Proteinaceous compounds and uses therefor

Abstract

The present invention discloses proteinaceous compounds that comprise at least a biologically active portion of a taipan natriuretic peptide (TNP) or a variant or derivative thereof. The invention also relates to the use of these compounds in methods for stimulating vasodilation, natriuresis, diuresis, renin-suppression, bactericidal activity, weight-loss or bone growth in a mammalian host. In specific embodiments, the compounds are useful in the treatment of congestive heart failure.

1 . An isolated proteinaceous compound comprising at least one activity selected from vasodilatory, natriuretic, diuretic, renin-suppressing, bactericidal, weight-reducing or bone growth plate size-increasing activities, in vertebrate animals including mammals, wherein the compound is represented by the formula:
   Δ-Θ-Ω  (I)
   
       wherein:
 Δ is absent or is a N-terminal portion of a natriuretic peptide or a variant or derivative of that portion; 
 Θ is the core ring structure of a natriuretic peptide or a variant or derivative of the structure; 
 Ω is a C-terminal portion of a natriuretic peptide or a variant or derivative of that portion; and 
 at least one of Δ, Θ and Ω comprises a biologically active portion of TNPc or a variant or derivative thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein the biologically active portion comprises a C-terminal portion of TNPc. 
     
     
         3 . A compound according to  claim 2 , wherein the C-terminal portion comprises a sequence selected from any one of SEQ ID NO:1-5, or a variant or derivative thereof. 
     
     
         4 . A compound according to  claim 1 , wherein the biologically active portion comprises the TNPc core ring structure sequence set forth in SEQ ID NO:6, or a variant or derivative thereof. 
     
     
         5 . A compound according to  claim 1 , wherein the biologically active portion comprises a N-terminal portion of TNPc. 
     
     
         6 . A compound according to  claim 5 , wherein the N-terminal portion comprises the sequence set forth in SEQ ID NO:7, or a variant or derivative thereof. 
     
     
         7 . A compound according to  claim 1 , wherein the variant or derivative of the biologically active portion of TNPc comprises a sequence having at least 80, 85, 90, 96, 97, 98 or 99% sequence similarity with, or differs at no more than 1, 2, 3, 4, 5 or 10 amino acid residues from, the corresponding portion represented by any one of SEQ ID NO:1-7, with the proviso that: (a) when the variant or derivative corresponds to a C-terminal portion of TNPc, it comprises a hydrophobic amino acid residue, at position 28 relative to the amino acid sequence of TNPc; and (b) when the variant or derivative corresponds to the core ring structure of TNPc, it comprises a basic amino acid residue, e.g., R or K at position 16 relative to the amino acid sequence of TNPc. 
     
     
         8 . A compound according to  claim 7 , wherein the variant or derivative of the biologically active portion of TNPc shares at least 90% sequence identity with any one of SEQ ID NO:1-7. 
     
     
         9 . A compound according to  claim 1 , wherein when Δ, Θ or Ω comprise a biologically active portion of a natriuretic peptide other than TNPc or its variants or derivatives, the natriuretic peptide is selected from ANP, BNP, CNP, DNP, VNP, PNP or an  Oxyuranus  natriuretic peptide other than TNPc, or its variants or derivatives. 
     
     
         10 . A compound according to  claim 1 , having the formula:
   Δ 1 -Θ 1 -Ω 1   (II)
   
       wherein:
 Δ 1  is absent or is a N-terminal portion of a natriuretic peptide or a variant or derivative of the portion; 
 Θ 1  is the core ring structure of a natriuretic peptide or a variant or derivative of the structure; and 
 Ω 1  is a C-terminal portion comprising an amino acid sequence having the formula:
     X   1   X   2 Φ 1   X   3   X   4   X   5   X   6 Σ 1   X   7   X   8 Λ  (III)
 
 
 wherein: 
 X 1-8  are independently selected from any amino acid residue, or modified form thereof; 
 Φ 1  is selected from any hydrophobic amino acid residue, or modified form thereof; and 
 Σ 1  is a small amino acid residue, or modified form thereof; and 
 Λ is absent or is a peptide comprising an amino acid sequence having the formula:
     X   9 Σ 2 Σ 3   X   10   X   11   (IV)
 
