Molecules and uses therefor

Abstract

Disclosed are proteinaceous 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 disclosure relates to proteinaceous ASIC inhibitors and their use for treating or inhibiting the development of a neurological condition, neuronal damage, ischaemia including cardiac and neuronal ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, an inflammatory condition or retinal detachment. The ASIC inhibitors are also useful for inhibiting damage to an organ during organ transplantation.

Description

TITLE OF THE INVENTIONMOLECULES AND USES THEREFOR'

[0001] This application claims priority to Australian Provisional Patent Application No. 2025901307 entitled " Molecules and uses therefor" filed 15 April 2025, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This invention relates generally to proteinaceous 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 including cardiac and neuronal ischaemia, pain, ischaemiareperfusion injury, a cancer, chronic kidney disease, acute kidney injury, an inflammatory condition or retinal detachment. The ASIC inhibitors are also useful for inhibiting damage to an organ during organ transplantation.BACKGROUND OF THE INVENTION

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

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

[0005] ASICs are widely expressed throughout the central and peripheral nervous system, in immune cells and in cardiomyocytes, and they have been associated with neurological conditions, ischaemia, pain, cancer, inflammatory conditions 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 playa role in intracellular signalling and membrane excitability. This isoform is the primary acid sensor in mammalian brain and is a key mediator of neuronal damage following ischaemia (Redd et al. (2021) Circulation, 144: 947-960; Chassagnon etal. (2017) PNAS, 114(14): 3750-3755).

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

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

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

[0010] There are currently no approved therapeutics that treat the cellular injury caused by ischaemia during a stroke or a cardiac event, such as myocardial infarction, despite the high prevalence of these conditions. 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, the inventors conceived that these proteinaceous molecules will be useful for treating or inhibiting the development of a condition associated with ASIC activity, such as a neurological condition, neuronal damage, ischaemia including cardiac and neuronal ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, an inflammatory condition or 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 or consisting essentially of an amino acid sequence represented by Formula I:X1X2RX3X4X5X6X7X8(I)wherein:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), O-methyltyrosine (Tyr(OMe)), homotyrosine (hTyr), 4-carboxy-phenylananine ((4C00H)Phe), D-tyrosine (D-Tyr), 3-fluoro-tyrosine ((3F)Tyr), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe), 2,6-dimethyl-tyrosine (dmTyr), pentafluoro-phenylalanine ((F5)Phe) or phosphotyrosine (Tyr(PO))]; small amino acid residues including S, A, G, T and modified forms thereof [e.g. cyclohexylalanine (Cha) or 2-furylalanine (2Fur)]; and basic amino acid residues including H, R, K and modified forms thereof [e.g. 1-methyl-histidine ((1Me)His)];X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba), phenylglycine (Phg) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb), homoarginine (hArg), citrulline (Cit) or N, N-dimethylarginine (R(Me2))]; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 5-methyl-proline (5MePro), 5,5-dimethyl-proline (5Me2Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4-(chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Idc) or 4-trifluoromethyl-proline (4CF3Pro)], sarcosine (Sar), N-methyl-serine (NMeSer), N-methyl-leucine (NMeLeu) and N-methyl-aspartic acid (NMeAsp); X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, 3-chloro-tyrosine ((3Cl)Tyr), (F5)Phe, 2-fluoro-tyrosine ((2F)Tyr), 3,5-difluorotyrosine (dFTyr)); Cha; and 2Fur;X6is selected from R, canavanine (Cav), a-methyl-arginine (aMeR), Agb, hArg, 2-amino-3-(4-guanidinophenyl)propanoic acid (Fgu), N-methylarginine (R(Me)), N-phenyl-arginine (R(Ph)), N-benzyl-arginine (R(Bz)), (4A)Phe, 2-amino-3-guanidinopropionic acid (Agp) and Cit;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)J; amide containing amino acid residues including N, Q and modified forms thereof; small amino acid residues including A, S, G, T and modified forms thereof; 3-aminomethylbenzoic acid (3Amb); 4-aminobutyric acid (4-Abu); D-Cys; and cysteine sulfoxide (Cys(O)); andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. 2-aminoisobutyric acid (Aib), p-alanine (bA)]; P 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 [e.g isoglutamic acid (iE)]; aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; aminohexanoic acid (Ahx); aminooctanoic acid (Aoc); and aminodecanoic acid (Adc).

[0013] In some embodiments:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. Dopa, F(pF) or F(pCI)]; and small amino acid residues including S, A, G, T and modified forms thereof;X2 is selected from L, Nle, Chg, Cpg, Cba and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. Agb];X4is selected from P and modified forms thereof [e.g. Hyp, Aze, Pip or aMeP], and Sar;Xs is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa);Xs is selected from R, Cav, aMeR and Agb;X7is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. hGlu); and amide containing amino acid residues including N, Q and modified forms thereof; andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. Aib); P 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; 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.

[0014] In some embodiments, Xi is Y, W, F, F(pF), F(pCI), Dopa or S. In particular embodiments, Xi is Y, W, F or Dopa; or Xi is Y.

[0015] In some embodiments, X2 is L, Nle or Chg. In particular embodiments, X2 is L or Chg.

[0016] In some embodiments, X3 is R or Agb. In particular embodiments, X3 is R.

[0017] In some embodiments, X4 is P, Hyp, Aze, Pip, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[Ac])Pro, (4A[Suc])Pro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, 4ChPro, 4PhPro, Thz, Ide or 4CF3Pro. In some embodiments, X4 is P, Hyp, Aze or Pip. In particular embodiments, X4 is P.

[0018] In some embodiments, X5 is Y, (3F)Tyr, (3CI)Tyr, 2Pal, 3Pal, 2Fur, (2F)Tyr or dFTyr. In some embodiments, X5 is Y or Dopa. In particular embodiments, X5 is Y.

[0019] In some embodiments, Xs is R, Cav, Agb, hArg, Fgu or R(Me). In some embodiments, Xs is R, aMeR or Cav. In particular embodiments, Xs is R.

[0020] In some embodiments, X7 is C, D, E, hGlu or Q. In some embodiments, X7 is C, E, hGlu, Q, 4-Abu or Cys(O). In particular embodiments, X7 is C, E or hGlu; or X7 is C.

[0021] In some embodiments, Xs is absent or is G, S or Aib. In particular embodiments, Xs is absent or is G.

[0022] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35 and 151-293:YLRRPYRCG [SEQ ID NO: 1];YLRRPYRC [SEQ ID NO: 2]; SLRRPYRCG [SEQ ID NO: 3]; YLRRX9YRCG [SEQ ID NO: 4]; YLRRPYRQG [SEQ ID NO: 5]; YLRKPYRCG [SEQ ID NO: 6]; YLRRPYRCGK [SEQ ID NO: 7]; YX10RRPYRCG [SEQ ID NO: 8]; YX11RRPYRCG [SEQ ID NO: 9]; YLRRX12YRCG [SEQ ID NO: 10]; FLRRPYRCG [SEQ ID NO: 11]; WLRRPYRCG [SEQ ID NO: 12]; X13LRRPYRCG [SEQ ID NO: 13]; X14LRRPYRCG [SEQ ID NO: 14]; YLRRPYX15CG [SEQ ID NO: 15]; YLRRPYREG [SEQ ID NO: 16]; YXieRRPYRCG [SEQ ID NO: 17]; YLRRPYRCGE [SEQ ID NO: 18]; YLRX17PYRCG [SEQ ID NO: 19]; YLRRPYX17CG [SEQ ID NO: 20]; YXieRRPYREG [SEQ ID NO: 21]; YXisRRPYRCG [SEQ ID NO: 22]; YX16RRX9YRCG [SEQ ID NO: 23]; YX16RRX19YRCG [SEQ ID NO: 24]; YX16RRX20YRCG [SEQ ID NO: 25]; YXieRRPYRDG [SEQ ID NO: 26]; YX16RRPYRX21G [SEQ ID NO: 27]; X22X16RRPYRCG [SEQ ID NO: 28]; YX16RRPX22RCG [SEQ ID NO: 29]; YX16RRX23YRCG [SEQ ID NO: 30]; YXieRRPYRC [SEQ ID NO: 31]; YX16RRPYRCX24 [SEQ ID NO: 32]; YXieRRPYRCS [SEQ ID NO: 33]; YX16RRPYX25CG [SEQ ID NO: 34]; YXisRRPYXisCG [SEQ ID NO: 35]; YX16RRPYX15X21G [SEQ ID NO: 151]; YX16RRPYRX27 [SEQ ID NO: 152]; SX16RRX20YRCG [SEQ ID NO: 153]; X22X16RRX20YRCG [SEQ ID NO: 154]; YX16RRX20YREG [SEQ ID NO: 155];YXisRRXigYREG [SEQ ID NO: 156]; YX16RRPX28RCG [SEQ ID NO: 157]; X28X16RRPYRCG [SEQ ID NO: 158]; YX16RX29PYRCG [SEQ ID NO: 159]; YX16RRPYX29CG [SEQ ID NO: 160]; YXieRRXsoYRC [SEQ ID NO: 161]; YX16RRX30YREG [SEQ ID NO: 162]; YX16RRX19YRE [SEQ ID NO: 163]; YX16RRX23YREG [SEQ ID NO: 164]; YX16RRX19YX15CG [SEQ ID NO: 165]; YX16RRX30YX15CG [SEQ ID NO: 166]; YXisRRPYXisC [SEQ ID NO: 167]; YX16RRX9YX15C [SEQ ID NO: 168]; YXisRRPYXisEG [SEQ ID NO: 169]; YX16RRPYX31CG [SEQ ID NO: 170]; YX16RRPYX32CG [SEQ ID NO: 171]; YX16RRX33YRCG [SEQ ID NO: 172]; X34X16RRPYRCG [SEQ ID NO: 173]; YX16RRPX34RCG [SEQ ID NO: 174]; YX35RRPYRCG [SEQ ID NO: 175]; YXisRRPYXssCG [SEQ ID NO: 176]; YXieRRPYRCE [SEQ ID NO: 177]; YX16RRPYRCX37 [SEQ ID NO: 178]; YXieRRPYRCGE [SEQ ID NO: 179]; YX16RRPYRCGX37 [SEQ ID NO: 180]; YXisRRPYXssCG [SEQ ID NO: 181]; YX16RRPYX39CG [SEQ ID NO: 182]; X40X16RRPYRCG [SEQ ID NO: 183]; X41X16RRPYRCG [SEQ ID NO: 184]; X42X16RRPYRCG [SEQ ID NO: 185]; YX16RRPX42RCG [SEQ ID NO: 186]; YX16RRPYRCGX43 [SEQ ID NO: 187]; YXisRRPYRCGK [SEQ ID NO: 188]; YX16RRPYX34CG [SEQ ID NO: 189]; X34X16RRPYX15CG [SEQ ID NO: 190]; X28X16RRX19YRCG [SEQ ID NO: 191]; X44X16RRPYRCG [SEQ ID NO: 192]; YX16RRX9YX15CG [SEQ ID NO: 193]; YX16RRPX44RCG [SEQ ID NO: 194];YXisRRPYRCGGE [SEQ ID NO: 195]; YX16RRPYRCX45E [SEQ ID NO: 196]; YX16RRX19YX32CG [SEQ ID NO: 197]; X46X16RRPYRCG [SEQ ID NO: 198]; YX16RRPX46RCG [SEQ ID NO: 199]; YX16RRPYRCX47E [SEQ ID NO: 200]; YX16RRPYRCX48E [SEQ ID NO: 201]; YX16RRPYRCX49E [SEQ ID NO: 202]; YXisRRXsoYRCG [SEQ ID NO: 203]; WXieRRPYRC [SEQ ID NO: 204]; XsiXisRRPYRC [SEQ ID NO: 205]; YX16RRX19YRCGE [SEQ ID NO: 206]; YXieRRPYRCGEK [SEQ ID NO: 207]; YX16RRX52YRC [SEQ ID NO: 208]; YX16RRX53YRC [SEQ ID NO: 209]; YX16RRX19YRCGEK [SEQ ID NO: 210]; YX16RRX19YX32CGE [SEQ ID NO: 211]; yXieRRPYRCG [SEQ ID NO: 212]; YX16RRX54YRC [SEQ ID NO: 213]; X55X16RRPYRCG [SEQ ID NO: 214]; XssXieRRPYRCG [SEQ ID NO: 215]; YXieRRPXssRCG [SEQ ID NO: 216]; YX16RRX57YRC [SEQ ID NO: 217]; XssXieRRPYRC [SEQ ID NO: 218]; YX16RRX52YREG [SEQ ID NO: 219]; X59X16RRPYRCG [SEQ ID NO: 220]; XeoXieRRPYRCG [SEQ ID NO: 221]; YXieRRXeiYRCG [SEQ ID NO: 222]; YX16RRX62YRCG [SEQ ID NO: 223]; YXieRRPXssRC [SEQ ID NO: 224]; YXisRRXssYRC [SEQ ID NO: 225]; YXieRRPYRQG [SEQ ID NO: 226]; YX16RRX52YX17CG [SEQ ID NO: 227]; YX16RRX52YX29CG [SEQ ID NO: 228]; YX16RRX52YX15CG [SEQ ID NO: 229]; YX16RRX52YRE [SEQ ID NO: 230]; YX16RRX52YRX64 [SEQ ID NO: 231]; YX16RRX52YRG [SEQ ID NO: 232]; YX16RRX52YRCG [SEQ ID NO: 233];YX16RRX52X55RC [SEQ ID NO: 234]; YX16RRX52X65RC [SEQ ID NO: 235]; FX16RRX52YRC [SEQ ID NO: 236]; HX16RRX52YRC [SEQ ID NO: 237]; YX16RX66X52YRC [SEQ ID NO: 238]; X67X16RRX52YRC [SEQ ID NO: 239]; X68X16RRX52YRC [SEQ ID NO: 240]; X69X16RRX52YRC [SEQ ID NO: 241]; X70X16RRX52YRC [SEQ ID NO: 242]; X71X16RRX52YRC [SEQ ID NO: 243]; YX16RRX52X71RC [SEQ ID NO: 244]; YX16RRX72YRC [SEQ ID NO: 245]; YX16RRX73YRC [SEQ ID NO: 246]; YX16RRX74YRC [SEQ ID NO: 247]; YX16RRX75YRC [SEQ ID NO: 248]; YX16RRX76YRC [SEQ ID NO: 249]; YX16RRX77YRC [SEQ ID NO: 250]; YX16RRX78YRC [SEQ ID NO: 251]; YX16RRX52X79RC [SEQ ID NO: 252]; YX16RRX52X67RC [SEQ ID NO: 253]; YX16RRX52X68RC [SEQ ID NO: 254]; YX16RRX52X80RC [SEQ ID NO: 255]; YX16RRX52YX66C [SEQ ID NO: 256]; X79X16RRX52YRC [SEQ ID NO: 257]; YX16RRX54YX15CG [SEQ ID NO: 258]; YX16RX66X52YX15CG [SEQ ID NO: 259]; YX16RRX52X55X15CG [SEQ ID NO: 260]; YX16RRX54YX29CG [SEQ ID NO: 261] X81X16RRX52YX29CG [SEQ ID NO: 262]; YX16RX66X52YX29C [SEQ ID NO: 263]; YX16REX52YRC [SEQ ID NO: 264]; YX16RQX52YRC [SEQ ID NO: 265]; X51X16RRX52YX29C [SEQ ID NO: 266]; X22X16RRX52YX29C [SEQ ID NO: 267]; X68X16RRX52YX29C [SEQ ID NO: 268] YX16RX82X52YX29C [SEQ ID NO: 269]; YX16RRX54X55RC [SEQ ID NO: 270]; X55X16RRX52X55RC [SEQ ID NO: 271]; YXieRRXssYRC [SEQ ID NO: 272];YX16RRX52X55X17C [SEQ ID NO 273];YX16RRX52X55X29C [SEQ ID NO 274];X81X16RRX52X55X29C [SEQ ID NO 275];X56X16RRX52X55RC [SEQ ID NO 276];YX16RRX52X84X29C [SEQ ID NO 277];YX16RRX52YX29C [SEQ ID NO 278];YX16RRX52X55RE [SEQ ID NO 279];YX16RRX52X55X17X85 [SEQ ID NO 280];YXieRRPYRXssG [SEQ ID NO 281];YXisRRPYRXss [SEQ ID NO 282];YX16RRX52YRX85 [SEQ ID NO 283];YX16RRX54YRX85 [SEQ ID NO 284];XssXisRRPYRXssG [SEQ ID NO 285];YX16RRX52X55RX85 [SEQ ID NO 286];YX16RRX52X55X29X85 [SEQ ID NO 287];YX16RRPYRCGEX87 [SEQ ID NO 288];YXieRRXssYRC [SEQ ID NO 289];YX16RRX53X55X17C [SEQ ID NO 290];YX16RRX52X55RCG [SEQ ID NO 291];YX16RRX52X55X17CG [SEQ ID NO 292]; andYXieRRXsgYRC [SEQ ID NO 293],wherein:X9 is Hyp; X10 is Cba; Xu is Nle; X12 is Sar; X13 is F(pF); X14 is F(pCI); X15 is Cav; Xis is Chg; X17 is Agb; Xis is Cpg; X19 is Aze; X20 is Pip; X21 is hGlu; X22 is Dopa; X23 is aMeP; X24 is Aib; X25 is aMeR; X27 is 3Amb; X28 is (4MeOH)Phe; X29 is hArg; X30 is Oxa; X31 is Agp; X32 is Fgu; X33 is NMeSer; X34 is (4A)Phe; X35 is Phg; X36 is R(Me); X37 is iE; X38 is R(Ph); X39 is R(Bz); X40 is (4CF3)Phe; X41 is (4tBu)Phe; X42 is Cha; X43 is PEG12; X44is Tyr(OMe); X45 is bA; X46 is hTyr; X47 is Ahx; X48 is Aoc; X49 is Adc; X50 is (4A)Pro; X51 is (4COOH)Phe; X52 is 5MePro; X53 is 5Me2Pro; X54 is 4FPro; X55 is (3F)Tyr; Xss is (4MeA)Phe; X57 is NMeLeu; X58 is 4Pal; X59 is (4MeA[Ac])Phe; Xso is (4MeA[Suc])Phe; Xsi is (4A[Ac])Pro; Xs2 is (4A[Suc])Pro; Xss is (4A[CIAc])Pro; Xs4 is 4-Abu; X65is (3Cl)Tyr; X66is Cit; Xs7 is 2Pal; X68is 3Pal; X69is (1Me)His; X70 is dmTyr; X71 is 2Fur; X72 is 5AzaPro; X73 is dfP; X74 is Oic; X75 is Mor; X76 is 4ChPro; X77 is 4PhPro; X78 is 4CF3Pro; X79 is (F5)Phe; Xso is (2F)Tyr; Xsi is Tyr(PO); X82is R(Me2); X83is NMeAsp; X84is dFTyr; Xss is Cys(O); X87is K(PEG11A); X88is Idc; and X89is Thz.

