRRRVAICG [SEQ ID NO: 51];YRPTIRRRRVRACG [SEQ ID NO: 52];CVYVPTIRRRRRRRC [SEQ ID NO: 53];X27VYVPTIRRRRRRRX27 [SEQ ID NO: 54];CTYRATIRRKRRKVC [SEQ ID NO: 55];CYTIPTIRRKRRKVC [SEQ ID NO: 56];CKYRSTIRRKRRRVC [SEQ ID NO: 57];CQYVATIRRKRRKVC [SEQ ID NO: 58];CRKPTIRRKLRC [SEQ ID NO: 59];VYVPTIRRRRRRRC [SEQ ID NO: 60];YRPTIRRRRVRIX28 [SEQ ID NO: 61];YRSLRHKX19RIVX28 [SEQ ID NO: 62];YLRRPYRSCG [SEQ ID NO: 63];YRPTX25RRRX21VRICG [SEQ ID NO: 64];YRPTX26RRRX21VRICG [SEQ ID NO: 65]; andWRPTIRRRX21VRICG [SEQ ID NO: 66], wherein X19 is Sar;X20 is Me-F;X21 is Me-R;X22 is Dip;X23 is Bip;X24 is Nal;X25 is Tie;X26 is Cha;X27 is Pen; andX28 is Ava .

20. A composition comprising, consisting of, or consisting essentially of, a proteinaceous molecule according to any one of claims 1-19 and a pharmaceutically acceptable carrier or diluent.

21. 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 1-19.

22. 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 according to any one of claims 1-19.

23. The method according to claim 22, 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 and retinal detachment.

24. The method according to claim 23, 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.

25. 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 1-19.

26. The method according to claim 25, wherein the ischaemic damage is cardiac ischaemic damage.

27. 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 1-19.

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