 
 wherein: 
 X 9  is selected from any amino acid residue, or modified form thereof; 
 Σ 2  is absent or is selected from any small amino acid residue, or modified form thereof; 
 Σ 3  is absent or is selected from any small amino acid residue, or modified form thereof, when Σ 2  is present; 
 X 10  is selected from any amino acid residue, or modified form thereof, when Σ 3  is present; and 
 X 11  is selected from any amino acid residue, or modified form thereof, when X 10  is present, 
 with the proviso that formula III excludes: 
 SEQ ID NO:8 when Δ 1 -Θ 1  consists of SEQ ID NO:187; 
 SEQ ID NO:9 when Δ 1 -Θ 1  consists of SEQ ID NO:188; 
 SEQ ID NO:10 when Δ 1 -Θ 1  consists of SEQ ID NO:189; 
 SEQ ID NO:11 when Δ 1 -Θ 1  consists of SEQ ID NO:190; 
 SEQ ID NO:12 when Δ 1 -Θ 1  consists of SEQ ID NO:191; and 
 SEQ ID NO:13 when Δ 1 -Θ 1  consists of SEQ ID NO:192. 
 
     
     
         11 . A compound according to  claim 10 , wherein X 1  is selected from a basic, neutral/polar or a small amino acid residue, or modified form thereof. 
     
     
         12 . A compound according to  claim 10 , wherein X 2  is selected from a hydrophobic, basic or a small amino acid residue, or modified form thereof. 
     
     
         13 . A compound according to  claim 10 , wherein Φ 1  is an amino acid residue that comprises an aliphatic or aromatic side chain, or modified form thereof. 
     
     
         14 . A compound according to  claim 10 , wherein X 3  is selected from a basic or hydrophobic amino acid residue, or modified form thereof. 
     
     
         15 . A compound according to  claim 10 , wherein X 4  is selected from a neutral/polar, basic amino acid residue, hydrophobic or acidic amino acid residue, or modified form thereof. 
     
     
         16 . A compound according to  claim 10 , wherein X 5  is selected from a neutral/polar, basic or small amino acid residue, or modified form thereof. 
     
     
         17 . A compound according to  claim 10 , wherein X 6  is selected from a basic or small amino acid residue, or modified form thereof. 
     
     
         18 . A compound according to  claim 10 , wherein Σ 1  is P, or modified form thereof. 
     
     
         19 . A compound according to  claim 10 , wherein X 7  is selected from a basic or a neutral/polar amino acid residue, or modified form thereof. 
     
     
         20 . A compound according to  claim 10 , wherein X 8  is selected from a basic or small amino acid residue, or modified form thereof. 
     
     
         21 . A compound according to  claim 10 , wherein X 9  is selected from a hydrophobic or small amino acid residue, or modified form thereof. 
     
     
         22 . A compound according to  claim 10 , wherein Σ 2  is S, or modified form thereof. 
     
     
         23 . A compound according to  claim 10 , wherein Σ 3  is selected from G or T, or modified form thereof. 
     
     
         24 . A compound according to  claim 10 , wherein X 10  is selected from an acidic or small amino acid residue, or modified form thereof. 
     
     
         25 . A compound according to  claim 10 , wherein X 11  is A, or modified form thereof. 
     
     
         26 . A compound according to  claim 10 , wherein formula (III) is represented by:
   π 1 Ψ 1 Φ 2 Φ 3 π 2 π 3   X   12 Σ 4 Ψ 2 Ψ 3 Γ  (V)
   
       wherein:
 π 1 , π 2  and π 3  are independently selected from any neutral/polar amino acid residue, or modified form thereof; 
 Ψ 1  Ψ 2  and Ψ3 are independently selected from any basic amino acid residue, or modified form thereof; 
 Φ 2  and Φ 3  are independently selected from any hydrophobic amino acid residue, or modified form thereof; 
 X 12  is selected from any amino acid residue, or modified form thereof; 
 Σ 4  is a small amino acid residue, or modified form thereof; and 
 Γ is absent or is a peptide of 1-10 amino acid residues. 
 