[0023] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35. In specific embodiments, the proteinaceous molecule comprises, consists or consistsessentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35.

[0024] In some embodiments, X7 is C or X7 is C(O) and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine or C(0) residue in the X7 position and the N-terminal amine of the amino acid residue in the X1 position.

[0025] In some embodiments, X7 is C and the side chain of the cysteine residue in the X7 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the X1 position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X7, and R1is C1-6 alkylene.

[0026] In particular embodiments, R1is methylene.

[0027] In some embodiments, the proteinaceous molecule comprises a lactam bond. For example, in particular embodiments, X7 is D, E or hGlu and the proteinaceous molecule comprises a lactam bond between the side chain of the amino acid residue in the X7 position and the N-terminal amine of the amino acid residue in the X1 position.

[0028] In some embodiments, the proteinaceous molecule comprises a C-terminal amide.

[0029] In some embodiments, the proteinaceous molecule is cyclized through N-to-C cyclisation.

[0030] In another aspect, there is provided a composition comprising, consisting or consisting essentially of a proteinaceous molecule of the invention and a pharmaceutically acceptable carrier or diluent.

[0031] Also provided is a proteinaceous molecule of the invention for use in therapy.

[0032] In a further aspect, there is provided a method of inhibiting an activity of an acid-sensing ion channel (ASIC), comprising contacting the ASIC with a proteinaceous molecule of the invention.

[0033] In some embodiments, the ASIC is ASICla.

[0034] 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 ASICis associated with effective treatment or inhibition of the development of the condition, comprising administering a proteinaceous molecule of the invention.

[0035] In some embodiments, 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, retinal detachment, arthritis and invertebral disc disease.

[0036] In particular 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. In specific embodiments, the neurological condition is stroke.

[0037] In some embodiments, the ischaemia is neuronal, ocular, renal or cardiac ischaemia. In some embodiments, the ocular ischaemia is acute retinal ischaemia.

[0038] In some embodiments, the cancer is a glioblastoma.

[0039] In some embodiments, the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.

[0040] In a 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.

[0041] 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. In some embodiments, the neurological condition is stroke.

[0042] In yet 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.

[0043] In a still 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.

[0044] In some embodiments, the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage. In particular embodiments, the ischaemic damage is cardiac ischaemic damage. In exemplary embodiments, the ischaemic damage is associated with a myocardial infarction.

[0045] In some embodiments, the ischaemic damage is neuronal ischaemic damage. In particular embodiments, the ischaemic damage is associated with a stroke,traumatic brain injury or perinatal brain injury. In some embodiments, the ischaemic damage is associated with a stroke.

[0046] A further aspect of the invention provides 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.

[0047] In some embodiments, the tissue is an organ transplant. In particular embodiments, the tissue is a heart, lung or kidney. In some embodiments, the tissue is a heart.

[0048] 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.

[0049] In some embodiments, the organ is a heart, lung or kidney; such as a heart.

[0050] In some embodiments, the damage is ischaemic damage.

[0051] In a further aspect, there is provided a method of treating or at least partially inhibiting the development of an inflammatory condition in a subject, comprising administering a proteinaceous molecule of the invention.

[0052] In some embodiments, the inflammatory condition is arthritis, such as rheumatoid arthritis or osteoarthritis.BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 is the structure of IB445.

[0054] Figure 2 is a mass spectrum of pure IB445 showing the expected ion sizes.

[0055] Figure 3 is a chromatogram from analytical RP-HPLC elution of purified IB445 using a Phenomenex C18 Luna column at 45°C. The peptide was eluted using a gradient of 10 to 36% buffer B (90% acetonitrile in water / 0.05% TFA) in buffer A (0.1% TFA in water) over 13 minutes. The flow rate was 0.5 mL / min.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0056] 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.

[0057] 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.

[0058] By "about" is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much 15% (e.g. up to 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.

[0059] 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.

[0060] 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 ascompositions comprising them and genetic molecules such as RNA, DNA and mimetics and chemical analogues thereof as well as cellular agents.

[0061] As used herein, the term "alkyl" refers to univalent straight or branched aliphatic hydrocarbon groups having from 1 to 6 carbon atoms, including from 1 to 5 carbon atoms, from 1 to 3 carbon atoms and from 1 to 2 carbon atoms. Examples of such alkyl groups include methyl (-CH3), ethyl (-CH2CH3), propyl, including n-propyl (-CH2CH2CH3), butyl, including n-butylene (-CH2CH2CH2CH3), and the like.

[0062] As used herein, the term "alkylene" refers to divalent straight or branched aliphatic hydrocarbon groups having from 1 to 6 carbon atoms, including from 1 to 5 carbon atoms, from 1 to 3 carbon atoms and from 1 to 2 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene, including n-propylene (-CH2CH2CH2-), butylene, including n-butylene (-CH2CH2CH2CH2-), and the like.

[0063] 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. All amino acids are L amino acids unless otherwise stated.

[0064] 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

[0065] 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).

[0066] 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.

[0067] 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, a-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0068] 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.

[0069] 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 thephrase "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 10 optional amino acids (and all integer optional amino acids in between) upstream of the specific amino acid sequence and / or about 1 to about 10 optional amino acids (and all integer optional amino acids in between) downstream of the specific amino acid sequence. In some embodiments, the upstream and / or downstream amino acid residues are other than Cys or a modified form thereof, penicillamine or 5-aminovaleric acid.

[0070] 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.

[0071] 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.

[0072] By "effective amount", in the context of treating or at least partially inhibiting the development of a condition, is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and / or treating existing symptoms, of that condition. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. An "effective amount", in the context of at least partially inhibiting the development of damage or an injury, is meant the administration or application of an amount of an agent or composition that is effective for inhibiting, minimising or reducing the damage or injury, such as cell death.

[0073] 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 may be used interchangeably with the term "prevent". 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.

[0074] 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.

[0075] 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.

[0076] As used herein, the terms "polypeptide", "proteinaceous molecule", "peptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. The term "proteinaceous" as used in for example "proteinaceous molecule" refers to the presence of at least a part of the molecule that resembles or is a protein, wherein "protein" is to be understood to include a chain of amino-acid residues at least two residues long, thus including a peptide, a polypeptide and a protein and an assembly of proteins or protein domains. These terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non-naturally-occurring amino acid, such as a chemical analogue of a corresponding naturally-occurring amino acid, as well as to naturally-occurring amino acid polymers. These termsdo not exclude modifications, for example, glycosylations, acetylations, phosphorylations, attachment of 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 stabilising moieties as described in detail herein.

[0077] 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.

[0078] 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 limitedto, 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.

[0079] The term "sequence identity" as used herein refers to the extent that sequences are identical on an amino acid-by-amino acid basis over a window of comparison. Thus, a "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical amino acid residue (e.g. Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, 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.

[0080] " 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.

[0081] 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 8 to 10 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 eta / . (1997) Nucl. Acids Res. 25: 3389. A detailed discussion of sequence analysis can be found in Unit 19.3 of Ausubel et al. (1998) Current Protocols in Molecular Biology, John Wiley & Sons Inc, Chapter 15; Lambert et al. (2003) Current Genomics, 4:131-146; and Bawano et al. (2017) Bioinformatics, Volume 1: Data, Sequence Analysis and Evolution (Methods in Molecular Biology (1525)), Humana Press, pages 167-189.

[0082] 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 suchas 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.

[0083] 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.

[0084] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Abbreviations

[0085] The following abbreviations are used throughout the application:PEG = polyethylene glycolASIC =acid-sensing ion channelASICla =acid-sensing ion channel lahASICla =human acid-sensing ion channel laAgb =2-amino-4-guanidino-butyric acidSar =sarcosineaMeR =alpha-methyl-arginineDopa =3,4-dihydroxyphenylalanineF(pF) =4-fluoro-phenylalanineF(pCI) =4-chloro-phenylalanineCpg =cyclopentylglycineCba =beta-cyclobutylalanineAze =azetidine-2-carboxylic acidPip = pi pecolic acidaMeP =a-methyl-prolineCav =canavaninehGlu =homoglutamic acidAib =2-aminoisobutyric acidERK =extracellular signal-regulated kinaseeq. =equivalentsDMF =dimethylformamideFmoc =fluorenylmethyloxycarbonylMBHA =4-methylbenzhydrylamineDCM =dichloromethaneTFA =trifluoroacetic acidHPLC = high-performance liquid chromatographyRP-HPLC =reversed-phase high-performance liquid chromatography LC-MS =HPLC-mass spectrometryHEPES =N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid BSA =bovine serum albuminsec =secondSEM =standard error of the meanAA =amino acidFLIPR =Fluorescence Imaging Plate Readerhr =hourmin =minuteHyp = hydroxyprolineChg =cyclohexylglycineMRGPRX2 =Mas-related G-protein coupled receptor member X2 DIPEA =N, N-diisopropylethylamineCABG =coronary artery bypass graftTAVI =transcatheter aortic valve insertionTNBS =2,4,6-trinitrobenzene sulfonic acidCHO =Chinese hamster ovaryPBS = phosphate buffered salineEDTA =ethylene diamine tetraacetic acidELISA =enzyme-linked immunosorbent assayNmeR =N-methyl-arginineBeta-R =beta-arginineaMeY =alpha-methyl-tyrosineCit =citrullineSPPS =solid-phase peptide synthesisFBS =foetal bovine serumHBSS =Hank's balanced salt solution(4MeOH)Phe =4-hydroxymethyl-phenylalanine(4A)Phe =4-amino-phenylalanine(4CF3)Phe =4-trifluoromethyl-phenylalanine(4tBu)Phe =4-tert-butyl-phenylalanineTyr(OMe) =O-methyltyrosinehTyr =Homotyrosine(4COOH)Phe =4-carboxy-D-Tyr or y =D-tyrosine(3F)Tyr =3-fluoro-tyrosine(4MeA)Phe =4-aminomethyl-phenylalanine2Pal = 2-pyridylalanine3Pal =3-pyridylalanine4Pal =4-pyridylalanine(4MeA[Ac])Phe =4-(methylacetyl)amino-phenylalanine (4MeA[Suc])Phe =4-(methylsuccinyl)amino-phenylalanine dmTyr =2,6-dimethyl-tyrosine(F5)Phe = pentafluoro-phenylalanineTyr(PO) = phosphotyrosineCha =cyclohexylalanine2Fur =2-furylalanine(1Me)His =1-methyl-histidinePhg =phenylglycinehArg =homoarginineR(Me2) =N, N-dimethylarginineOxa =1,3-oxazole-4-carboxylic acid(4A)Pro =4-amino-proline5MePro =5-methyl-proline5Me2Pro =5,5-dimethyl-proline4FPro =4-fluoro-proline(4A[Ac])Pro =4-aminoacetyl-proline(4A[Suc])Pro =4-aminosuccinyl-proline(4A[CIAc])Pro =4-(chloroacetyl)ami no-proline5AzaPro =5-azaspiro[2.4]heptane-6-carboxylic acid dfP =4,4-difluoro-prolineOic =octahydroindole-2-carboxylic acidMor =1,4-morpholine-3-carboxylic acid4ChPro =4-cyclohexyl-proline4PhPro =4-phenyl-proline4CF3Pro =4-trifluoromethyl-prolineNMeSer =N-methyl-serineNMeLeu =N-methyl-leucineNMeAsp =N-methyl-aspartic acid(3CI)Tyr =3-chloro-tyrosine(2F)Tyr =2-fluoro-tyrosinedFTyr =3,5-difluorotyrosineFgu =2-amino-3-(4-guanidinophenyl)propanoic acidR(Me) =N-methylarginineR(Ph) = N-phenyl-arginineR(Bz) =N-benzyl-arginine3Amb =3-aminomethylbenzoic acid4-Abu =4-aminobutyric acidCys(O) or C(O) =cysteine sulfoxidebA =β-alanineIE =isoglutamic acidAhx =aminohexanoic acidAoc =aminooctanoic acidAdc =aminodecanoic acidDIC = N, N '-diisopropylcarbodiimideD-Cys or c =D-cysteineThz =thioproline or thiazolidine-4-carboxylic acid Ide =indoline-2-carboxylic acidAgp =2-amino-3-guanidinopropionic acidHATU =O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphateOxyma =ethyl 2-cyano-2-(hydroxyimino)acetate3. Proteinaceous Molecules

[0086] The present invention is based, in part, on the design of proteinaceous molecules that inhibit ASIC activity, particularly ASICla activity. Based on this activity, the inventors conceived that these proteinaceous molecules, including proteinaceous molecules of Formula I, III, IV, V and VI, 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 including cardiac and neuronal ischaemia, pain, ischaemia-reperfusion 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.

[0087] Accordingly, in one aspect, there is provided a proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:X1X2RX3X4X5X6X7X8(I)wherein:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), O-methyltyrosine (Tyr(OMe)), homotyrosine (hTyr), 4-carboxy-phenylananine ((4COOH)Phe), D-tyrosine (D-Tyr), 3-fluoro-tyrosine ((3F)Tyr), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe), 2,6-dimethyl-tyrosine (dmTyr), pentafluoro-phenylalanine ((F5)Phe) or phosphotyrosine (Tyr(PO))]; small amino acid residues including S, A, G, T and modified forms thereof [e.g. cyclohexylalanine (Cha) or 2-furylalanine (2Fur)]; and basic amino acid residues including H, R, K and modified forms thereof [e.g. 1-methyl-histidine ((1Me)His)];X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba), phenylglycine (Phg) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb), homoarginine (hArg), citrulline (Cit) or N, N-dimethylarginine (R(Me2))]; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 5-methyl-proline (5MePro), 5,5-dimethyl-proline (5Me2Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4-(chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Idc) or 4-trifluoromethyl-proline (4CF3Pro)], sarcosine (Sar), N-methyl-serine (NMeSer), N-methyl-leucine (NMeLeu) and N-methyl-aspartic acid (NMeAsp); X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, 3-chloro-tyrosine ((3Cl)Tyr), (F5)Phe, 2-fluoro-tyrosine ((2F)Tyr), 3,5-difluorotyrosine (dFTyr)); Cha; and 2Fur;X6is selected from R, canavanine (Cav), a-methyl-arginine (aMeR), Agb, hArg, 2-amino- 3-(4-guanidinophenyl)propanoic acid (Fgu), N-methylarginine (R(Me)), N-phenyl-arginine (R(Ph)), N-benzyl-arginine (R(Bz)), (4A)Phe, 2-amino-3-guanidinopropionic acid (Agp) and Cit;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)]; amide containing amino acid residues including N, Q and modified forms thereof; small amino acid residues including A, S, G, T and modified forms thereof; 3-aminomethylbenzoic acid (3Amb); 4-aminobutyric acid (4-Abu); D-Cys; and cysteine sulfoxide (Cys(O)); andX8 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. 2-aminoisobutyric acid (Aib), β-alanine (bA)]; P 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 [e.g isoglutamic acid (iE); aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; aminohexanoic acid (Ahx); aminooctanoic acid (Aoc); and aminodecanoic acid (Adc).

[0088] In some embodiments:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. Dopa, F(pF) or F(pCI)]; and small amino acid residues including S, A, G, T and modified forms thereof;X2 is selected from L, Nle, Chg, Cpg, Cba and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. Agb];X4is selected from P and modified forms thereof [e.g. Hyp, Aze, Pip or aMeP], and Sar; X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa);Xs is selected from R, Cav, aMeR and Agb;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. hGlu]; and amide containing amino acid residues including N, Q and modified forms thereof; andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. Aib]; P 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; 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.

[0089] In some embodiments:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), O-methyltyrosine (Tyr(OMe)), homotyrosine (hTyr), 4-carboxy-phenylananine ((4COOH)Phe), D-tyrosine (D-Tyr), 3-fluoro-tyrosine ((3F)Tyr), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe), 2,6-dimethyl-tyrosine (dmTyr), pentafluoro-phenylalanine ((F5)Phe) or phosphotyrosine (Tyr(PO))]; and small amino acid residues including S, A, G, T and modified forms thereof [e.g. cyclohexylalanine (Cha) or 2-furylalanine (2Fur)];X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb), homoarginine (hArg), citrulline (Cit) or N, N-dimethylarginine (R(Me2))];X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 5-methyl-proline (5MePro), 5,5-dimethyl-proline (5Me2Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4-(chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Ide) or 4-trifluoromethyl-proline (4CF3Pro)], and sarcosine (Sar);X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, 3-chloro-tyrosine ((3CI)Tyr), (F5)Phe, 2-fluoro-tyrosine ((2F)Tyr), 3,5-difluorotyrosine (dFTyr));X6 is selected from R, canavanine (Cav), a-methyl-arginine (aMeR) and Agb;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)]; and amide containing amino acid residues including N, Q and modified forms thereof; andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof[e.g. 2-aminoisobutyric acid (Aib), p-alanine (bA)]; P 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 [e.g isoglutamic acid (IE); 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.

[0090] In some embodiments, X1 is Y, W, F, Dopa, F(pF), F(pCl), (4MeOH)Phe, (4A)Phe, (4CF3)Phe, (4tBu)Phe, Tyr(OMe), hTyr, (4COOH)Phe, D-Tyr, (3F)Tyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (4MeA[Ac])Phe, (4MeA[Suc])Phe, dmTyr, (F5)Phe, Tyr(PO), S, A, G, T, Cha, 2Fur, H, R, K or (1Me)His. In some embodiments, X1 is Y, W, F, Dopa, F(pF), F(pCl), (4MeOH)Phe, (4A)Phe, (4CF3)Phe, (4tBu)Phe, Tyr(OMe), hTyr, (4COOH)Phe, D-Tyr, (3F)Tyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (4MeA[Ac])Phe, (4MeA[Suc])Phe, dmTyr, (F5)Phe, Tyr(PO), S, Cha, 2Fur, H or (1Me)His. In some embodiments, X1 is Y, W, F, Dopa, (4MeOH)Phe, (4A)Phe, (3F)Tyr, (4MeA)Phe, 3Pal, 4Pal, 2Fur, H, (1Me)His or (4COOH)Phe; or X1 is Y, F, Dopa, (4MeOH)Phe, (4A)Phe, (3F)Tyr or (4MeA)Phe. In some embodiments, X1 is Y.