     
     
         27 . A compound according to  claim 26 , wherein π 1  is a polar/large amino acid residue, or modified form thereof. 
     
     
         28 . A compound according to  claim 26 , wherein Ψ 1  is R, or modified form thereof. 
     
     
         29 . A compound according to  claim 26 , wherein Φ 2  is an amino acid residue that comprises an aliphatic side chain, or an aromatic side chain, or modified form thereof. 
     
     
         30 . A compound according to  claim 26 , wherein Φ 3  is selected from M or V, or modified form thereof. 
     
     
         31 . A compound according to  claim 26 , wherein π 2  is a polar/large amino acid residue, or modified form thereof. 
     
     
         32 . A compound according to  claim 26 , wherein π 3  is a polar/large amino acid residue, or modified form thereof. 
     
     
         33 . A compound according to  claim 26 , wherein X 12  is a small or basic amino acid residue, or modified form thereof. 
     
     
         34 . A compound according to  claim 26 , wherein Σ 4  is P, or modified form thereof. 
     
     
         35 . A compound according to  claim 26 , wherein Ψ 2  is K, or modified form thereof. 
     
     
         36 . A compound according to  claim 26 , wherein Ψ 3  is K, or modified form thereof. 
     
     
         37 . A compound according to  claim 26 , wherein π 1  is N, or modified form thereof, Ψ 1  is R, or modified form thereof, Φ 2  is I, L or F, or modified form thereof, Φ 3  is M or V, or modified form thereof, π 2  is Q, or modified form thereof, π 3  is N, or modified form thereof, X 12  is selected from R or P, or modified form thereof, Σ 4  is P, or modified form thereof, and each of Ψ 2  and Ψ 3  are K or modified form thereof. 
     
     
         38 . A compound according to  claim 26 , wherein Γ is present and is represented by the formula:
   Φ 4 Σ 5 Σ 6 Ξ  (VI)
 
 
       wherein:
 Φ 4  is a hydrophobic amino acid residue; 
 Σ 5  is small amino acid residue, or modified form thereof; 
 Σ 6  is small amino acid residue, or modified form thereof; and 
 Ξ is an acidic amino acid residue, or modified form thereof. 
 
     
     
         39 . A compound according to  claim 38 , wherein formula (VI) is represented by the sequence set forth in SEQ ID NO:14, or a variant or derivative thereof. 
     
     
         40 . A compound according to  claim 10 , wherein the C-terminal portion represented by Φ 1  is selected from any one of: SEQ ID NO:15-48. 
     
     
         41 . A compound according to  claim 10 , wherein Δ 1  and Φ 1  are independently selected from N-terminal portions and core structures, respectively, of natriuretic peptides selected from ANP, BNP, CNP, DNP, VNP, PNP or an  Oxyuranus  natriuretic peptide such as a natriuretic peptide from  Oxyuranus microlepidotus , or their variants or derivatives. 
     
     
         42 . A compound according to  claim 10 , wherein Δ 1  is present and is represented by the formula:
     OΣ   1   ∂X   1   X   2   X   3   X   4   X   5 Σ 2   (VII)
 
 
       wherein:
 O is absent or is a peptide of 1-10 amino acid residues; 
 Σ 1-2  are independently selected from any small amino acid residue, or modified form thereof; 
 ∂ is selected from any charged amino acid residue, or modified form thereof; and 
 X 1-5  are independently selected from any amino acid residue, or modified form thereof. 
 
     
     
         43 . A compound according to  claim 42 , wherein O is selected from a small amino acid residue, or modified form thereof, or a protecting moiety. 
     
     
         44 . A compound according to  claim 42 , wherein Σ 1  is selected from P or S, or modified form thereof. 
     
     
         45 . A compound according to  claim 42 , wherein ∂ is selected from an acidic or basic amino acid residue, or modified form thereof. 
     