[0091] In some embodiments, Xi is Y, W, F, Dopa, F(pF), F(pCI), S, A, G or T. In particular embodiments, Xi is Y, W, F, F(pF), F(pCI), Dopa or S. In particular embodiments, Xi is Y, W, F or Dopa; or Xi is Y or Dopa. In some embodiments, Xi is Y.

[0092] In some embodiments, X2 is L, Nle, Chg, Cpg, Phg or Cba. In some embodiments, X2 is L, Nle, Phg or Chg.

[0093] In some embodiments, X2 is L, Nle, Chg, Cpg or Cba. In some embodiments, X2 is L, Nle or Chg. In particular embodiments, X2 is L or Chg. In some embodiments, X2 is L. In alternative embodiments, X2 is Chg.

[0094] In some embodiments, X3 is R, K, Agb, hArg, Cit, R(Me2), D, E, N or Q. In some embodiments, X3 is R, Agb, hArg, Cit, R(Me2), E or Q. In some embodiments, X3 is R, Agb, hArg, Cit or Q.

[0095] In some embodiments, X3 is R, K or Agb. In some embodiments, X3 is R or Agb. In some embodiments, X3 is Agb. In particular embodiments, X3 is R. In some embodiments, X3 is other than r.

[0096] In some embodiments, X4 is P, Hyp, Aze, Pip, aMeP, Sar, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[Ac])Pro, (4A[Suc])Pro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, 4ChPro, 4PhPro, Thz, Ide, 4CF3Pro, NMeSer, NMeLeu or NMeAsp. In some embodiments, X4 is P, Hyp, Aze, Pip, Sar, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, Thz, Ide, 4CF3Pro, NMeSer or NMeLeu. In some embodiments, X4 is P, Hyp, Aze, 4FPro, 5MePro or 5Me2Pro. In some embodiments, X4 is P, 4FPro, 5MePro or 5Me2Pro. In some embodiments, X4 is P, 4FPro or 5MePro. In someembodiments, X4 is 4FPro or 5MePro. In some embodiments, X4 is P or 5MePro. In some embodiments, X4 is 5MePro.

[0097] In some embodiments, X4 is P, Hyp, Aze, Pip, aMeP or Sar. In some embodiments, X4 is P, Hyp, Aze or Pip. In some embodiments, X4 is P, Hyp or Aze. In particular embodiments, X4 is P.

[0098] In some embodiments, X5 is Y, W, F, Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, (3CI)Tyr, (F5)Phe, (2F)Tyr, dFTyr, Cha or 2Fur. In some embodiments, X5 is Y, Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, (3CI)Tyr, (F5)Phe, (2F)Tyr, dFTyr, Cha or 2Fur. In some embodiments, X5 is Y, Dopa, (4A)Phe, 2Pal, 3Pal, (3F)Tyr, (3CI)Tyr, dFTyr or 2Fur. In some embodiments, X5 is Y or (3F)Tyr.

[0099] In some embodiments, X5 is Y, W, F or Dopa. In some embodiments, X5 is Y or Dopa. In some embodiments, X5 is Dopa. In particular embodiments, X5 is Y.

[0100] In some embodiments, X6 is R, aMeR, Cav, Agb, hArg, Fgu, R(Me), R(Ph), R(Bz), (4A)Phe, Agp or Cit. In some embodiments, X6 is R, aMeR, Cav, Agb, hArg, Fgu, R(Me), R(Ph), R(Bz), (4A)Phe or Agp. In some embodiments, X6 is R, hArg, Fgu, R(Me), Agb or Cav. In some embodiments, X6 is R, hArg, Cav or Agb. In some embodiments, X6 is other than Cit.

[0101] In some embodiments, X6 is R, aMeR or Cav. In some embodiments, X6 is R or Cav. In some embodiments, X6 is Cav. In particular embodiments, X6 is R.

[0102] In some embodiments, X7 is C, D, E, hGlu, N, Q A, S, G, T, 3Amb, 4-Abu, D-Cys or Cys(O). In some embodiments, X7 is C, D, E, hGlu, Q, G, 3Amb, 4-Abu, D-Cys or Cys(O). In some embodiments, X7 is C, D, E, hGlu, Q, G, 3Amb, 4-Abu or Cys(O). In some embodiments, X7 is C, E, 4-Abu or Cys(O). In some embodiments, X7 is C, 4-Abu, 3Amb or Cys(O), or X7 is C or Cys(O). In some embodiments, X7 is other than D-Cys.

[0103] In some embodiments, X7 is C, D, E, hGlu, N or Q. In some embodiments, X7 is C, D, E, hGlu or Q. In particular embodiments, X7 is C, E or hGlu; or X7 is C.

[0104] In some embodiments, X8 is absent or is selected from R, K, H, A, G, S, T, Aib, bA, P, V, L, I, D, E, iE, Ahx, Aoc, Adc, Y, W, F, N and Q. In some embodiments, X8 is absent or is selected from A, G, S, T, Aib, bA, P, V, L, I, E, iE, Ahx, Aoc, Adc, Y, W, F, N and Q. In some embodiments, X8 is absent or is selected from G, Aib, bA, Ahx, Aoc, Adc, iE, E, Aib and S. In some embodiments, X8 is absent or is selected from G, bA, Ahx, iE, Aib and S.

[0105] In some embodiments, X8 is absent or is selected from R, K, H, A, G, S, T, Aib, P, V, L, I, D, E, Y, W, F, N and Q. In some embodiments, X8 is absent or is selected from

[0106] In some embodiments, Xs is absent or is selected from small amino acid residues including A, G, S, T and modified forms thereof (e.g. Aib). In some embodiments, Xs is absent or is A, G, S, T or Aib. In some embodiments, Xs is absent or is G, S or Aib. In particular embodiments, Xs is absent or is G. In exemplary embodiments, Xs is absent. In alternative embodiments, Xs is G. In some embodiments, Xs is other than D.

[0107] In some embodiments, Xs is other than an amino acid residue selected from C and modified forms thereof (e.g. D-Cys), penicillamine, 5-aminovaleric acid and basic amino acid residues including R, K and modified forms thereof.

[0108] In some embodiments:X1 is Y, W, F, Dopa, F(pF), F(pCI), S, A, G orT;X2 is L, Nle, Chg, Cpg or Cba;X3 is R, K or Agb;X4 is P, Hyp, Aze, Pip, aMeP or Sar;X5 is Y, W, F or Dopa;Xs is R, Cav, aMeR or Agb;X? is C, D, E, hGlu, N or Q; and / orXs is absent or is selected from R, K, H, A, G, S, T, Aib, P, V, L, I, D, E, Y, W, F, N and Q.

[0109] In some embodiments:X1 is Y, W, F, Dopa, F(pF), F(pCI), S, A, G orT;X2 is L, Nle, Chg, Cpg or Cba;X3 is R, K or Agb;X4 is P, Hyp, Aze, Pip, aMeP or Sar;X5 is Y, W, F or Dopa;Xs is R, Cav, aMeR or Agb;X7 is C, D, E, hGlu, N or Q; and / orXs is absent or is A, G, S, T or Aib.

[0110] In some embodiments:X1 is Y, W, F, F(pF), F(pCI), Dopa or S;X2 is L, Nle, Chg, Cpg or Cba;X3 is R, K or Agb;X4 is P, Hyp, Aze, Pip, aMeP or Sar;Xs is Y or Dopa;Xs is R, Cav, aMeR or Agb;X? is C, D, E, hGlu or Q; and / orXs is absent or is G, S or Aib.

[0111] In some embodiments: Xi is Y, W, F or Dopa;X2 is L, Nle or Chg;X3 is R or Agb;X4 is P, Hyp, Aze or Pip;Xs is Y or Dopa;Xs is R, Cav or aMeR;X7 is C, E or hGlu; and / orXs is absent or is G, S or Aib.

[0112] In some embodiments: Xi is Y or Dopa;X2 is L or Chg;X3 is R or Agb;X4 is P, Hyp or Aze;X5 is Y or Dopa;Xs is R or Cav;X7 is C, E or hGlu; and / orXs is absent or is G.

[0113] In some embodiments: Xi is Y;X2 is L or Chg;X3is R;X4 is P, Hyp or Aze;X5 is Y or Dopa;Xs is R or Cav;X? is C or hGlu; and / orXs is absent or is G.

[0114] In some embodiments:X1 is Y, W, F, Dopa, F(pF), F(pCI), (4MeOH)Phe, (4A)Phe, (4CF3)Phe, (4tBu)Phe, Tyr(OMe), hTyr, (4C00H)Phe, D-Tyr, (3F)Tyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (4MeA[Ac])Phe, (4MeA[Suc])Phe, dmTyr, (F5)Phe, Tyr(PO), S, A, G, T, Cha, 2Fur, H, R, K or (lMe)His; X2 is L, Nle, Chg, Cpg, Phg or Cba;X3is R, K, Agb, hArg, Cit, R(Me2), D, E, N or Q;X4 is P, Hyp, Aze, Pip, aMeP, Sar, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[Ac])Pro, (4A[Suc])Pro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, 4ChPro, 4PhPro, Thz, Ide, 4CF3Pro, NMeSer, NMeLeu or NMeAsp;X5is Y, W, F, Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, (3CI)Tyr, (F5)Phe, (2F)Tyr, dFTyr, Cha or 2Fur;Xs is R, aMeR, Cav, Agb, hArg, Fgu, R(Me), R(Ph), R(Bz), (4A)Phe, Agp or Cit;X7 is C, D, E, hGlu, N, Q A, S, G, T, 3Amb, 4-Abu, D-Cys or Cys(O); and / orXs is absent or is selected from R, K, H, A, G, S, T, Aib, bA, P, V, L, I, D, E, iE, Ahx, Aoc, Adc, Y, W, F, N and Q.

[0115] In some embodiments:X1 is Y, W, F, Dopa, F(pF), F(pCI), (4MeOH)Phe, (4A)Phe, (4CF3)Phe, (4tBu)Phe, Tyr(OMe), hTyr, (4C00H)Phe, D-Tyr, (3F)Tyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (4MeA[Ac])Phe, (4MeA[Suc])Phe, dmTyr, (F5)Phe, Tyr(PO), S, Cha, 2Fur, H or (lMe)His;X2 is L, Nle, Chg, Cpg, Phg or Cba;X3is R, Agb, hArg, Cit, R(Me2), E or Q;X4 is P, Hyp, Aze, Pip, Sar, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, Thz, Ide, 4CF3Pro, NMeSer or NMeLeu;X5is Y, Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, (3CI)Tyr, (F5)Phe, (2F)Tyr, dFTyr, Cha or 2Fur;Xs is R, aMeR, Cav, Agb, hArg, Fgu, R(Me), R(Ph), R(Bz), (4A)Phe, Agp or Cit; or R, aMeR, Cav, Agb, hArg, Fgu, R(Me), R(Ph), R(Bz), (4A)Phe or Agp;X7 is C, D, E, hGlu, Q, G, 3Amb, 4-Abu, D-Cys or Cys(O); or C, D, E, hGlu, Q, G, 3Amb, 4-Abu or Cys(O); and / orXs is absent or is selected from A, G, S, T, Aib, bA, P, V, L, I, E, iE, Ahx, Aoc, Adc, Y, W, F, N and Q.

[0116] In some embodiments:X1 is Y, W, F, Dopa, (4MeOH)Phe, (4A)Phe, (3F)Tyr, (4MeA)Phe, 3Pal, 4Pal, 2Fur, H, (IMe)His or (4C00H)Phe;X2 is L, Nle, Phg or Chg;X3 is R, Agb, hArg, Cit or Q;X4 is P, Hyp, Aze, 4FPro, 5MePro or 5Me2Pro;X5is Y, Dopa, (4A)Phe, 2Pal, 3Pal, (3F)Tyr, (3CI)Tyr, dFTyr or 2Fur;Xs is R, hArg, Cav or Agb;X7 is C, E, 4-Abu or Cys(O); and / orXs is absent or is selected from G, Aib, bA, Ahx, Aoc, Adc, IE, E, Aib and S.

[0117] In some embodiments:Xi is Y, F, Dopa, (4MeOH)Phe, (4A)Phe, (3F)Tyr or (4MeA)Phe;X2 is L, Nle, Phg or Chg;X3 is R, Agb, hArg, Cit or Q;X4 is P, 4FPro, 5MePro or 5Me2Pro;X5is Y, Dopa, (4A)Phe, 2Pal, 3Pal, (3F)Tyr, (3CI)Tyr, dFTyr or 2Fur;Xs is R, hArg, Cav or Agb;X7 is C, E, 4-Abu or Cys(O); and / orXs is absent or is selected from G, Aib, bA, Ahx, Aoc, Adc, IE, E, Aib and S; or is absent or is selected from G, bA, Ahx, iE, Aib and S.

[0118] In some embodiments:Xi is Y, F, Dopa, (4MeOH)Phe, (4A)Phe, (3F)Tyr or (4MeA)Phe;X2 is L, Nle or Chg;X3 is R, Agb, hArg or Cit;X4 is P, 4FPro, 5MePro or 5Me2Pro;X5is Y, Dopa, (4A)Phe, 2Pal, 3Pal, (3F)Tyr, (3CI)Tyr or dFTyr;Xs is R, Cav or Agb;X7 is C or E; and / orXs is absent or is selected from G, Aib, bA, iE, E, Aib and S; or is absent or is selected from G, bA, iE, Aib and S.

[0119] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula III:X1X2RX3X4X5X6X7X8X26 (III)wherein:Xi to Xs are as defined for Formula I supra; andX26 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P 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 (e.g. IE); aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; and a PEG (e.g. PEG12),wherein when Xs is absent, X26 is absent.

[0120] In some embodiments, X26 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof; P 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; 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.

[0121] In some embodiments, X26 is absent or is selected from R, K, H, A, G, S, T, P, V, L, I, D, E, iE, Y, W, F, N, Q and a PEG (e.g. PEG12). In some embodiments, X26 is absent or is selected from R, K, H, A, G, S, T, P, V, L, I, D, E, Y, W, F, N and Q.

[0122] In some embodiments, X26 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; acidic amino acid residues including D, E and modified forms thereof (e.g. IE); small amino acid residues, including A, S, G, T and modified forms thereof; and a PEG (e.g. PEG12). In some embodiments, X26 is absent or is R, K, H, D, E, iE, A, G, S, T or a PEG. In some embodiments, X26 is absent or is E, K. IE, G or PEG12.

[0123] In some embodiments, X26 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; and acidic amino acid residues including D, E and modified forms thereof. In some embodiments, X26 is absent or is R, K, H, D or E. In some embodiments, X26 is absent or is E or K. In particular embodiments, X26 is absent or is K. In exemplary embodiments, X26 is absent.

[0124] In some embodiments, X26 is other than an amino acid residue selected from C and modified forms thereof (e.g. D-Cys), penicillamine, 5-aminovaleric acid and basic amino acid residues including R, K and modified forms thereof.

[0125] Suitable embodiments of Xi to Xs are as described supra.

[0126] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula IV:X1X2RRX4X5X6X7X8 (IV)wherein:Xi, X2 and X4 to Xs are as defined for Formula I supra.

[0127] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula V:X1X2RRX4X5X6X7X8X26 (V)wherein:Xi, X2, X4 to Xs and X26 are as defined for Formula III supra.

[0128] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by Formula VI:X1X2 X3X4X5X6X7X8X26X86 (VI)wherein:Xi to Xs are as defined for Formula I supra; andX26 is as defined for Formula III supra; andX86 absent or is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. K(PEG11A)); small amino acid residues including A, G, S, T and modified forms thereof; P 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; aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; and a PEG,wherein when X8 is absent, X26 is absent, and when X26 is absent, X86 is absent.

[0129] In some embodiments, X86 is absent or is selected from R, K, H, A, G, S, T, P, V, L, I, D, E, Y, W, F, N, Q, K(PEG11A) and a PEG.

[0130] In some embodiments, X86 is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof (e.g. K(PEG11A)); and acidic amino acid residues including D, E and modified forms thereof. In some embodiments, X86 isabsent or is R, K, H, K(PEG11A), D or E. In particular embodiments, X86 is absent or is K, K(PEG11A) or E. In some embodiments, X86 is absent.

[0131] In some embodiments, when X26 is E, X86 is other than E.

[0132] In some embodiments, the proteinaceous molecule of the invention (e.g. of any one of Formula I, III, IV, V or VI) comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35 and 151-293.

[0133] In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35. 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, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35. 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, 2, 15, 17, 21, 23, 24, 27-29, 31-33 and 35.

[0134] 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, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33, 35, 151, 154-163, 165-169, 171-183, 185, 187, 188, 190, 191, 193, 195-198, 200, 201, 203-211, 213-215, 217-220, 222, 225-248, 251-263, 265-271, 273-287 and 289-293. 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, 2, 15, 17, 21, 23, 24, 27-29, 31-33, 35, 162, 166, 167, 206, 213, 227-229, 233, 234, 238, 260, 261, 270, 271, 273, 274, 277, 279, 280, 282-284, 286 and 289-293. In some embodiments, the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 208, 219, 227-244, 252-257, 259, 260, 262-269, 271, 273-280, 283, 286, 287 and 289-293.

[0135] In some embodiments (e.g. of any one of Formulae I and III to VI), when X7 is an acidic amino acid residue (e.g. D, E or a modified form thereof), or a small amino acid residue (e.g. A, S, G, T and modified forms thereof), at least one of Xs and X26, when present, is other than an amino acid residue selected from C and modified forms thereof (e.g. D-Cys), penicillamine, 5-aminovaleric acid and basic amino acid residues including R, K and modified forms thereof. In some embodiments, when X7 is 3Amb or 4-Abu, at least one of Xs and X26, when present, is other than an amino acid residue selected from C and modified forms thereof (e.g. D-Cys), penicillamine, 5-aminovaleric acid and basic amino acid residues including R, K and modified forms thereof. In some embodiments, when X7 is selected from acidic amino acid residues including D, E and modified forms thereof [e.g. hGlu], amide containing amino acid residues including N, Q and modified forms thereof,small amino acid residues including A, S, G, T and modified forms thereof, 3Amb and 4-Abu, the proteinaceous molecule does not comprise C or a modified form thereof (e.g. D-Cys), penicillamine or 5-aminovaleric acid.

[0136] In some embodiments, X? is other than basic amino acid residues including R, K and modified forms thereof (e.g. N-methyl-arginine, ornithine, betaarginine, hArg, 2-amino-4-guanidinobutyric acid, Cit or guanidinyl-alkylated-arginine); small amino acid residues including A, G, S, T and modified forms thereof (e.g. sarcosine); 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.