     
         46 . A compound according to  claim 42 , wherein X 1  is selected from a hydrophobic, small or acidic amino acid residue, or modified form thereof. 
     
     
         47 . A compound according to  claim 42 , wherein X 2  is selected from a basic or hydrophobic amino acid residue, or modified form thereof. 
     
     
         48 . A compound according to  claim 42 , wherein X 3  is selected from a hydrophobic, neutral/polar or basic amino acid residue, or modified form thereof. 
     
     
         49 . A compound according to  claim 42 , wherein X 4  is selected from a small, basic or hydrophobic amino acid residue, or modified form thereof. 
     
     
         50 . A compound according to  claim 42 , wherein X 5  is selected from a neutral/polar, small, basic or acidic amino acid residue, or modified form thereof. 
     
     
         51 . A compound according to  claim 42 , wherein Σ 2  is selected from P, S or G, or modified form thereof. 
     
     
         52 . A compound according to  claim 42 , wherein Σ 1  is S, or modified form thereof, ∂ is D, or modified form thereof, X 1  is selected a small amino acid residue, or modified form thereof, X 2  is K, or modified form thereof, X 3  is I, or modified form thereof, X 4  is G, or modified form thereof, X 5  is selected from D or N, or modified form thereof, and Σ 2  is G, or modified form thereof. 
     
     
         53 . A compound according to  claim 42 , wherein Δ 1  is represented by a sequence selected from any one of SEQ ID NO:49-67. 
     
     
         54 . A compound according to  claim 10 , wherein Φ 1  is represented by the formula:
     CFGX   1   X   2 Φ 1   DRIX   3   X   4   X   5   SX   6   LGC   (VIII)
 
 
       wherein:
 X 1-6  are each independently selected from any amino acid residue, or modified form thereof; 
 Φ 1  is selected from a hydrophobic amino acid residue, or modified form thereof; and the two C residues are connected by a bridging bond. 
 
     
     
         55 . A compound according to  claim 54 , wherein X 1  is selected from a basic, hydrophobic, neutral/polar or a small amino acid residue, or modified form thereof. 
     
     
         56 . A compound according to  claim 54 , wherein X 2  is selected from a small or basic amino acid residue, or modified form thereof. 
     
     
         57 . A compound according to  claim 54 , wherein Φ 1  is selected from M, L or I, or modified form thereof. 
     
     
         58 . A compound according to  claim 54 , wherein X 3  is selected from a small, neutral/polar or basic amino acid residue, or modified form thereof. 
     
     
         59 . A compound according to  claim 54 , wherein X 4  is selected from a small or basic amino acid residue, or modified form thereof. 
     
     
         60 . A compound according to  claim 54 , wherein X 5  is selected from a small, basic, neutral/polar, or hydrophobic amino acid residue, or modified form thereof. 
     
     
         61 . A compound according to  claim 54 , wherein X 6  is selected from a small, basic or neutral/polar amino acid residue, or modified form thereof. 
     
     
         62 . A compound according to  claim 54 , wherein Φ 1  is represented by a sequence selected from any one of SEQ ID NO:68-81. 
     
     
         63 . A compound according to  claim 1 , which is represented by the formula:
   Δ 2 -Θ 2 -≠ 2   (IX)
   
       wherein:
 Δ 2  is absent or is a N-terminal portion of a natriuretic peptide or a variant or derivative of that portion; 
 Ω 2  is a C-terminal portion of a natriuretic peptide or a variant or derivative of that portion; and 
 Θ 2  comprises an amino acid sequence having the formula:
     CFGΦ   1   PLDRIX   1   SVSGLGC   (X)
 
 
 
       wherein:
 Φ 1  is selected from any hydrophobic amino acid residue, or modified form thereof; and 
 X 1  is selected from any small or a basic amino acid residue, or modified form thereof. 
 
     
     
         64 . A compound according to  claim 63 , wherein Φ 1  is selected from an amino acid residue having an aromatic side chain, or one having an aliphatic side chain, or modified form thereof. 
     
     
         65 . A compound according to  claim 63 , wherein X 1  is selected from G, S, R or K, or modified form thereof. 
     
     
         66 . A compound according to  claim 63 , wherein Δ 2  and Ω 2  are independently selected from N- and C-terminal portions, respectively, of natriuretic peptides selected from ANP, BNP, CNP, DNP, VNP, PNP or an  Oxyuranus  natriuretic peptide, or their variants or derivatives. 
     
     
         67 . A compound according to  claim 1 , which is represented by the formula:
   Δ 3 -Θ 3 -Ω 3   (XI)
   
       wherein:
 Φ 3  is a core ring structure of a natriuretic peptide or a variant or derivative of the structure; 
 Ω 3  is a C-terminal portion of a natriuretic peptide or a variant or derivative of the portion; and 
 Δ 3  comprises an amino acid sequence having the formula:
   SDΣ 1 KGX 1 G  (XII)
 
 
 
       wherein:
 Σ 1  is selected from any small amino acid residue, or modified form thereof; and 
 X 1  is selected from any amino acid residue, or modified form thereof. 
 
     
     
         68 . A compound according to  claim 67 , wherein Σ 1  is S or P, or modified form thereof. 
     
     
         69 . A compound according to  claim 67 , wherein X 1  is an acidic or neutral polar amino acid residue, or modified form thereof. 
     
     
         70 . A compound according to  claim 67 , wherein Θ 3  and Ω 3  are independently selected from core structures and C-terminal portions, respectively, of natriuretic peptides selected from ANP, BNP, CNP, DNP or an  Oxyuranus  natriuretic peptide, or their variants or derivatives. 
     
     
         71 . An isolated proteinaceous compound having at least one activity selected from vasodilatory, natriuretic, diuretic, renin-suppressing, bactericidal, weight-reducing or bone growth plate size-increasing activities, in vertebrate animals including mammals, wherein the compound has the formula:
     Z   1   SDΣ   1   KIGX   1   GCFGΦ   1   PLDB   1   IX   2   SVSGLGCNRX   3 Φ 2   QNX   4   PKKZ   2   (XIII)
   
       wherein:
 Z 1  is absent or is a peptide from about 1 to about 50 amino acids or is a protecting moiety; 
 Σ 1  is a small amino acid residue, or modified form thereof; 
 X 1  is an acidic or neutral/polar amino acid residue, or modified form thereof; 
 Φ 1  is a hydrophobic amino acid residue, or modified form thereof; 
 B 1  is a basic amino acid residue, or modified form thereof; 
 X 2  is a basic or small amino acid residue, or modified form thereof; 
 X 3  is a small or hydrophobic amino acid residue, or modified form thereof; 
 Φ 2  is a hydrophobic amino acid residue, or modified form thereof; 
 X 4  is a basic or small amino acid residue, or modified form thereof; and 
 Z 2  is absent or is a peptide of from about 1 to about 10 amino acids, 
 the two C residues are connected by a bridging bond, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         72 . A compound according to  claim 71 , wherein Σ 1  is selected from P or S, or modified form thereof. 
     
     
         73 . A compound according to  claim 71 , wherein X 1  is selected from Q, K, A, S, D or N, or modified form thereof. 
     
     
         74 . A compound according to  claim 71 , wherein Φ 1  is selected from L or F, or modified form thereof. 
     
     
         75 . A compound according to  claim 71 , wherein B 1  is selected from H, K or R, or modified form thereof. 
     
     
         76 . A compound according to  claim 71 , wherein X 2  is selected from G, S, R or K, or modified form thereof. 
     
     
         77 . A compound according to  claim 71 , wherein X 3  is selected from P or I, or modified form thereof. 
     
     
         78 . A compound according to  claim 71 , wherein Φ 2  is selected from V, Nle or M, or modified form thereof. 
     
     
         79 . A compound according to  claim 71 , wherein X 4  is selected from R or P, or modified form thereof. 
     
     
         80 . A compound according to  claim 71 , wherein the sequence Asn-Pro is replaced by a sequence selected from Ala-Pro, Gln-Pro, Ala-Hyp or Gln-Hyp. 
     