[0137] In some embodiments, the proteinaceous molecule of the invention (e.g. Formula I, III, IV, V or VI) comprises an intramolecular linkage, such as a thioether bond, a disulfide bond, a thioether linkage, a lanthionine bridge, an amide bond, lactam bond (also referred to as amide bond herein), an ester linkage, a thioester linkage, a carbamoyl linkage, an alkyl linkage, an alkenyl linkage, an ether linkage, an amine linkage or a thioamide linkage. In some embodiments, the proteinaceous molecule of the invention (e.g. Formula I, III, IV, V or VI) comprises a thioether bond or an amide bond or lactam bond. In some embodiments, the intramolecular linkage is formed between the amino acid residue in the X? or Xs position (e.g. the side chain or C-terminal acid) and the N-terminal amine of the N-terminal amino acid residue.

[0138] For example, in some embodiments, the proteinaceous molecule (e.g. of any one of Formulae I and III to VI) comprises an intramolecular linkage between the side chain of the amino acid residue in the X? position and the N-terminal amine of the N-terminal amino acid residue (i.e. the amino acid residue in the Xi position).

[0139] In some embodiments, X? is C or Cys(O) and the proteinaceous molecule (e.g. of any one of Formulae I and III to VI) comprises a thioether bond between the side chain of the cysteine or Cys(O) residue in the X7 position and the N-terminal amine of the amino acid residue in the X1 position.

[0140] In some embodiments, X? is C and the side chain of the cysteine residue in the X? position forms a thioether linkage with the N-terminal amine of the amino acid residue in the Xi position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X7, and R1is C1-6 alkylene.

[0141] In some embodiments, R1is methylene or ethylene, especially methylene.

[0142] Alternatively, the proteinaceous molecule (e.g. Formula I, III, IV, V or VI) may comprise a lactam bond or bridge between the side chain of the amino acid residue in the X7 position and the N-terminal amine of the N-terminal amino acid residue (i.e. Xi). For example, in some embodiments, X7 is D, E or hGlu and the proteinaceous molecule comprises a lactam bond (or amide bond) between the side chain of the amino acid residue in the X7 position (i.e. the acidic side chain) and the N-terminal amine of the amino acid residue in the Xi position.

[0143] In some embodiments, the proteinaceous molecule (e.g. Formula I, III, IV, V or VI) is cyclised through N-to-C cyclisation (head to tail cyclisation), such as through an amide bond (e.g. an amide bond between the N- and C-termini of the linear peptide). In some embodiments, the proteinaceous molecules of the invention have an amide-cyclised peptide backbone. In some embodiments, X7 is other than C, such as an amide containing amino acid residue (e.g. N, Q or a modified form thereof), a small amino acid residue (e.g. G), 4-Abu or 3Amb, and the proteinaceous molecule is cyclised through N-to-C cyclisation.

[0144] 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, an amine linkage or a thioamide linkage. In alternative embodiments, the proteinaceous molecule is an acyclic molecule.

[0145] In some embodiments where the proteinaceous molecule of the invention comprises an N- and / or C-terminus, the proteinaceous molecule of the invention (e.g. Formula I, III, IV, V or VI) has 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 molecule of the invention is a cyclic peptide and, thus, may not comprise N- and / or C-terminal amino acid residues. In preferred embodiments, the proteinaceous molecule of the invention has a primary amide, or a free carboxyl group (C-terminal acid) at the C-terminus and a primary amine at the N-terminus. In some embodiments, the proteinaceous molecule (e.g. Formula I, III, IV, V or VI) comprises a C-terminal amide.

[0146] The proteinaceous molecule of the invention (e.g. Formula I, III, IV, V or VI) may be between 8 amino acid residues and 15 amino acid residues in length (and all integer amino acid residues therebetween); especially between 8 amino acid residues and 12 amino acid residues in length, between 8 amino acid residues and 11 amino acidresidues in length or between 8 amino acid residues and 10 amino acid residues in length; including about 8, 9, 10, 11 or 12 amino acid residues in length. In some embodiments, the proteinaceous molecule is up to 10 amino acid residues in length or up to 11 amino acid residues in length.

[0147] The proteinaceous molecule may, in some embodiments, be 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.

[0148] In some embodiments, the proteinaceous molecule of Formula I, III, IV, V or VI 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1. In some embodiments, the proteinaceous molecule of Formula I, III, IV or V 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1. In such molecules, the variance occurs at one or more of Xi to Xs or X26 when present in the subject Formula.

[0149] In some embodiments, the proteinaceous molecule of the invention is other than IB535, IB536, IB537, IB538, IB541, IB542, IB549, SCP117, SCP159-SCP161, SCP167, SCP227, SCP230, SCP047, SCP007, SCP054, SCP048, SCP049, SCP008, SCP010, SCP015, SCP022-SCP024, SCP028, SCP031, SCP032, SCP035, SCP036, SCP038, SCP052 and / or SCP062. In some embodiments, Xi and / or X5 is other than alpha-methyl-tyrosine. In some embodiments, X26 is other than K(C18A) and / or K(C16). In some embodiments, X5 is other than y. In some embodiments, X3 is other than citrulline. In some embodiments, X? is other than bA.

[0150] The present invention also contemplates proteinaceous molecules that are variants of any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1. Such "variant" proteinaceous molecules include proteinaceous molecules derived from any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, by deletion or addition of one or more amino acids(such as from 1-5 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 1-3 amino acid residues and all integer amino acids therebetween) at one or more sites in the proteinaceous molecule, or substitution of one or more amino acids at one or more sites in the proteinaceous molecule. For example, in some embodiments, the variant proteinaceous molecule comprises an addition of one amino acid residue or deletion of one amino acid residue.

[0151] 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.

[0152] The proteinaceous molecules of any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35 may be prepared by mutagenesis of nucleic acids encoding the amino acid sequence of any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35. 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, etal. (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.

[0153] 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: 1-35.

[0154] 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35; any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35; or SEQ ID NO: 1. A "conservative amino acid substitution" is one in which the amino acid residue isreplaced 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] Amide-containing: The residues contain an amide in their side chain, such as glutamine and asparagine.

[0161] Aromatic: The residues contain an aromatic group in their side chain and include phenylalanine, tyrosine and tryptophan.

[0162] This description also characterises 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 a-amino group, as well as the a-carbon. For the purposes of the present invention, proline is not classified as a "small" amino acid unless otherwise specified. Small amino acid residues include glycine, serine, alanine and threonine.

[0163] 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.

[0164] Amino acid residues can be further sub-classified as cyclic or non-cyclic, and aromatic or non-aromatic, self-explanatory classifications with respect to the side chain substituent groups of the residues, and as small or large. The residue is considered small if it contains a total of four carbon atoms or less, inclusive of the carboxyl carbon, provided an additional polar substituent is present; three or less if not. Small amino acid residues are, of course, always non-aromatic. Dependent on their structural properties, amino acid residues may fall in two or more classes. For the naturally-occurring protein amino acids, sub-classification according to this scheme is presented in Table 1 in Section 1 supra.

[0165] 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

[0166] 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).

[0167] 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.

[0168] Accordingly, the present invention also contemplates variants of the proteinaceous molecules of any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, as determined by sequence alignment programs described herein using default parameters. Variants of any one of SEQ ID NOs: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any oneof SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, 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 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: 1-35 and 151-293, or any one of SEQ ID NOs: 1-35, such as any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35, or SEQ ID NO: 1, by at least 1, but by less than 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, III, IV, V or VI. In particular embodiments, the variant proteinaceous molecule of the invention inhibits an activity of ASICla.

[0169] 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.

[0170] In some embodiments, calculations of sequence similarity or sequence identity between sequences are performed as follows:

[0171] 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 acid sequence 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.

[0172] 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 numberof gaps and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0173] 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 Wünsch 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).

[0174] The proteinaceous molecules of the invention may also encompass modified amino acid residues. Modified amino acid residues may include residues with modified side chains, a-methyl amino acids, residues with acetylated N-termini, beta amino acids, and the like.

[0175] Examples of side chain modifications include modifications of amino groups, such as by acetylation with acetic anhydride; acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; amidination with methylacetimidate; carbamoylation of amino groups with cyanate; pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with sodium borohydride; reductive alkylation by reaction with an aldehyde followed by reduction with sodium borohydride; and trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The carboxyl group may be modified by carbodiimide activation through O-acylisourea formation followed by subsequent derivatization, for example, to a corresponding amide. The guanidine group of arginine residues may be modified by formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal. Tryptophan residues may be modified, for example, by alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfonyl halides, or by oxidation with / V-bromosuccinimide. Tyrosine residues may be modified by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.

[0176] Suitable modified arginine residues include, but are not limited to, Nw-carboxymethyl-L-arginine, Nw-carboxyethyl-L-arginine, Na-acetyl-L-arginine, di(phenylglyoxal)-L-arginine, N-methyl-arginine (R(Me)), alpha-methyl-arginine (aMeR),beta-arginine, N'-nitro-L-arginine, N', N"-dimethyl-L-arginine or N, N-dimethylarginine (R(Me2)), N', N"-diethyl-L-arginine, homoarginine (hArg), canavanine (Cav), citrulline (Cit), 2-amino-4-guanidino-butyric acid (Agb), N-phenyl-arginine (R(Ph)), 2-amino-3-guanidinopropionic acid (Agp) and N-benzyl-arginine (R(Bz)).

[0177] 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, a-methyllysine, p-lysine, Na-acetyl-L-lysine, Ne-acetyl-L-lysine, Ne-methyl-L-lysine, Ne-dimethyl-L-lysine and Ne-formyl-L-lysine.

[0178] Representative modified histidine residues include, but are not limited to, 1-methyl-histidine ((1Me)His), N3-methyl-L-histidine, N-methyl-L-histidine, a-methylhistidine, homohistidine and [3-histidine.

[0179] Suitable modified alanine residues include, but are not limited to, N-methylalanine, a-methylalanine, p-alanine (bA), Na-acetyl-L-alanine, 2-aminoisobutyric acid (Alb), homoalanine, cyclohexylalanine (Cha), 2-furylalanine (2Fur) and p-homoalanine.

[0180] Suitable modified leucine residues include, but are not limited to, a-methylleucine, N-methylleucine (NMeLeu), p-leucine, t-butylglycine, homoleucine, No-acetyl-L-leucine, tert-leucine, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba) and p-homoleucine.

[0181] Suitable modified glutamine residues include, but are not limited to, a-methylglutamine, Na-methylglutamine, NY-methylglutamine, p-glutamine, homoglutamine, Na-acetyl-L-glutamine and p-homoglutamine.

[0182] Exemplary modified asparagine residues include Np-methyl-Np-methoxy-asparagine, a-methylasparagine, Na-methylasparagine, Np-methylasparagine, p-asparagine, homoasparagine, Na-acetyl-L-asparagine and p-homoasparagine.

[0183] Modified glycine residues include, but are not limited to, N-methylglycine, P-homoglycine, sarcosine (Sar), and Na-acetyl-L-glycine.

[0184] Modified serine residues may include N-methylserine (NMeSer), a-methylserine, p-serine, Na-acetyl-L-serine, isoserine, O-methylserine, homoserine and p-homoserine.

[0185] Exemplary modified threonine residues include N-methylthreonine, a-methylthreonine, p-threonine, Na-acetyl-L-threonine, O-methylthreonine, homothreonine and p-homothreonine.

[0186] Exemplary modified proline residues include p-proline, Na-acetyl-L-proline, 4-phenoxy-pyrrolidine-2-carboxylic acid, 5,5-dimethylpyrrolidine-2-carboxylicacid or 5,5-dimethyl-proline (5Me2Pro), 5-methylpyrrolidine-2-carboxylic acid or 5-methyl-proline (5MePro), homoproline, hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), g-homoproline, 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4-(chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Ide) and 4-trifluoromethyl-proline (4CF3Pro).

[0187] Suitable modified isoleucine residues include, but are not limited to, a-methylisoleucine, N-methylisoleucine, p-isoleucine, homoisoleucine, Na-acetyl-L-isoleucine, p-methylisoleucine and p-homoisoleucine.

[0188] Modified valine residues may include, but are not limited to, norvaline, a-methylvaline, N-methylvaline, g-valine, g-homovaline and Na-acetyl-L-valine.

[0189] Suitable modified phenylalanine residues include, but are not limited to, a-methylphenylalanine, N-methyl-phenylalanine, g-phenylalanine, g-methyl phenylalanine, p,p-dimethyl phenylalanine, g-hydroxyphenylalanine, homophenylalanine, Na-acetyl-L-phenylalanine, g-homophenylalanine, 4-fluoro-L-phenylalanine, 4-methyl-L-phenylalanine, 3,3-diphenyl-L-alanine, 4,4'-biphenyl-L-alanine, 1-naphthyl-L-alanine, 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-tert-butyl-phenylalanine, 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), 4-carboxy-phenylananine ((4C00H)Phe), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe) and pentafluoro-phenylalanine ((F5)Phe).

[0190] Exemplary modified tyrosine residues include a-methyltyrosine, N-methyltyrosine, g-tyrosine, g-methyltyrosine, p,p-dimethyltyrosine, g-hydroxytyrosine, homotyrosine (hTyr), O-methylhomotyrosine, Na-acetyl-L-tyrosine, O-methyltyrosine (Tyr(OMe)), O-ethyltyrosine, m-tyrosine, 3,4-dihydroxyphenylalanine (Dopa), g-homotyrosine, D-tyrosine, 3-fluoro-tyrosine ((3F)Tyr), 2,6-dimethyl-tyrosine (dmTyr), 2-fluoro-tyrosine ((2F)Tyr), 3,5-difluorotyrosine (dFTyr) and phosphotyrosine (Tyr(PO)).

[0191] Suitable modified tryptophan residues include, but are not limited to, a-methyltryptophan, N-methyltryptophan, g-tryptophan, g-methyltryptophan, homotryptophan, N-formyl-tryptophan, 2-methyltryptophan, Na-acetyl-L-tryptophan and g-homotryptophan.

[0192] Suitable modified glutamic acid residues include, but are not limited to, N-methylglutamic acid, a-methylglutamic acid, p-glutamic acid, Na-acetyl-L-glutamic acid, glutamic acid y-methyl ester, y-carboxy glutamic acid, homoglutamic acid (hGlu), isoglutamic acid (iE) and p-homoglutamic acid.

[0193] Suitable modified aspartic acid residues include, but are not limited to, N-methylaspartic acid (NMeAsp), a-methylaspartic acid, p-aspartic acid, Na-acetyl-L-aspartic acid, aspartic acid p-methyl ester and p-homoaspartic acid.

[0194] 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.

[0195] 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

[0196] Structures of some of the unnatural amino acids recited herein are provided in Table 4.TABLE 4STRUCTURES OF PARTICULAR UNNATURAL AMINO ACIDS

[0197] Also encompassed are amino acid residues with stabilising moieties attached to the side chain. Suitable stabilising moieties are discussed elsewhere herein.

[0198] 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 (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) comprise a stabilising moiety. The stabilising moiety may be conjugated at any point on the proteinaceous molecule. The stabilising 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 moieties which may be used.

[0199] Exemplary stabilising 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 Psubunit 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 organic molecule such as 6-(4-(4-iodophenyl)butanamido)hexanoate (Albutag); an Fc region or single chain Fc region comprising a functional neonatal Fc receptor (FcRn) binding partner comprising an Fc domain, variant, or fragment thereof; a polymer such as a PEG, a polysialic acid or a derivative thereof, hydroxyethyl starch or a derivative thereof, ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran or polyvinyl alcohol; a glycan or polysaccharide; a lipid moiety; or a capping moiety, including an acetyl group, pyroglutamate or an amino group.

[0200] In some embodiments, the stabilising moiety is a PEG. The PEG can be of any molecular weight and can be branched or unbranched. In one embodiment, the molecular weight is between about 1 kDa and about 100 kDa, such as about 1 kDa to about 50 kDa, about 1 kDa to about 40 kDa, about 1 kDa to about 20 kDa, about 1 kDa to about 10 kDa or about 1 kDa to about 5 kDa. Other sizes can be used, depending on the desired profile (e.g. the duration of sustained release desired, the effects, if any on biological activity, the ease in handling and other known effects of the PEG to a peptide or protein). For example, the PEG can have an average molecular weight of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 kDa. In some embodiments, the PEG has an average molecular weight of about 5, 10, 20 or 40 kDa, such as 5 or 10 kDa.

[0201] The PEG may, in some embodiments, comprise between 1 and 50 ethylene glycol units (and all integer units in between), such as about 1 to 40, about 1 to 30, about 1 to 20, about 2 to 15, about 2 to 12, about 20 to 40 or about 30 to 40 ethylene glycol units. In some embodiments, the PEG comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 ethylene glycol units. In some embodiments, the PEG comprises 12 ethylene glycol units (i.e. is PEG12). When the PEG is at the N-terminus of the proteinaceous molecule or attached to a side chain of an amino acid residue, the PEG is, in some embodiments, represented by the Formula: CH3-O-[(CH2)2O]n-(CH2)2-CO-; wherein n is an integer from 1 to 50 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50. In some embodiments, such as when the PEG is at the C-terminus of the proteinaceous molecule or attached to a side chain of an amino acid residue, the PEG is represented by the Formula: -NH-[(CH2)2O]n-(CH2)2-COOH, -NH-[(CH2)2O]n-(CH2)2-CONH2 or -C(O)-[(CH2)2O]n-(CH2)2-COOH, wherein n is an integer from 1 to 50 (and all integers in between); especially 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50.

[0202] For example, the structure of PEG12 is as follows:

[0203] The structure of PEG11A is as follows:

[0204] In some embodiments, the stabilising moiety is a lipid moiety. The lipid moiety may be a lipid moiety comprising 6 to 24 carbon atoms in the alkyl chain (and all integers therebetween); such as from about 14 to 20 carbon atoms. For example, the lipid moiety may be hexanoyl (Cs), heptanoyl (C?), octanoyl (Cs), nonanoyl (C9), decanoyl (C10), undecanoyl (CH), dodecanoyl (C12), tridecanoyl (C13), tetradecanoyl (C14), pentadecanoyl (C15), hexadecanoyl (Cis) (also referred to herein as palmitoyl or " Pal"), heptadecanoyl (C17) or octadecanoyl (Cis). In some embodiments, the lipid moiety is derived from a diacid. For example, in some embodiments, the lipid moiety is -C(O)-C4-C22 alkyl-COOH; especially -C(O)-C4alkyl-COOH, -C(O)-C5alkyl-COOH, -C(O)-Ce alkyl-COOH, -C(O)-C7alkyl-COOH, -C(O)-Cs alkyl-COOH, -C(O)-C9alkyl-COOH, -C(0)-Cio alkyl-COOH, -C(O)-Cn alkyl-COOH, -C(O)-Ci2 alkyl-COOH, -C(O)-Ci3alkyl-COOH, -C(O)-Ci4 alkyl-COOH, -C(O)-Ci5 alkyl-COOH or -C(O)-Cis alkyl-COOH (also referred to herein as C18A).

[0205] The stabilising moiety may be, for example, conjugated to the N-terminal or C-terminal amino acid residue of the proteinaceous molecule or through a side chain of an amino acid residue, including through the amine of the side chain of a basic amino acid residue, such as K. In some embodiments, the stabilising moiety is attached through the C-terminal amino acid residue, such as through the amino group of the C-terminal amide or the carboxylic acid of the C-terminal acid (e.g. via the formation of an amide bond), or through the amino group of a basic amino acid residue side chain (e.g. the e-amino group of a lysine side chain). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue (e.g. wherein Xs or X26 is K), with a stabilising moiety conjugated to the side chain of the lysine residue.

[0206] 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.

[0207] While in some embodiments, the stabilising moiety is directly conjugated to the side chain of an amino acid, the invention also contemplates embodiments wherein the stabilising moiety is conjugated indirectly (e.g. via an intervening spacer) to the side chain of an amino acid of the proteinaceous molecule of the invention(e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35or a variant thereof). For example, in some embodiments, the stabilising moiety is conjugated via an intervening spacer. Suitable spacers include any atom, molecule or group of molecules which places the proteinaceous molecule and stabilising moiety in a desirable configuration. In some embodiments, the spacer places the proteinaceous molecule and stabilising moiety in a configuration which does not substantially reduce the efficacy of the proteinaceous molecule (i.e. the ability to inhibit ASIC activity). Suitable spacers include, but are not limited to, a peptide, such as a peptide of 2-10 residues in length (e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues, optionally wherein the amino acid residues are other than Cys or a modified form thereof, penicillamine or 5-aminovaleric acid); a small molecule, such as a C1-20 alkyl chain; an amino acid residue; a polymer, including a PEG; and the like. In some embodiments, longer or shorter spacing moieties may be required. A skilled person will be well aware of suitable spacers, and methods of introducing such spacers.

[0208] When present, a capping moiety, such as an 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.

[0209] In some embodiments, the proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: l-35or a variant thereof) does not comprise a stabilising moiety.

[0210] The proteinaceous molecule (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) may, in some embodiments, 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: 36), TFFYGGSRGKRNNFKTEEY [Angiopep2 (ANG); SEQ ID NO: 37]; RRWRRWWRRWWRRWRR(W / R; SEQ ID NO: 38), CWKis (AlkCWKis; SEQ ID NO: 39), KisWCCWKis (Di-CWKis; SEQ ID NO: 40), WTLNSAGYLLGKINLKALAALAKKIL (Transportan; SEQ ID NO: 41), GLFEALEELWEAK (DipaLytic; SEQ ID NO: 42), KieGGCRGDMFGCAKieRGD (KieRGD; SEQ ID NO: 43), KieGGCMFGCGG (Pl; SEQ ID NO: 44), KielCRRARGDNPDDRCT (P2; SEQ ID NO: 45), KKWKMRRNQFWVKVQRbAK (B) bA (P3; SEQ ID NO: 46), VAYISRGGVSTYYSDTVKGRFTRQKYNKRA (P3a; SEQ ID NO: 47), IGRIDPANGKTKYAPKFQDKATRSNYYGNSPS (P9.3; SEQ ID NO: 48), KETWWETWWTEWSQPKKKRKV (Pep-1; SEQ ID NO: 49), PLAEIDGIELTY (Plae; SEQ ID NO: 50), KieGGPLAEIDGIELGA (Kplae; SEQ ID NO: 51), KieGGPLAEIDGIELCA (cKplae; SEQ ID NO: 52), GALFLGFLGGAAGSTMGAWSQPKSKRKV (MGP; SEQ ID NO: 53), WEAK(LAKA)2-LAKH(LAKA)2LKAC (HA2; SEQ ID NO: 54), (LARL)6NHCH3(LARL4&; SEQ ID NO: 55), KLLKLLLKLWLLKLLL (Hel-11-7; SEQ ID NO: 56), (KKKK)2GGC (KK; SEQ ID NO: 57), (KWKK)2GCC (KWK; SEQ ID NO: 58), (RWRR)2GGC (RWR; SEQ ID NO: 59), PKKKRKV (SV40 NLS7; SEQ ID NO: 60), PEVKKKRKPEYP (NLS12; SEQ ID NO: 61), TPPKKKRKVEDP (NLS12a; SEQ ID NO: 62), GGGGPKKKRKVGG (SV40 NLS13; SEQ ID NO: 63), GGGFSTSLRARKA (AV NLS13; SEQ ID NO: 64), CKKKKKKSEDEYPYVPN (AV RME NLS17; SEQ ID NO: 65), CKKKKKKKSEDEYPYVPNFSTSLRARKA (AV FP NLS28; SEQ ID NO: 66), LVRKKRKTEEESPLKDKDAKKSKQE (SV40 N1 NLS24; SEQ ID NO: 67), and KgK^KsGGKs (Loligomer; SEQ ID NO: 68); 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: 69); the Drosophila melanogaster Antennapedia domain Antp (amino acids 43-58), RQIKIWFQNRRMKWKK (SEQ ID NO: 70); Buforin II, TRSSRAGLQFPVGRVHRLLRK (SEQ ID NO: 71); hClock-(amino acids 35-47) (human Clock protein DNA-binding peptide), KRVSRNKSEKKRR (SEQ ID NO: 72); MAP (model amphipathic peptide), KLALKLALKALKAALKLA (SEQ ID NO: 73); K-FGF, AAVALLPAVLLALLAP (SEQ ID NO: 74); Ku70-derived peptide, comprising a peptide selected from the group comprising VPMLKE (SEQ ID NO: 75), VPMLK (SEQ ID NO: 76), PMLKE (SEQ ID NO: 77) or PMLK (SEQ ID NO: 78); Prion, Mouse Prpe (amino acids 1-28), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO: 79); pVEC, LLIILRRRIRKQAHAHSK (SEQ ID NO: 80); Pep-I, KETWWETWWTEWSQPKKKRKV (SEQ ID NO: 81); SynBI, RGGRLSYSRRRFSTSTGR (SEQ ID NO: 82); Transportan, GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 83); Transportan-10, AGYLLGKINLKALAALAKKIL (SEQ ID NO: 84); CADY, Ac-GLWRALWRLLRSLWRLLWRA-cysteamide (SEQ ID NO: 85); Pep-7, SDLWEMMMVSLACQY (SEQ ID NO: 86); HN-1, TSPLNIHNGQKL (SEQ ID NO: 87); VT5, DPKGDPKGVTVTVTVTVTGKGDPKPD (SEQ ID NO: 88); pISL, RVIRVWFQNKRCKDKK (SEQ ID NO: 89); 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: 90),KLFMALVAFLRFLT (PepH2; SEQ ID NO: 91), AGILKRW (PepH3; SEQ ID NO: 92) or KSKAINVLRGFRKEIGRMLNILN (PepH4; SEQ ID NO: 93); RKKRRRESRKKRRRES (DPV3; SEQ ID NO: 94); GRPRESGKKRKRKRLKP (DPV6; SEQ ID NO: 95); RQIKIWFQNRRMKWKK (penetratin; SEQ ID NO: 96); GRRRRRRRRRPPQ (R9-TAT; SEQ ID NO: 97); RVRVFVVHIPRLT (ARF 19-31; SEQ ID NO: 98); VSALK (Bip4; SEQ ID NO: 99); GIGAVLKVLTTGLPALISWIKRKRQQ (Melittin; SEQ ID NO: 100); or HGLASTLTRWAHYNALIRAF (gH625; SEQ ID NO: 101).

[0211] 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 side chain (i.e. the e-amino group). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue with a cell-penetrating peptide conjugated to the side chain of the lysine residue.

[0212] 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 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, such as wherein the amino acid residues are other than Cys or a modified form thereof, penicillamine or 5-aminovaleric acid). In some embodiments, the proteinaceous molecule does not comprise a cell penetrating moiety.

[0213] In some embodiments, the proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: l-35or a variant thereof) comprises a moiety that enhances or assists penetration through the blood brain barrier. For example, in some embodiments, the proteinaceous molecule further comprises a moiety that binds to a receptor expressed on the blood brain barrier (e.g. blood brain barrier endothelia), such as a transferrin receptor, insulin receptor, CD98hc, glucose transporter 1, basigin (CD147), leptin receptor, lipoprotein receptor or insulin-like growth factor 1 receptor. The moiety may be, for example, a polypeptide, protein, antibody, Fc domain, small molecule, genetic molecules such as RNA, DNA and mimetics and chemical analogues thereof, or a combination thereof. In some embodiments, the moiety that enhances penetration through the blood brain barrier is a transferrin receptor binding polypeptide or Fc polypeptide disclosed in US 20210130485 Al, US 20230235072 Al, US 20190249155 Al or US 20240024432 Al, the entire contents of which are incorporated herein by reference.

[0214] The moiety that enhances penetration through the blood brain barrier may be conjugated to the N-terminal or C-terminal amino acid residue of the proteinaceousmolecule 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 side chain (i.e. the e-amino group). For example, in some embodiments, the proteinaceous molecule has a C-terminal lysine residue with a moiety that enhances penetration through the blood brain barrier conjugated to the side chain of the lysine residue.

[0215] The moiety that enhances penetration through the blood brain barrier may be directly attached to the proteinaceous molecule or may be attached using a suitable linker, such as a PEG moiety 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, such as wherein the amino acid residues are other than Cys or a modified form thereof, penicillamine or 5-aminovaleric acid). In some embodiments, the proteinaceous molecule does not comprise a moiety that enhances penetration through the blood brain barrier.

[0216] The proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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.

[0217] The proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) may be in the form of a salt or prodrug. The salt of the proteinaceous molecule of the invention is preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention.

[0218] The proteinaceous molecule may be in crystalline form and / or in the form of a solvate, for example, a hydrate. Solvation may be performed using methods known in the art.

[0219] 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, suchas the proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by any one of Formulae I and III to VI or any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof as described herein.

[0220] 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.

[0221] Although the nucleic acid molecules are typically isolated, in some embodiments the nucleic acid molecules may be integrated into, ligated to, or otherwise fused or associated with other genetic molecules, such as an expression vector. Generally an expression vector includes transcriptional and translational regulatory nucleic acid operably linked to the polynucleotide sequence. Accordingly, in another aspect of the invention, there is provided an expression vector comprising a polynucleotide sequence that encodes a proteinaceous molecule of the invention, such as a proteinaceous molecule comprising, consisting or consisting essentially of a sequence represented by any one of Formulae I and III to VI or any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 as described herein.

[0222] In some embodiments, the proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: l-35or a variant thereof) 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.

[0223] The invention contemplates recombinantly producing the proteinaceous molecule 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).

[0224] 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 terminatorsequence, 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 etal. (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.

[0225] 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.

[0226] 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.

[0227] 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 may be 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, infectionmembrane 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).

[0228] The proteinaceous molecules (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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, thioether bonds may be formed using N, N-diisopropylethylamine (DIPEA), followed by acidification in trifluoroacetic acid (TFA). Lactam (amide) bonds may be formed using DIPEA and a coupling agent such as benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate chloroacetic acid.

[0229] In some embodiments, the proteinaceous molecules of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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 Common (Camb), 2 ~. -. 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), benzotriazol-l-yloxytripyrrol id I nophosphonium hexafluorophosphate chloroacetic acid, PyAOP (7-azabenzotriazol-l-yloxy tris pyrrolidino phosphonium hexafluorophosphate), AOP (7-azabenzotriazol-l-yloxy-tris-dimethyl aminophosphonium hexafluorophosphate), HBTU (O-(benzotriazol-l-yl)-l, 1,3,3-tetramethyl uronium hexafluorophosphate), TBTU (O-(benzotriazol-l-yl)-l, 1,3,3-tetramethyl uronium tetrafluoroborate), HATU (O-(7-azabenzotriazol-l-yl)-l, 1,3,3-tetramethyl uronium hexafluorophosphate), HAPyU (O-(7-azabenzotriazol-l-yl)-l, 1,3,3-tetra methylene uronium hexafluorophosphate), HAPipU (O-(7-azabenzotriazol-l-yl)-1,1,3,3-pentamethylene uranium hexafluorophosphate), DCC (N, N'-dicyclohexylcarbodiimide), DIC ( / V, / V'-diisopropylcarbodiimide), and / or EDC [l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride], optionally in the presence of DIPEA. 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.

[0230] In some embodiments, the proteinaceous molecules of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) are prepared using recombinant DNA techniques. For example, the proteinaceous molecules 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. Formation of intramolecular linkages may be achieved chemically following expression of the peptide. This may be preceded by a reductive step to provide the linear peptide. Suitable conditions for reduction of the peptide and linkage formation will be readily determined by a person skilled in the art.4. Compositions

[0231] The proteinaceous molecules are also useful in compositions for treating or inhibiting the development of a condition associated with ASIC activity, such as a neurological condition, neuronal damage, ischaemia including cardiac and neuronal 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 bein the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises, consists or consists essentially of a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) and a pharmaceutically acceptable carrier or diluent.

[0232] The proteinaceous molecule may be formulated into the pharmaceutical composition as a neutral or salt form.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] Identification of preferred pH ranges and suitable excipients, such as antioxidants, is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press). Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane(Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers. Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulfite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] Pharmaceutical formulations for parenteral administration include aqueous solutions of the composition in water-soluble form. Additionally, suspensions of the proteinaceous molecule may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodiumcarboxymethyl 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.

[0241] 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.

[0242] Pharmaceutical preparations for oral use can be obtained by combining the proteinaceous molecules with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilising processes.

[0243] 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.

[0244] Pharmaceuticals which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilisers. In soft capsules, the active compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilisers may be added.

[0245] 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).

[0246] The proteinaceous molecules may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil-or gel-based formulations.

[0247] 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.

[0248] 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.

[0249] It is advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. The determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0250] 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.

[0251] Accordingly, in another aspect of the invention, there is provided a composition comprising a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) and an anti-inflammatory agent, anticoagulant, thrombolytic agent, antiplatelet agent, antihypertensive agent, diuretic or a treatment for a neurological condition.

[0252] 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.

[0253] 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.

[0254] Representative thrombolytic agents include tissue plasminogen activator (e.g. alteplase, reteplase, tenecteplase and anistreplase), streptokinase and urokinase.

[0255] Suitable antiplatelet agents include acetylsalicylic acid, clopidogrel, dipyridamole, cangrelor, prasugrel, ticagrelor, ticlopidine, apciximab, eptifibatide, tirofiban, triflusal, cilostazol, vorapaxar, terutroban, ifetroban, naproxen and picotamide.

[0256] Suitable antihypertensive agents include, but are not limited to, diuretics (e.g. indapamide, bendroflumethiazide, amiloride and spironolactone), angiotensinconverting enzyme inhibitors (e.g. captopril, enalapril, lisinopril, perindopril and ramipril),calcium channel blockers (e.g. amlodipine, felodipine, nifedipine, diltiazem and verapamil), beta blockers (e.g. atenolol, metoprolol and bisoprolol), alpha blockers (e.g. doxazosin) and angiotensin-2 receptor blockers (e.g. candesartan, irbesartan, losartan, valsartan and olmesartan).

[0257] 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.

[0258] The present invention also contemplates concurrent administration with a treatment for a neurological condition, such as Parkinson's disease, multiple sclerosis or Alzheimer's disease, representative examples of which include levodopa (optionally with carbidopa), pramipexole, apomorphine, selegiline, rasagiline, safinamide, entacapone, opicapone, tolcapone, benztropine, trihexylphenidyl, amantadine, istradefyl line, nuplazid, corticosteroids such as prednisone and methylprednisolone, glatiramer acetate, ofatumumab, interferon beta (e.g. interferon beta-la), teriflunomide, dimethyl fumarate, diroximel fumarate, monomethyl fumarate, fingolimod, siponimod, ozanimod, ponesimod, cladribine, natalizumab, ocrelizumab, alemtuzumab, donepezil, galantamine, rivastigmine, memantine, aducanumab, lecanemab, tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, olanzapine, aripiprazole, levitiracetam, clonazepam, citalopram, escitalopram, fluoxetine, sertraline, quetiapine, olanzapine, divalproex, carbamazepine and lamotrigine.

[0259] Ranolazine may also be administered concurrently with the proteinaceous molecule of the invention.

[0260] 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).

[0261] 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.

[0262] The present invention also contemplates the use of the proteinaceous molecules of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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 (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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.

[0263] 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.

[0264] In some embodiments, the composition has a temperature in the range of from 0-4 °C.5. Methods of Use

[0265] 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 associatedwith ASIC activity, especially ASICla activity, such as a neurological condition, neuronal damage, ischaemia including cardiac and neuronal ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, an inflammatory condition or retinal detachment; as well as for inhibiting damage to an organ during organ transplantation. Accordingly, a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) for use in therapy is contemplated.

[0266] In another aspect, there is provided a method of inhibiting an activity of an ASIC, comprising, consisting or consisting essentially of contacting the ASIC with a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof). 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.

[0267] In particular embodiments, the ASIC is ASICla.

[0268] 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.

[0269] The methods and uses may comprise contacting a cell expressing ASIC with a proteinaceous molecule of the invention. Suitable cells include, but are not limited to, a neuron (e.g. a sensory neuron or a retinal ganglion cell), cardiomyocyte, microglia, astrocyte, oligodendrocyte, macrophage, T cell, dendritic cell, epithelial cell (e.g. renal tubular epithelial cell), endothelial cell (e.g. cardiac endothelial cell, pulmonary arterial endothelial cell), fibroblast, pulmonary arterial smooth muscle cell and osteoblast.

[0270] In particular embodiments, the cell is a cell of the brain, kidney, heart, eye, lung, spinal cord or bone.

[0271] Also provided is a method of antagonising an ASIC, preferably ASICla, comprising, consisting or consisting essentially of contacting the ASIC with a proteinaceous molecule of the invention.

[0272] In another aspect, there is provided a method of treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition,comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof). Also provided is a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effective treatment or inhibition of the development of the condition.