     
         81 . A compound according to  claim 71 , wherein the sequence Asn-Gly is replaced by a sequence selected from Gln-Gly or Ala-Gly. 
     
     
         82 . A compound according to  claim 71 , wherein M is replaced by Nor or V. 
     
     
         83 . A compound according to  claim 71 , wherein one or both C residues are replaced by selenocysteine 
     
     
         84 . A compound according to  claim 71 , wherein the N-terminus is blocked by pGlu, Pro, Hyp or any N-acetylated residue. 
     
     
         85 . A compound according to  claim 71 , wherein the C-terminus is blocked by amidation or cyclization. 
     
     
         86 . A compound according to  claim 71 , wherein the peptide Z 2  is present and comprises the sequence set forth in SEQ ID NO:14. 
     
     
         87 . A compound according to  claim 71 , wherein the bridging bond that connects the two C residues is selected from the group consisting of a disulfide bond, a lanthionine bond, a diselenide or mixed sulfide-selenide bond, a methylene bond, a dimethylene bridge, a sulfide/methylene bond, an amide bond and an ester bond. In specific embodiments, the bridging bond is a disulfide bond. 
     
     
         88 . A compound according to  claim 71 , wherein the bridging bond is a disulfide bond. 
     
     
         89 . An isolated proteinaceous compound having at least one activity selected from vasodilatory, natriuretic, diuretic, renin-suppressing, bactericidal, weight-reducing or bone growth plate size-increasing activities, in vertebrate animals including mammals, wherein the compound has the formula:
     Z   1   SDΣ   1   KIGX   1   GCFGX   2   B   1 Φ 1   DRIX   3   X   4   X   5   SX   6   LGCNRX   3 Φ 2   QNX   4   PKKZ   2   (XVIII)
   wherein:
 Z 1  is absent or is a peptide from about 1 to about 50 amino acids or is a protecting moiety; 
 Σ 1  is a small amino acid residue, or modified form thereof; 
 X 1  is an acidic or neutral/polar amino acid residue, or modified form thereof; 
 B 1  is a basic amino acid residue, or modified form thereof; 
 Φ 1  is a hydrophobic amino acid residue, or modified form thereof; 
 X 2  is a small, hydrophobic or basic amino acid residue, or modified form thereof; 
 X 3  is a small or neutral/polar amino acid residue, or modified form thereof; 
 X 4  is a small or basic amino acid residue, or modified form thereof; 
 X 5  is a small, hydrophobic or neutral/polar amino acid residue, or modified form thereof; 
 X 6  is a small or neutral/polar amino acid residue, or modified form thereof; 
 X 7  is a small or hydrophobic amino acid residue, or modified form thereof; 
 Φ2 is a hydrophobic amino acid residue, or modified form thereof; 
 X 8  is a basic or small amino acid residue, or modified form thereof; and 
 Z 2  is absent or is a peptide of from about 1 to about 10 amino acids, 
 the two C residues are connected by a bridging bond, 
 or a pharmaceutically acceptable salt thereof. 
   
     
     
         90 . A compound according to  claim 89 , wherein Σ 1  is selected from P or S, or modified form thereof. 
     
     
         91 . A compound according to  claim 89 , wherein X 1  is selected from Q, K, A, S, D or N, or modified form thereof. 
     
     
         92 . A compound according to  claim 89 , wherein B 1  is selected from K or R, or modified form thereof. 
     
     
         93 . A compound according to  claim 89 , wherein X 2  is selected from G, F, L, H or R, or modified form thereof. 
     
     
         94 . A compound according to  claim 89 , wherein Φ 1  is selected from L, I or M, or modified form thereof. 
     
     
         95 . A compound according to  claim 89 , wherein X 3  is selected from G, S or N, or modified form thereof. 
     
     
         96 . A compound according to  claim 89 , wherein X 4  is selected from A, S or H, or modified form thereof. 
     
     
         97 . A compound according to  claim 89 , wherein X 5  is selected from S, V, M or Q, or modified form thereof. 
     