[0273] In particular embodiments, the ASIC is ASICla.

[0274] In some embodiments, inhibiting an ASIC effects treatment or inhibition of the development of the condition.

[0275] 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 (e.g. arthritis), muscle crush injury, central retinal artery occlusion, invertebral disc disease 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, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury, retinal detachment, arthritis and invertebral disc disease. In some embodiments, the condition is selected from the group consisting of a neurological condition, neuronal damage (e.g. infarction), ischaemia, pain, ischaemia-reperfusion injury, a cancer, chronic kidney disease, acute kidney injury and retinal detachment; especially a neurological condition, ischaemia, pain or ischaemia-reperfusion injury.

[0276] 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.

[0277] While it is contemplated that the proteinaceous molecules will be useful for the treatment of both ischaemic and haemorrhagic stroke, in particular embodiments, the stroke is an ischaemic stroke.

[0278] In some embodiments, the condition is ischaemia, such as neuronal, ocular (e.g. acute retinal ischaemia), renal or cardiac ischaemia.

[0279] 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.

[0280] 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.

[0281] 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).

[0282] 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 artery bypass graft (CABG) surgery or transcatheter aortic valve insertion (TAVI; also known as transcatheter aortic valve replacement).

[0283] 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.

[0284] 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.

[0285] In alternative embodiments, the condition is pain. The pain may be nociceptive, inflammatory or neuropathic pain.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] Other types of pain in which administration of the molecules of the invention may be useful include, but are not limited to, pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis or pyomyositis; heart or vascular pain, including pain resulting from angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma or skeletal muscle ischaemia; head pain including migraine, cluster headache, tension-type headache, mixed headache or headache associated with vascular disorders; breakthrough pain; or orofacial pain, including dental pain, otic pain, burning mouth syndrome or temporomandibular myofascial pain. In some embodiments, the pain is migraine pain.

[0290] The use of the proteinaceous molecule of the invention for treating or inhibiting the development of 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.

[0291] In some embodiments, the condition is an inflammatory condition, for example asthma, arthritis (e.g. rheumatoid arthritis or osteoarthritis, especially rheumatoid arthritis) or chronic rhinosinusitis.

[0292] Accordingly, in another aspect, there is provided a method of treating or at least partially inhibiting the development of an inflammatory condition in a subject, comprising, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof). In a further aspect, there is provided a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of an inflammatory condition in a subject, a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of an inflammatory condition in a subject, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of an inflammatory condition in a subject.

[0293] Suitable inflammatory conditions are as described supra. In some embodiments, the inflammatory condition is asthma, arthritis or chronic rhinosinusitis. In some embodiments, the inflammatory condition is arthritis, such as rheumatoid arthritis or osteoarthritis. In some embodiments, the inflammatory condition is rheumatoid arthritis. In some embodiments, the inflammatory condition is osteoarthritis.

[0294] In a still further aspect, there is provided a method of treating or at least partially inhibiting the development of a neurological condition in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof). In another aspect, there is provided a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of a neurological condition in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibiting the development of a neurological condition in a subject, and a use of a proteinaceous molecule of the invention in the manufacture of a medicament for treating or at least partially inhibiting the development of a neurological condition in a subject.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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).

[0299] Also provided herein is a method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof). 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.

[0300] Suitable types of ischaemia are as discussed supra.

[0301] The inventors have conceived that the proteinaceous molecule of the invention (e.g. of Formula Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) may be useful for inhibiting the development of ischaemic damage. As such, in a further aspect, there is provided a method of treating or at least partially inhibiting the development of ischaemic damage in a subject, comprising, consisting or consisting essentially of administering a proteinaceous molecule of the invention, a use of a proteinaceous molecule of the invention for treating or at least partially inhibiting the development of ischaemic damage in a subject, a proteinaceous molecule of the invention for use in treating or at least partially inhibitingthe 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.

[0302] In some embodiments, the methods and uses comprise at least partially inhibiting the development of ischaemic damage.

[0303] Ischaemic damage includes tissue damage resulting from the ischaemic cascade, especially cell death via apoptosis, necroptosis or necrosis, including infarction.

[0304] 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.

[0305] In some embodiments, the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.

[0306] 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.

[0307] In alternative embodiments, the ischaemic damage is neuronal ischaemic damage; especially ischaemic damage associated with a stroke, traumatic brain injury or perinatal brain injury. In some embodiments, the ischaemic damage is associated with a stroke.

[0308] In particular embodiments, the proteinaceous molecule reduces or minimises the infarct size (i.e. the amount of dead tissue).

[0309] 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.

[0310] The proteinaceous molecule (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) is also proposed to be useful for inhibiting ischaemia-reperfusion injury in a tissue, or the progression thereof. Accordingly, also provided herein, in another aspect, is a method of at least partially inhibiting the development of ischaemia-reperfusion injury in a tissue, comprising, consisting or consisting essentially of contacting the tissue with a proteinaceous molecule of the invention, a use of a proteinaceous molecule of the inventionfor 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 ischaemia-reperfusion 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.

[0311] 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.

[0312] 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).

[0313] 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.

[0314] 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, subcutaneous, intrathecal, intraventricular, intracerebroventricular or intracerebral administration; especially intravenous administration.

[0315] The tissue may be contacted with the proteinaceous molecule prior to the period of ischaemia, after the period of ischaemia but before the return of the blood supply (i.e. before reperfusion), and / or after both the period of ischaemia and reperfusion of the tissue. In particular embodiments, the tissue may be contacted with the proteinaceous molecule prior to the period of ischaemia and may be continued (e.g. continuously or periodically) until after reperfusion of the tissue, or may be contacted with the proteinaceous molecule after the period of ischaemia but prior to reperfusion and may be continued (e.g. continuously or periodically) until after reperfusion of the tissue.

[0316] 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.

[0317] The proteinaceous molecules of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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 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.

[0318] 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.

[0319] 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).

[0320] The organ may be contacted with the proteinaceous molecule by, for example, immersing the tissue in or perfusing the tissue with a liquid comprising the proteinaceous molecule (i.e. in solubilised form). The organ may, in some embodiments, be contacted with the proteinaceous molecule of the invention from when the organ is removed from the donor subject to when the organ is transplanted into the recipient subject. In some embodiments, the organ is contacted with the proteinaceous molecule for a duration in the range of from about 1 hour to about 50 hours (and all integer minutes therebetween); especially about 2 hours to about 36 hours, about 2 hours to about 16 hours, about 4 hours to about 12 hours, about 4 hours to about 8 hours, or about 4 hours to about 6 hours. Accordingly, in some embodiments, the methods and uses are ex vivo methods and uses.

[0321] The proteinaceous molecule may also be administered to the recipient subject following transplantation of the organ, e.g. by intravenous, intrathecal, intraventricular, intracerebroventricular, intranasal, subcutaneous or intracerebral administration; especially intravenous or intranasal administration; more especially intravenous administration as discussed elsewhere herein.

[0322] Also provided herein is a neuroprotective and / or cardioprotective agent comprising a proteinaceous molecule of the invention (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof), and the use of a proteinaceous molecule of the invention for neuroprotection or cardioprotection.

[0323] In some embodiments of any one of the aspects described above, the ASIC is ASICla. In particular embodiments, the ASIC is a human channel, such as hASICla.

[0324] Any one of the methods and uses described herein 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 (e.g. of Formula I, III, IV, V or VI, any one of SEQ ID NOs: 1-35 and 151-293 or any one of SEQ ID NOs: 1-35 or a variant thereof) 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.

[0325] 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 5mg / 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 μg / kg body weight of the subject. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages and frequency of administration are determined by reference to the usual dose and manner of administration of the said ingredients. In particular embodiments, the peptide is administered to a subject in need of such treatment, although the peptide may be administered prophylactically.

[0326] 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.

[0327] 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.

[0328] 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.EMBODIMENTS

[0329] Exemplary embodiments include, but are not limited to:1. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:X1X2RX3X4X5X6X7X8(I)wherein:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)) or 4-chloro-phenylalanine (F(pCI))]; and small amino acid residues including S, A, G, T and modified forms thereof;X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb)];X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip) or a-methyl-proline (aMeP)], and sarcosine (Sar); X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa);X6 is selected from R, canavanine (Cav), a-methyl-arginine (aMeR) and Agb;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)]; and amide containing amino acid residues including N, Q and modified forms thereof; andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. 2-aminoisobutyric acid (Alb)]; P 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; 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.2. The proteinaceous molecule according to embodiment 1, wherein X1is Y, W, F, F(pF), F(pCI), Dopa or S.3. The proteinaceous molecule according to embodiment 1, wherein X1is Y, W, F or Dopa.4. The proteinaceous molecule according to embodiment 1, wherein X1is Y. 5. The proteinaceous molecule according to any one of embodiments 1-4, wherein X2is L, Nle or Chg.6. The proteinaceous molecule according to any one of embodiments 1-4, wherein X2is L or Chg.7. The proteinaceous molecule according to any one of embodiments 1-6, wherein X3is R or Agb.8. The proteinaceous molecule according to any one of embodiments 1-6, wherein X3is R.9. The proteinaceous molecule according to any one of embodiments 1-8, wherein X4is P, Hyp, Aze or Pip.10. The proteinaceous molecule according to any one of embodiments 1-8, wherein X4is P.11. The proteinaceous molecule according to any one of embodiments 1-10, wherein X5is Y or Dopa.12. The proteinaceous molecule according to any one of embodiments 1-10, wherein X5is Y.13. The proteinaceous molecule according to any one of embodiments 1-12, wherein X6is R, aMeR or Cav.14. The proteinaceous molecule according to any one of embodiments 1-12, wherein X6is R.15. The proteinaceous molecule according to any one of embodiments 1-14, wherein X7is C, D, E, hGlu or Q.16. The proteinaceous molecule according to any one of embodiments 1-14, wherein X7is C, E or hGlu.17. The proteinaceous molecule according to any one of embodiments 1-14, wherein X7is C.18. The proteinaceous molecule according to any one of embodiments 1-17, wherein X8is absent or is G, S or Aib.19. The proteinaceous molecule according to any one of embodiments 1-17, wherein X8is absent or is G.20. The proteinaceous molecule according to embodiment 1, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35.21. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:XIX2RX3X4X5X6X7X8(I)wherein:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), O-methyltyrosine (Tyr(OMe)), homotyrosine (hTyr), 4-carboxy-phenylananine ((4COOH)Phe), D-tyrosine (D-Tyr), 3-fluoro-tyrosine ((3F)Tyr), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe), 2,6-dimethyl-tyrosine (dmTyr),pentafluoro-phenylalanine ((F5)Phe) or phosphotyrosine (Tyr(PO))]; small amino acid residues including S, A, G, T and modified forms thereof [e.g. cyclohexylalanine (Cha) or 2-furylalanine (2Fur)]; and basic amino acid residues including H, R, K and modified forms thereof [e.g. 1-methyl-histidine ((1Me)His)];X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba), phenylglycine (Phg) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb), homoarginine (hArg), citrulline (Cit) or N, N-dimethylarginine (R(Me2))]; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 5-methyl-proline (5MePro), 5,5-dimethyl-proline (5Me2Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4-(chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Ide) or 4-trifluoromethyl-proline (4CF3Pro)], sarcosine (Sar), N-methyl-serine (NMeSer), N-methyl-leucine (NMeLeu) and N-methyl-aspartic acid (NMeAsp); X5is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, 3-chloro-tyrosine ((3CI)Tyr), (F5)Phe, 2-fluoro-tyrosine ((2F)Tyr) or 3,5-difluorotyrosine (dFTyr)); Cha; and 2Fur;X6is selected from R, canavanine (Cav), a-methyl-arginine (aMeR), Agb, hArg, 2-amino- 3-(4-guanidinophenyl)propanoic acid (Fgu), N-methylarginine (R(Me)), N-phenyl-arginine (R(Ph)), N-benzyl-arginine (R(Bz)), (4A)Phe, 2-amino-3-guanidinopropionic acid (Agp) and Cit;X7is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)J; amide containing amino acid residues including N, Q and modified forms thereof; small amino acid residues including A, S, G, T and modified forms thereof; 3-aminomethylbenzoic acid (3Amb); 4-aminobutyric acid (4-Abu); D-Cys; and cysteine sulfoxide (Cys(O)); andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. 2-aminoisobutyric acid (Aib), p-alanine (bA)]; P 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 [e.g isoglutamic acid (iE)]; aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; aminohexanoic acid (Ahx); aminooctanoic acid (Aoc); and aminodecanoic acid (Adc).22. The proteinaceous molecule according to embodiment 21, wherein X1is Y, W, F, F(pF), F(pCI), Dopa or S.23. The proteinaceous molecule according to embodiment 21, wherein X1is Y. 24. The proteinaceous molecule according to any one of embodiments 21-23, wherein X2is L or Chg.25. The proteinaceous molecule according to any one of embodiments 21-24, wherein X3 is R.26. The proteinaceous molecule according to any one of embodiments 21-25, wherein X4 is P, Hyp, Aze or Pip.27. The proteinaceous molecule according to any one of embodiments 21-25, wherein X4 is P, Hyp, Aze, Pip, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[Ac])Pro, (4A[Suc])Pro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, 4ChPro, 4PhPro, Thz, Ide or 4CF3Pro.28. The proteinaceous molecule according to any one of embodiments 21-27, wherein X5is Y, (3F)Tyr, (3CI)Tyr, 2Pal, 3Pal, 2Fur, (2F)Tyr or dFTyr.29. The proteinaceous molecule according to any one of embodiments 21-27, wherein X5 is Y.30. The proteinaceous molecule according to any one of embodiments 21-29, wherein X6is R, aMeR or Cav.31. The proteinaceous molecule according to any one of embodiments 21-29, wherein X6is R, Cav, Agb, hArg, Fgu or R(Me).32. The proteinaceous molecule according to any one of embodiments 21-31, wherein X7is C, E, hGlu, Q, 4-Abu or Cys(O).33. The proteinaceous molecule according to any one of embodiments 21-31, wherein X7is C, E or hGlu.34. The proteinaceous molecule according to any one of embodiments 21-33, wherein X8is absent or is G.35. The proteinaceous molecule according to embodiment 21, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35 and 151-293.36. The proteinaceous molecule according to embodiment 20 or embodiment 35, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1, 2, 5, 7, 9, 11, 12, 15, 17, 19, 21, 23-25, 27-29, 31-33 and 35.37. The proteinaceous molecule according to any one of embodiments 1-36, wherein when X? is selected from acidic amino acid residues including D, E and modified forms thereof [e.g. hGlu], amide containing amino acid residues including N, Q and modified forms thereof, small amino acid residues including A, S, G, T and modified forms thereof, 3Amb and 4-Abu, the proteinaceous molecule does not comprise C or a modified form thereof (e.g. D-Cys), penicillamine or 5-aminovaleric acid.38. The proteinaceous molecule according to any one of embodiments 1-37, wherein X7 is C and the proteinaceous molecule comprises a thioether bond between the side chain of the cysteine residue in the X7 position and the N-terminal amine of the amino acid residue in the Xi position.39. The proteinaceous molecule according to any one of embodiments 1-37, wherein X7 is C and the side chain of the cysteine residue in the X7 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the X1 position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X7, and R1is C1-6 alkylene.40. The proteinaceous molecule according to embodiment 39, wherein R1is methylene.41. The proteinaceous molecule according to any one of embodiments 1-37, wherein the proteinaceous molecule comprises a lactam bond.42. The proteinaceous molecule according to embodiment 41, wherein X7 is D, E or hGlu and the proteinaceous molecule comprises a lactam bond between the side chain of the amino acid residue in the X7 position and the N-terminal amine of the amino acid residue in the X1 position.43. The proteinaceous molecule according to any one of embodiments 1-42, wherein the proteinaceous molecule comprises a C-terminal amide.44. The proteinaceous molecule according to any one of embodiments 1-37, wherein the proteinaceous molecule is cyclized through N-to-C cyclisation.45. A composition comprising, consisting or consisting essentially of a proteinaceous molecule according to any one of embodiments 1-44 and a pharmaceutically acceptable carrier or diluent.46. A proteinaceous molecule according to any one of embodiments 1-44 for use in therapy.47. 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 1-44.48. The method according to embodiment 47, wherein the ASIC is ASICla.49. 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 1-44.50. The method according to embodiment 49, 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, retinal detachment, arthritis and invertebral disc disease.51. The method according to embodiment 50, 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.52. The method according to embodiment 51, wherein the neurological condition is stroke.53. The method according to embodiment 50, wherein the ischaemia is neuronal, ocular, renal or cardiac ischaemia.54. The method according to embodiment 51, wherein the ocular ischaemia is acute retinal ischaemia.55. The method according to embodiment 50, wherein the cancer is a glioblastoma.56. The method according to embodiment 50, wherein the ischaemia-reperfusion injury is renal ischaemia-reperfusion injury.57. 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 1-44.58. The method according to embodiment 57, 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.59. The method according to embodiment 58, wherein the neurological condition is stroke.60. 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 1-44.61. 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 1-44.62. The method according to embodiment 61, wherein the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.63. The method according to embodiment 62, wherein the ischaemic damage is cardiac ischaemic damage.64. The method according to embodiment 61, wherein the ischaemic damage is associated with a myocardial infarction.65. The method according to embodiment 62, wherein the ischaemic damage is neuronal ischaemic damage.66. The method according to embodiment 61, wherein the ischaemic damage is associated with a stroke, traumatic brain injury or perinatal brain injury.67. The method according to embodiment 66, wherein the ischaemic damage is associated with a stroke.68. 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 1-44.69. The method according to embodiment 68, wherein the tissue is an organ transplant.70. The method according to embodiment 68 or embodiment 69, wherein the tissue is a heart, lung or kidney.71. The method according to embodiment 70, wherein the tissue is a heart.72. 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 1-44.73. The method according to embodiment 72, wherein the organ is a heart, lung or kidney.74. The method according to embodiment 73, wherein the organ is a heart.75. The method according to any one of embodiments 72-74, wherein the damage is ischaemic damage.76. A method of treating or at least partially inhibiting the development of an inflammatory condition in a subject, comprising administering a proteinaceous molecule according to any one of embodiments 1-44.77. The method according to embodiment 76, wherein the inflammatory condition is arthritis.78. The method according to embodiment 77, wherein the arthritis is rheumatoid arthritis or osteoarthritis.

[0330] 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 EXAMPLE 1 - SYNTHESIS OF THIOETHER-CYCLISED IB445 AND ANALOGUES THEREOF Materials and Methods

[0331] Linear IB445 (CICH2C(O)NH-YLRRPYRCG-NH2; SEQ ID NO: 102) was prepared via solid-phase peptide synthesis (SPPS) and then cyclised. IB445 was synthesised on a OEM Liberty Blue automated microwave peptide synthesiser (OEM Corporation, Charlotte, North Carolina, USA) using Rink Amide 4-methylbenzhydrylamine (MBHA) resin (CEM) and standard fluorenylmethyloxycarbonyl (Fmoc)-protected amino acid building blocks. During assembly, each amino acid (AA) attachment cycle was performed as following: The resin was treated with a solution of Fmoc-AA-OH (5 eq.), N, N'-diisopropylcarbodiimide (DIC) (10 eq.) and Oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) (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.), DIC (5 eq.) and Oxyma (5 eq.) in DMF for 20 minutes. After that, the resin was washed with DMF, followed by dichloromethane (DCM) and dried under vacuum.

[0332] The resin was then treated with a solution of TFA:triisopropylsilane: 3,6-dioxa-l,8-octanedithiol:water (10:0.4:0.2:0.4; 10 mL per 0.1 mmol synthesis scale) and agitated at room temperature for 2 hours. The resin was then filtered using a stream of nitrogen to remove all liquid from resin. The filtrate was cooled on ice before adding cold tert-butylmethyl ether (4-5-fold in volume). The precipitate was separated by centrifugation, redissolved in 50% acetonitrile and freeze-dried.Thioether Cyclisation

[0333] The crude linear peptide was dissolved in 50% acetonitrile (at 0.5-1 mg / mL concentration) and combined with DIPEA (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

[0334] IB445 (LCH2C(O)NH- YLRRPYRCG-NH2; SEQ ID NO: 103; refer to Table 5) 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

[0335] IB445 purity and identity were evaluated via HPLC-mass spectrometric (LC-MS) analysis on a Shimadzu LCMS-2020 System (Shimadzu Corporation, Kyoto, Japan) using a Phenomenex C18 Luna column (Phenomenex, Torrance, California, USA) and a Shimadzu LCMS-2020 mass spectrometer (Shimadzu Corporation, Kyoto, Japan). The mobile phases were 0.05% TFA in water (buffer A) and 90% acetonitrile in water / 0.05% TFA (buffer B), and the peptide was eluted using a gradient of 10-36% buffer B over 13 minutes at a flow rate of 0.5 mL / min. Under these conditions, the mass spectrum of IB445 displayed a mixture of m / z adduct ions consisting of [M+xH]+x.Other analogues

[0336] The other thioether cyclised peptides in Table 5 were prepared using a similar procedure. In some cases, the DIC / Oxyma coupling step was alternatively performed at 50 °C for 30 minutes, yielding similar results. For peptides containing Cav or unprotected tyrosine side chains, the DIC / Oxyma couplings were carried out for 1-2 hours without microwave heating. Additionally, when certain amino acids were available only in limited quantities, their coupling was performed outside the peptide synthesiser by incubating the resin with Fmoc-protected amino acid (1.5-2.0 eq.), HATU (1.5-2.0 eq.), and DIPEA (4.0 eq.) in DMF for 4-20 hours.

[0337] The C-terminal acid peptides (refer to Table 5) were synthesised using the same microwave-assisted solid-phase synthesis procedure as described above for IB445 but assembled on a preloaded-Wang resin (CEM). SCP254 and SCP255 were assembled by manually adding Fmoc-Gly-OH (4 eq.) to 2-chlorotrityl chloride resin in the presence of 16 eq. DIPEA in DMF. The reaction was left at room temperature for 30 minutes to 1 hour before capping unreacted Cl. The remainder of the synthesis of these peptides was conducted manually at room temperature using an alternative coupling protocol with Fmoc-protected amino acid (4-5 eq.), HATU (4-5 eq.), and DIPEA (8-10 eq.) in DMF for 0.5-lh followed by Fmoc-removal with 20% piperidine in DMF at room temperature.

[0338] The sulfoxide bridged peptides SCP245-252 were prepared using the same microwave-assisted solid-phase synthesis procedure as described above for IB445 but including a final oxidation step carried out by treating the pure thioether-peptide with 3% H2O2solution for 18-22 hrs at room temperature, followed by purification by HPLC.TABLE 5SEQUENCES OF THIOETHER-CYCLISED PEPTIDES Representative structure showing thioether cyclisation:wherein: * = C-terminal amide; NmeR = N-methyl-arginine; beta-R = beta-arginine; aMeY = alpha-methyl-tyrosine; Cit = citrulline; meC = methyl-cysteine; Nip = nipecotic acid; tBuAla = tert-butyl-alanine;Results

[0339] Following synthesis, cyclisation and HPLC purification 15 mg of IB445 (Figure 1) was obtained from a 0.05 mmol scale synthesis (yield = 24%). The mass spectrum of the final product showed the expected ion sizes (Figure 2). Peptide purity estimated from the area under the IB445 peak in the final analytical HPLC chromatogram (Figure 3) was >95%.EXAMPLE 2 - SYNTHESIS OF HEAD-TO-TAIL CYCLISED PEPTIDES Materials and Methods

[0340] Linear IB496 (NH₂-YLRRPYRQG-COOH; SEQ ID NO: 5) was prepared via solid-phase peptide synthesis (SPPS) and then cyclised in solution. IB496 was synthesised 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% hexafluoroisopropanol in dichloromethane for 1 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-butyl methyl ether (4-5-fold in volume). The precipitate was separated by centrifugation, redissolved in 50% acetonitrile and freeze-dried.

[0341] Cyclisation was carried out at room temperature by combining the crude fully-protected linear IB496 peptide with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate chloroacetic acid (2 eq.), N, N-diisopropylethylamine (4 eq.) in DMF for 2.5 hrs. The reaction solution was then diluted 10x 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 IB496 (refer to Table 6).

[0342] The other head-to-tail cyclised peptides in Table 6 were prepared using a similar procedure unless otherwise stated.TABLE 6SEQUENCE OF HEAD-TO-TAIL CYCLISED PEPTIDESRepresentative structure:00496 is as follows:

[0344] The structure of SCP076 is as follows:EXAMPLE 3 - SYNTHESIS OF HEAD-TO-SIDECHAIN CYCLISED PEPTIDES Materials and Methods

[0345] Linear IB529 (NH2-YLRRPYREG-NH2; SEQ ID NO: 150) was prepared via SPPS and then cyclised in solution. The linear IB529 was synthesised on a CEM Liberty Blue automated microwave peptide synthesiser (CEM Corporation, Charlotte, North Carolina, USA) using the same method described for linear IB445, without conjugation of chloroacetic acid at the N-terminus.

[0346] Cyclisation was carried out at room temperature by combining the crude unprotected linear IB529 peptide with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate chloroacetic acid (2 eq.), DIPEA (10 eq.) in DMF for 1 hr. DMF was removed in vacuum, the resulting solid was dissolved in 0.1% TFA and purified by preparative RP-HPLC as described in Example 1 to form head-to-sidechain cyclised IB529 (refer to Table 7).

[0347] IB575, IB580 and IB581 and other analogues (refer to Table 7) were prepared using the same procedure as described above for IB529, except for SCP186 and SCP244.

[0348] SCP186 and SCP244 were prepared using the same procedure as described above for IB496, but attaching the 2-chlorotrityl resin to the side-chain of a glutamic acid residue instead of the C-terminus.TABLE 7SEQUENCE OF LACTAM BOND (HEAD-TO-SIDECHAIN) CYCLISED PEPTIDESRepresentative structure:wherein: * = C-terminal amide; and # = sidechain forming an amide bond with N-terminal amine.

[0349] The structure of IB00581 is as follows:- Ill -EXAMPLE 4 -INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) BY SYNTHETIC PEPTIDESMaterials and Methods

[0350] Peptides were synthesised in accordance with Examples 1-3. The ability of the peptides to inhibit the activity of hASICla was assessed using a Fluorescence Imaging Plate Reader (FLIPR) calcium influx assay on a FLIPR Penta (Molecular Devices, USA). Experiments were carried out using human ASICla acid-sensing ion channel (human ACCN2 gene) transfected CHO cells where over-expression was induced using tetracycline (Charles River Laboratories, USA). The complete growth medium for the cells was as follows, Ham's F12 with the addition of 10% Foetal Bovine Serum (FBS) Tetracycline-screened, 100 units / mL of Penicillin-Streptomycin, 0.01 mg / mL of Blasticidin and 0.4 mg / mL of Zeocin. Cells were passaged and seeded (at 10,000 cells per well) a day prior to the FLIPR assay. After 18 hrs of tetracycline-induced ASICla overexpression, the cells were loaded with Calcium 6 dye (Molecular Devices, USA) diluted in Hank's balanced salt solution (HBSS) (+Ca and Mg) + 20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4. Serial dilutions of the peptides (prepared in accordance with Examples 1-3) were made in HBSS (+Ca and Mg) + 20 mM HEPES, + 0.1% bovine serum albumin (BSA), pH 7.4. Ten 1:2 serial dilutions were prepared from a top concentration of 1 pM. Cells were exposed to the peptide 10 minutes before ASICla stimulation with low pH buffer. Fluorescence recording was initiated immediately prior to stimulation and a minimum of three replicates was collected for each concentration. Results were analysed using Prism 10 (GraphPad Software, Boston, MA, USA). Non-linear regression, specifically the log(inhibitor) vs normalized response-variable slope was fitted to the data for calculation of the concentration required for half-maximal inhibition (IC50).Results

[0351] The results are presented in Table 8.EXAMPLE 5 - PEPTIDE STABILITY IN HUMAN SERUMMaterials and Methods

[0352] The stability of the peptides to human serum proteases was assessed after incubation with human serum for 2 hrs. Peptides (prepared in accordance with Examples 1-3) were mixed with human serum (100%) to a final concentration of 50 pM and incubated at 37°C. Aliquots were taken after 0, 30, 60 and 120 min, mixed with 3% TFA / acetonitrile and incubated on ice for serum protein precipitation. After centrifugation to separate the pellet, samples were analysed by LC-MS. Each peptide stability test was performed at least in duplicate. The data is reported as half-life (in minutes), indicating the time it takes for a substance to reduce to half of its initial concentration in human serum at 37°C.Results

[0353] The results are presented in Table 8.EXAMPLE 6 - PEPTIDE STABILITY IN MOUSE BRAIN HOMEGENATE Materials and Methods

[0354] The stability of the peptides in mouse brain homogenate was assessed after incubation with the tissue homogenate for up to 1 hr. Peptides (prepared in accordance with Examples 1-3) were mixed with mouse brain homogenate (1 g brain weight / 8 mL phosphate saline buffer) to a final concentration of 20 pM of the peptide and incubated at 37°C. Aliquots were taken after 0, 15, 30 and 60 min, mixed with 3% TFA / acetonitrile and incubated on ice for protein precipitation. After centrifugation to separate the pellet, samples were analysed by LC-MS. The data is reported as half-life (in minutes), indicating the time it takes for a substance to reduce to half of its initial concentration in human serum at 37°C.Results

[0355] The results are presented in Table 8.EXAMPLE 7 - PEPTIDE STABILITY IN PLASMINMaterials and Methods

[0356] The stability of the peptides in a solution containing plasmin (10 pg / mL) was assessed up to 3.5 hr. Peptides (prepared in accordance with Examples 1-3) were mixed with plasmin (10 pg / mL) in phosphate buffer saline pH 7.4 to a final concentration of 25 pM and incubated at 37°C. Aliquots were taken after 0, 60 and 220 min, mixed with 1% TFA / 50% acetonitrile. After centrifugation, samples were analysed by LC-MS. Each peptide stability test was performed at least in duplicate. The data is reported as half-life (in hours), indicating the time it takes for a substance to reduce to half of its initial concentration in the plasmin solution at 37°C.Results

[0357] The results are presented in Table 8.EXAMPLE 8 - ACTIVATION OF THE HUMAN MAS-RELATED G-PROTEIN COUPLED RECEPTOR X2 (MRGPRX2)Materials and Methods

[0358] The agonist activity of the peptides was measured using FLIPR calcium mobilisation assay on a FLIPR Penta (Molecular Devices, USA). The stable cell line of Human CHO-K1 / MRGPRX2 was sourced from GenScript. The complete growth medium for the cells was as follows, Ham's F12 (Kaighn's) medium with the addition of 10% FBS, 100 units / mL of Penicillin-Streptomyocin, and 0.2mg / mL of Zeocin. Cells were seeded at 10,000 cellsper well a day prior to the FLIPR assay. After 18 hrs, cells were loaded with Calcium 6 dye (Molecular Devices, USA) diluted in HBSS (- Ca, Mg) + 20 mM HEPES, pH 7.4. Serial dilutions of the peptides (prepared in accordance with Examples 1-3) were made in HBSS (-Ca, Mg) + 20 mM HEPES, + 0.1% BSA, pH 7.4. Ten 1:3 serial dilutions were prepared from a top concentration of 1 mM. Fluorescence recording was initiated prior to peptide addition and a minimum of three replicates was collected for each concentration. Results were analysed using Prism 10 (GraphPad Software, Boston, MA, USA). Non-linear regression, specifically the log(agonist) vs response -variable slope (four parameters) was fitted to the data for calculation of the concentration required for half-maximal activation (ECso).Results

[0359] The results are presented in Table 8.TABLE 8INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A ACTIVITY, STABILITY IN HUMAN SERUM, PLASMIN AND MOUSE BRAIN HOMOGENATE AND AGONIST ACTIVITY AT MRGPRX2EXAMPLE 9 - INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A (hASICla) IN OOCYTES BY SYNTHETIC PEPTIDESMaterials and Methods

[0360] The ability of the peptides to inhibit the activity of hASICla was also 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.

[0361] 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 MgCl₂,5 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES); pH 7.45). Peptide serial dilutions were made in regular ND96 solution (96 mM NaCI, 2 mM KCI, 1.8 mM CaCH, 2 mM MgCl₂, 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.

[0362] Oocytes were clamped at -60 mV (Axoclamp 900A; Molecular Devices, San Jose, CA, USA) using microelectrodes filled with 3 M KCI solution (0.5-1.0 M resistance). Data acquisition (sampled at 2 kHz and filtered at 0.01 kHz) was performed using pClamp 10 software (Molecular Devices, LLC, San Jose, CA, USA). Concentrationresponse data were obtained using serial dilutions of the peptide (prepared in accordance with Examples 1-3) applied at pH 7.45 directly to the oocyte bath for 4 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.

[0363] Data were analysed using Prism 11 (GraphPad Software, Boston, MA, USA). The Hill equation (specifically the "log(inhibitor) vs response-variable slope (four parameters)" in Prism) was fit to the data with no constraints. Data are expressed as mean ± SEM.Results

[0364] The results are presented in Table 9.TABLE 9INHIBITION OF HUMAN ACID-SENSING ION CHANNEL 1A ACTIVITY IN OOCYTES

[0365] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0366] 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.

[0367] 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.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A proteinaceous molecule comprising, consisting or consisting essentially of an amino acid sequence represented by Formula I:X1X2RX3X4X5X6X7X8(I)wherein:X1is selected from aromatic amino acid residues including Y, W, F and modified forms thereof [e.g. 3,4-dihydroxyphenylalanine (Dopa), 4-fluoro-phenylalanine (F(pF)), 4-chloro-phenylalanine (F(pCI)), 4-hydroxymethyl-phenylalanine ((4MeOH)Phe), 4-amino-phenylalanine ((4A)Phe), 4-trifluoromethyl-phenylalanine ((4CF3)Phe), 4-tert-butyl-phenylalanine ((4tBu)Phe), O-methyltyrosine (Tyr(OMe)), homotyrosine (hTyr), 4-carboxy-phenylananine ((4COOH)Phe), D-tyrosine (D-Tyr), 3-fluoro-tyrosine ((3F)Tyr), 4-aminomethyl-phenylalanine ((4MeA)Phe), 2-pyridylalanine (2Pal), 3-pyridylalanine (3Pal), 4-pyridylalanine (4Pal), 4-(methylacetyl)amino-phenylalanine ((4MeA[Ac])Phe), 4-(methylsuccinyl)amino-phenylalanine ((4MeA[Suc])Phe), 2,6-dimethyl-tyrosine (dmTyr), pentafluoro-phenylalanine ((F5)Phe) or phosphotyrosine (Tyr(PO))]; small amino acid residues including S, A, G, T and modified forms thereof [e.g. cyclohexylalanine (Cha) or 2-furylalanine (2Fur)]; and basic amino acid residues including H, R, K and modified forms thereof [e.g. 1-methyl-histidine ((1Me)His)];X2is selected from L, Nle, cyclohexylglycine (Chg), cyclopentylglycine (Cpg), betacyclobutylalanine (Cba), phenylglycine (Phg) and modified forms thereof;X3is selected from basic amino acid residues including R, K and modified forms thereof [e.g. 2-amino-4-guanidino-butyric acid (Agb), homoarginine (hArg), citrulline (Cit) or N, N-dimethylarginine (R(Me2))]; acidic amino acid residues including D, E and modified forms thereof; and amide containing amino acid residues including N, Q and modified forms thereof;X4is selected from P and modified forms thereof [e.g. hydroxyproline (Hyp), azetidine-2-carboxylic acid (Aze), pipecolic acid (Pip), a-methyl-proline (aMeP), 1,3-oxazole-4-carboxylic acid (Oxa), 4-amino-proline ((4A)Pro), 5-methyl-proline (5MePro), 5,5-dimethyl-proline (5Me2Pro), 4-fluoro-proline (4FPro), 4-aminoacetyl-proline ((4A[Ac])Pro), 4-aminosuccinyl-proline ((4A[Suc])Pro), 4- (chloroacetyl)amino-proline ((4A[CIAc])Pro), 5-azaspiro[2.4]heptane-6-carboxylic acid (5AzaPro), 4,4-difluoro-proline (dfP), octahydroindole-2-carboxylic acid (Oic), 1,4-morpholine-3-carboxylic acid (Mor), 4-cyclohexyl-proline (4ChPro), 4-phenyl-proline (4PhPro), thioproline (Thz), indoline-2-carboxylic acid (Ide) or 4-trifluoromethyl-proline (4CF3Pro)], sarcosine (Sar), N-methyl-serine (NMeSer), N-methyl-leucine (NMeLeu) and N-methyl-aspartic acid (NMeAsp);Xs is selected from aromatic amino acid residues including Y, W, F and modified forms thereof (e.g. Dopa, (4MeOH)Phe, (4A)Phe, Tyr(OMe), hTyr, (4MeA)Phe, 2Pal, 3Pal, 4Pal, (3F)Tyr, 3-chloro-tyrosine ((3CI)Tyr), (F5)Phe, 2-fluoro-tyrosine ((2F)Tyr) or 3,5-difluorotyrosine (dFTyr)); Cha; and 2Fur;X6is selected from R, canavanine (Cav), a-methyl-arginine (aMeR), Agb, hArg, 2-amino-3-(4-guanidinophenyl)propanoic acid (Fgu), N-methylarginine (R(Me)), N-phenyl-arginine (R(Ph)), N-benzyl-arginine (R(Bz)), (4A)Phe, 2-amino-3-guanidinopropionic acid (Agp) and Cit;X7 is selected from C; acidic amino acid residues including D, E and modified forms thereof [e.g. homoglutamic acid (hGlu)]; amide containing amino acid residues including N, Q and modified forms thereof; small amino acid residues including A, S, G, T and modified forms thereof; 3-aminomethylbenzoic acid (3Amb); 4-aminobutyric acid (4-Abu); D-Cys; and cysteine sulfoxide (Cys(O)); andX8is absent or is selected from basic amino acid residues including R, K, H and modified forms thereof; small amino acid residues including A, G, S, T and modified forms thereof [e.g. 2-aminoisobutyric acid (Aib), p-alanine (bA)]; P 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 [e.g isoglutamic acid (IE)]; aromatic amino acid residues including Y, W, F and modified forms thereof; amide containing amino acid residues including N, Q and modified forms thereof; aminohexanoic acid (Ahx); aminooctanoic acid (Aoc); and aminodecanoic acid (Adc).