     
         98 . A compound according to  claim 89 , wherein X 6  is selected from G or N, or a modified form thereof. 
     
     
         99 . A compound according to  claim 89 , wherein X 7  is selected from P or I, or modified form thereof. 
     
     
         100 . A compound according to  claim 89 , wherein Φ 2  is selected from V or M, or modified form thereof. 
     
     
         101 . A compound according to  claim 89 , wherein X 8  is selected from R or P, or modified form thereof. 
     
     
         102 . A compound according to  claim 89 , wherein the sequence Asn-Pro is replaced by a sequence selected from Ala-Pro, Gln-Pro, Ala-Hyp or Gln-Hyp. 
     
     
         103 . A compound according to  claim 89 , wherein the sequence Asn-Gly is replaced by a sequence selected from Gln-Gly or Ala-Gly. 
     
     
         104 . A compound according to  claim 89 , wherein M is replaced by Nor or V. 
     
     
         105 . A compound according to  claim 89 , wherein one or both C residues are replaced by selenocysteine 
     
     
         106 . A compound according to  claim 89 , wherein the N-terminus is blocked by pGlu, Pro, Hyp or any N-acetylated residue. 
     
     
         107 . A compound according to  claim 89 , wherein the C-terminus is blocked by amidation or cyclization. 
     
     
         108 . A compound according to  claim 89 , wherein the peptide Z 2  is present and comprises the sequence set forth in SEQ ID NO:14. 
     
     
         109 . A compound according to  claim 89 , wherein the bridging bond that connects the two C residues is selected from the group consisting of a disulfide bond, a lanthionine bond, a diselenide or mixed sulfide-selenide bond, a methylene bond, a dimethylene bridge, a sulfide/methylene bond, an amide bond and an ester bond. In specific embodiments, the bridging bond is a disulfide bond. 
     
     
         110 . A compound according to  claim 89 , wherein the bridging bond is a disulfide bond. 
     
     
         111 . A compound according to  claim 71 , wherein the compound comprises any one of the sequences set forth in SEQ ID NO: 90, 91, 94-114, 117, 118, 120, 123, 124, 126-130, 132-134, 150, 154, 160, 166-169, 173, 176 and 178-192. 
     
     
         112 . A compound according to  claim 89 , wherein the compound comprises any one of the sequences set forth in SEQ ID NO: 131 and 193-196 
     
     
         113 . An isolated polynucleotide that comprises a nucleotide sequence encoding a compound according to any one of  claim 1 ,  71  or  89 . 
     
     
         114 . A vector that comprises a polynucleotide according to  claim 113 , which is operably connected to a regulatory sequence. 
     
     
         115 . A host cell containing a vector according to  claim 114 . 
     
     
         116 . A process for producing a compound according to any one of  claim 1 ,  71  or  89 , comprising culturing a host cell containing a vector that comprises a polynucleotide operably connected to a regulatory sequence and encoding said compound, under conditions sufficient to produce the compound and isolating the compound. 
     
     
         117 . An antigen-binding molecule that is immuno-interactive with a compound according to any one of  claim 1 ,  71  or  89 . 
     
     
         118 . A pharmaceutical composition comprising a compound according to any one of  claims 1 ,  71  and  89 , and a pharmaceutically acceptable carrier, excipient and/or diluent. 
     
     
         119 . A method for inducing, stimulating or otherwise promoting in a subject at least one activity in a subject selected from vasodilatory, natriuretic, diuretic, renin-suppressing, bactericidal, weight-reducing or bone growth plate size-increasing activities, comprising administering to the subject an effective amount of a compound according to any one of  claim 1 ,  71  or  89 . 
     
     
         120 . A method for treating or preventing at least one of condition selected from heart failure, nephrotic syndrome, cirrhosis of the liver, hypertension, kidney failure, bacterial infections, weight loss, asthma, inflammatory-related diseases; erectile dysfunction; hypercholesterolemia; skeletal dysplasias and as a protectant for toxicity of anti-cancer drugs, in a subject, comprising administering to the subject an effective amount of a according to any one of  claim 1 ,  71  or  89 .