2. The proteinaceous molecule according to claim 1, wherein X1is Y, W, F, F(pF), F(pCI), Dopa or S.

3. The proteinaceous molecule according to claim 1, wherein X1is Y.

4. The proteinaceous molecule according to any one of claims 1-3, wherein X2is L or Chg.

5. The proteinaceous molecule according to any one of claims 1-4, wherein X3is R.

6. The proteinaceous molecule according to any one of claims 1-5, wherein X4 is P, Hyp, Aze or Pip.

7. The proteinaceous molecule according to any one of claims 1-5, wherein X4 is P, Hyp, Aze, Pip, Oxa, (4A)Pro, 5MePro, 5Me2Pro, 4FPro, (4A[Ac])Pro, (4A[Suc])Pro, (4A[CIAc])Pro, 5AzaPro, dfP, Oic, Mor, 4ChPro, 4PhPro, Thz, Ide or 4CF3Pro.

8. The proteinaceous molecule according to any one of claims 1-7, wherein X5is Y, (3F)Tyr, (3CI)Tyr, 2Pal, 3Pal, 2Fur, (2F)Tyr or dFTyr.

9. The proteinaceous molecule according to any one of claims 1-7, wherein X5is Y.

10. The proteinaceous molecule according to any one of claims 1-9, wherein X6is R, aMeR or Cav.

11. The proteinaceous molecule according to any one of claims 1-9, wherein X6is R, Cav, Agb, hArg, Fgu or R(Me).

12. The proteinaceous molecule according to any one of claims 1-11, wherein X7is C, E, hGlu, Q, 4-Abu or Cys(O).

13. The proteinaceous molecule according to any one of claims 1-11, wherein X7is C, E or hGlu.

14. The proteinaceous molecule according to any one of claims 1-13, wherein Xs is absent or is G.

15. 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: 1-35 and 151-293:YLRRPYRCG [SEQ ID NO: 1];YLRRPYRC [SEQ ID NO: 2];SLRRPYRCG [SEQ ID NO: 3];YLRRX9YRCG [SEQ ID NO: 4];YLRRPYRQG [SEQ ID NO: 5];YLRKPYRCG [SEQ ID NO: 6];YLRRPYRCGK [SEQ ID NO: 7];YX10RRPYRCG [SEQ ID NO: 8];YX11RRPYRCG [SEQ ID NO: 9];YLRRX12YRCG [SEQ ID NO: 10]FLRRPYRCG [SEQ ID NO: 11]WLRRPYRCG [SEQ ID NO: 12]X13LRRPYRCG [SEQ ID NO: 13]X14LRRPYRCG [SEQ ID NO: 14]YLRRPYX15CG [SEQ ID NO: 15]YLRRPYREG [SEQ ID NO: 16]YXisRRPYRCG [SEQ ID NO: 17]YLRRPYRCGE [SEQ ID NO: 18]YLRX17PYRCG [SEQ ID NO: 19]YLRRPYX17CG [SEQ ID NO: 20]YXisRRPYREG [SEQ ID NO: 21]YXisRRPYRCG [SEQ ID NO: 22]YX16RRX9YRCG [SEQ ID NO: 23]YXisRRXigYRCG [SEQ ID NO: 24]; YX16RRX20YRCG [SEQ ID NO: 25]; YXieRRPYRDG [SEQ ID NO: 26]; YX16RRPYRX21G [SEQ ID NO: 27]; X22X16RRPYRCG [SEQ ID NO: 28]; YX16RRPX22RCG [SEQ ID NO: 29]; YX16RRX23YRCG [SEQ ID NO: 30]; YXieRRPYRC [SEQ ID NO: 31]; YX16RRPYRCX24 [SEQ ID NO: 32]; YXieRRPYRCS [SEQ ID NO: 33]; YX16RRPYX25CG [SEQ ID NO: 34]; YXisRRPYXisCG [SEQ ID NO: 35]; YX16RRPYX15X21G [SEQ ID NO: 151] YX16RRPYRX27 [SEQ ID NO: 152] SX16RRX20YRCG [SEQ ID NO: 153] X22X16RRX20YRCG [SEQ ID NO: 154] YX16RRX20YREG [SEQ ID NO: 155] YX16RRX19YREG [SEQ ID NO: 156] YX16RRPX28RCG [SEQ ID NO: 157] X28X16RRPYRCG [SEQ ID NO: 158] YX16RX29PYRCG [SEQ ID NO: 159] YX16RRPYX29CG [SEQ ID NO: 160] YX16RRX30YRC [SEQ ID NO: 161] YX16RRX30YREG [SEQ ID NO: 162] YX16RRX19YRE [SEQ ID NO: 163] YX16RRX23YREG [SEQ ID NO: 164] YX16RRX19YX15CG [SEQ ID NO: 165] YX16RRX30YX15CG [SEQ ID NO: 166] YXisRRPYXisC [SEQ ID NO: 167] YX16RRX9YX15C [SEQ ID NO: 168] YXisRRPYXisEG [SEQ ID NO: 169] YX16RRPYX31CG [SEQ ID NO: 170] YX16RRPYX32CG [SEQ ID NO: 171] YX16RRX33YRCG [SEQ ID NO: 172] X34X16RRPYRCG [SEQ ID NO: 173] YX16RRPX34RCG [SEQ ID NO: 174] YX35RRPYRCG [SEQ ID NO: 175] YXisRRPYXssCG [SEQ ID NO: 176]YXisRRPYRCE [SEQ ID NO: 177] YX16RRPYRCX37 [SEQ ID NO: 178] YXieRRPYRCGE [SEQ ID NO: 179] YX16RRPYRCGX37 [SEQ ID NO: 180] YXieRRPYXssCG [SEQ ID NO: 181] YX16RRPYX39CG [SEQ ID NO: 182] X40X16RRPYRCG [SEQ ID NO: 183] X41X16RRPYRCG [SEQ ID NO: 184] X42X16RRPYRCG [SEQ ID NO: 185] YX16RRPX42RCG [SEQ ID NO: 186] YX16RRPYRCGX43 [SEQ ID NO: 187] YXieRRPYRCGK [SEQ ID NO: 188] YX16RRPYX34CG [SEQ ID NO: 189] X34X16RRPYX15CG [SEQ ID NO: 190] X28X16RRX19YRCG [SEQ ID NO: 191] X44X16RRPYRCG [SEQ ID NO: 192] YX16RRX9YX15CG [SEQ ID NO: 193] YX16RRPX44RCG [SEQ ID NO: 194] YXieRRPYRCGGE [SEQ ID NO: 195] YX16RRPYRCX45E [SEQ ID NO: 196] YX16RRX19YX32CG [SEQ ID NO: 197] X46X16RRPYRCG [SEQ ID NO: 198] YX16RRPX46RCG [SEQ ID NO: 199] YX16RRPYRCX47E [SEQ ID NO: 200] YX16RRPYRCX48E [SEQ ID NO: 201] YX16RRPYRCX49E [SEQ ID NO: 202] YXisRRXsoYRCG [SEQ ID NO: 203] WXieRRPYRC [SEQ ID NO: 204] XsiXisRRPYRC [SEQ ID NO: 205] YX16RRX19YRCGE [SEQ ID NO: 206] YXieRRPYRCGEK [SEQ ID NO: 207] YX16RRX52YRC [SEQ ID NO: 208] YX16RRX53YRC [SEQ ID NO: 209] YX16RRX19YRCGEK [SEQ ID NO: 210] YX16RRX19YX32CGE [SEQ ID NO: 211] yXieRRPYRCG [SEQ ID NO: 212] YX16RRX54YRC [SEQ ID NO: 213] X55X16RRPYRCG [SEQ ID NO: 214]XssXisRRPYRCG [SEQ ID NO: 215]; YXisRRPXssRCG [SEQ ID NO: 216]; YXI6RRX57YRC [SEQ ID NO: 217]; XssXieRRPYRC [SEQ ID NO: 218]; YX16RRX52YREG [SEQ ID NO: 219]; X59X16RRPYRCG [SEQ ID NO: 220]; XeoXieRRPYRCG [SEQ ID NO: 221]; YXieRRXeiYRCG [SEQ ID NO: 222]; YX16RRX62YRCG [SEQ ID NO: 223]; YXisRRPXssRC [SEQ ID NO: 224]; YXieRRXesYRC [SEQ ID NO: 225]; YXieRRPYRQG [SEQ ID NO: 226]; YX16RRX52YX17CG [SEQ ID NO: 227]; YX16RRX52YX29CG [SEQ ID NO: 228]; YX16RRX52YX15CG [SEQ ID NO: 229]; YX16RRX52YRE [SEQ ID NO: 230]; YX16RRX52YRX64 [SEQ ID NO: 231]; YX16RRX52YRG [SEQ ID NO: 232]; YX16RRX52YRCG [SEQ ID NO: 233]; YX16RRX52X55RC [SEQ ID NO: 234]; YX16RRX52X65RC [SEQ ID NO: 235]; FX16RRX52YRC [SEQ ID NO: 236]; HX16RRX52YRC [SEQ ID NO: 237]; YX16RX66X52YRC [SEQ ID NO: 238]; X67X16RRX52YRC [SEQ ID NO: 239]; X68X16RRX52YRC [SEQ ID NO: 240]; X69X16RRX52YRC [SEQ ID NO: 241]; X70X16RRX52YRC [SEQ ID NO: 242]; X71X16RRX52YRC [SEQ ID NO: 243]; YX16RRX52X71RC [SEQ ID NO: 244]; YX16RRX72YRC [SEQ ID NO: 245]; YX16RRX73YRC [SEQ ID NO: 246]; YX16RRX74YRC [SEQ ID NO: 247]; YX16RRX75YRC [SEQ ID NO: 248]; YX16RRX76YRC [SEQ ID NO: 249]; YX16RRX77YRC [SEQ ID NO: 250]; YX16RRX78YRC [SEQ ID NO: 251]; YX16RRX52X79RC [SEQ ID NO: 252];YX16RRX52X67RC [SEQ ID NO: 253]; YX16RRX52X68RC [SEQ ID NO: 254]; YXi6RRX52XsoRC [SEQ ID NO: 255]; YX16RRX52YX66C [SEQ ID NO: 256]; X79X16RRX52YRC [SEQ ID NO: 257]; YX16RRX54YX15CG [SEQ ID NO: 258]; YX16RX66X52YX15CG [SEQ ID NO: 259]; YX16RRX52X55X15CG [SEQ ID NO: 260]; YX16RRX54YX29CG [SEQ ID NO: 261] X81X16RRX52YX29CG [SEQ ID NO: 262]; YX16RX66X52YX29C [SEQ ID NO: 263]; YX16REX52YRC [SEQ ID NO: 264]; YX16RQX52YRC [SEQ ID NO: 265]; X51X16RRX52YX29C [SEQ ID NO: 266]; X22X16RRX52YX29C [SEQ ID NO: 267]; X68X16RRX52YX29C [SEQ ID NO: 268] YX16RX82X52YX29C [SEQ ID NO: 269]; YX16RRX54X55RC [SEQ ID NO: 270]; X55X16RRX52X55RC [SEQ ID NO: 271]; YXieRRXssYRC [SEQ ID NO: 272]; YX16RRX52X55X17C [SEQ ID NO: 273]; YX16RRX52X55X29C [SEQ ID NO: 274]; X81X16RRX52X55X29C [SEQ ID NO: 275]; X56X16RRX52X55RC [SEQ ID NO: 276]; YX16RRX52X84X29C [SEQ ID NO: 277]; YX16RRX52YX29C [SEQ ID NO: 278]; YX16RRX52X55RE [SEQ ID NO: 279]; YX16RRX52X55X17X85 [SEQ ID NO: 280]; YXieRRPYRXssG [SEQ ID NO: 281]; YXisRRPYRXss [SEQ ID NO: 282]; YX16RRX52YRX85 [SEQ ID NO: 283]; YX16RRX54YRX85 [SEQ ID NO: 284]; XssXisRRPYRXssG [SEQ ID NO: 285]; YX16RRX52X55RX85 [SEQ ID NO: 286]; YX16RRX52X55X29X85 [SEQ ID NO: 287]; YX16RRPYRCGEX87 [SEQ ID NO: 288]; YXieRRXssYRC [SEQ ID NO: 289]; YX16RRX53X55X17C [SEQ ID NO: 290];YX16RRX52X55RCG [SEQ ID NO: 291];YX16RRX52X55X17CG [SEQ ID NO: 292]; and YXieRRXsgYRC [SEQ ID NO: 293], wherein:X9 is Hyp;X10 is Cba;Xu is Nle;X12 is Sar;X13 is F(pF);X14 is F(pCI);X15 is Cav;Xis is Chg;X17 is Agb;Xis is Cpg;X19 is Aze;X20 is Pip;X21 is hGlu;X22 is Dopa;X23 is aMeP;X24 is Aib;X25 is aMeR;X27 is 3Amb;X28 is (4MeOH)Phe;X29 is hArg;X30 is Oxa;X31 is Agp;X32 is Fgu;X33 is NMeSer;X34 is (4A)Phe;X35 is Phg;X36 is R(Me);X37 is iE;X38 is R(Ph);X39 is R(Bz);X40 is (4CF3)Phe;X41 is (4tBu)Phe;X42 is Cha;X43 is PEG12;X44 is Tyr(OMe);X45 is bA;X46 is hTyr;X47 is Ahx;X48 is Aoc;X49 is Adc;X50 is (4A)Pro;X51 is (4COOH)Phe;X52 is 5MePro;X53 is 5Me2Pro;X54 is 4FPro;X55 is (3F)Tyr;X56 is (4MeA)Phe;X57 is NMeLeu;X58is 4Pal;X59 is (4MeA[Ac])Phe; Xso is (4MeA[Suc])Phe; Xei is (4A[Ac])Pro;X62is (4A[Suc])Pro;X63 is (4A[CIAc])Pro; X64 is 4-Abu;X65is (3Cl)Tyr;X66is Cit;X67is 2Pal;X68is 3Pal;X69is (1Me)His;X70 is dmTyr;X71 is 2Fur;X72 is 5AzaPro;X73 is dfP;X74 is Oic;X75 is Mor;X76 is 4ChPro;X77 is 4PhPro;X78 is 4CF3Pro;X79 is (F5)Phe;Xso is (2F)Tyr;Xsi is Tyr(PO);X82 is R(Me2);X83is NMeAsp;X84 is dFTyr;X85is Cys(O);X87 is K(PEG11A);X88is Idc; andX89is Thz.

16. The proteinaceous molecule according to claim 15, wherein the proteinaceous molecule comprises, consists or consists essentially of an amino acid sequence represented by any one of SEQ ID NOs: 1-35.

17. The proteinaceous molecule according to any one of claims 1-16, wherein X? is C and the side chain of the cysteine residue in the X7 position forms a thioether linkage with the N-terminal amine of the amino acid residue in the Xi position, wherein the thioether linkage is represented by Formula II:wherein the amine is the N-terminal amine of X1, the sulfur atom is the sulfur atom from X7, and R1is C1-6 alkylene.

18. The proteinaceous molecule according to claim 17, wherein R1is methylene.

19. The proteinaceous molecule according to any one of claims 1-16, wherein the proteinaceous molecule comprises a lactam bond.

20. The proteinaceous molecule according to any one of claims 1-16, wherein the proteinaceous molecule is cyclized through N-to-C cyclisation.

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

22. A proteinaceous molecule according to any one of claims 1-20 for use in therapy.

23. 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 1-20.

24. A method of treating or at least partially inhibiting the development of a condition in a subject in which inhibiting an ASIC is associated with effectivetreatment or inhibition of the development of the condition, comprising administering a proteinaceous molecule according to any one of claims 1-20.

25. A method of treating or at least partially inhibiting the development of a neurological condition in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-20.

26. The method according to claim 25, 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.

27. The method according to claim 26, wherein the neurological condition is stroke.

28. A method of treating or at least partially inhibiting the development of ischaemia in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-20.

29. 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 1-20.

30. The method according to claim 29, wherein the ischaemic damage is cardiac, ocular, renal or neuronal ischaemic damage.

31. The method according to claim 30, wherein the ischaemic damage is cardiac ischaemic damage.

32. The method according to claim 29, wherein the ischaemic damage is associated with a myocardial infarction.

33. The method according to claim 30, wherein the ischaemic damage is neuronal ischaemic damage.

34. A method of at least partially inhibiting the development of ischaemiareperfusion injury in a tissue, comprising contacting the tissue with a proteinaceous molecule according to any one of claims 1-20.

35. The method according to claim 34, wherein the tissue is an organ transplant.

36. The method according to claim 34 or claim 35, wherein the tissue is a heart, lung or kidney.

37. 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 1-20.

38. The method according to claim 37, wherein the organ is a heart, lung or kidney.

39. The method according to claim 37 or claim 38, wherein the damage is ischaemic damage.

40. A method of treating or at least partially inhibiting the development of an inflammatory condition in a subject, comprising administering a proteinaceous molecule according to any one of claims 1-20.

41. The method according to claim 40, wherein the inflammatory condition is arthritis.

Images