C-Type Natriuretic Peptides and Methods Thereof in Treating Acute Lung Injury

A method of treating a subject having, or at risk of developing ALI or ARDS, comprising

• administering to the subject a therapeutically effective bolus dose of a composition comprising a long acting CNP derivative or a very long acting CNP derivative comprising U-GLSKGCFGLKLDRIGSMSGLGC [SEQ ID NO. 2], U-GLSKGCFGLK(U)LDRIGSMSGLGC [SEQ ID NO. 3], GLSKGCFGLK(U)LDRIGSMSGLGC [SEQ ID NO. 4], U-CFGLKLDRIGSxSGLGC, where x is a natural or unnatural amino acid residue [SEQ ID NO. 11], or any combination thereof,
• wherein:
• U is a moiety of Formula (I) or (II), where Formula (I) is
• (aliphatic)a-(X)-;
• (I)
• wherein
• a is 1;
• aliphatic is an optionally substituted C4-24 chain (e.g., an optionally substituted C10-24 chain, an optionally substituted C12-18 chain), covalently bound to X via a chemical linkage, such as a carbonyl (e.g., as part of an amide or an ester linkage), a thioether, an ether, a thioether, a carbamate moiety, a bond, or the like with X;
• preferably via a carbonyl as part of an amide or an ester linkage;
• or more preferably via a carbonyl as part of an amide linkage with X;
• X is a 1-10 amino acid residue or peptide sequence, wherein each amino acid residue is independently selected from lysine (K), arginine (R), glycine (G), alanine (A), glutamic acid (E), and aspartic acid (D);
• or
• X is a linker (γE)m-(B)n wherein B is 1-8 amino acid residue or peptide sequence wherein each amino acid residue is independently selected from 2-[2-(2-aminoethoxy)ethoxy]acetic acid residue, Gly, Ala, Leu, Ser, Arg, and Lys;
• m is 0, 1, 2, or 3;
• n is 0, 1, 2, or 3;
• and the sum of m and n is at least 1;
• and Formula (II) is
• (polymer)a-(Y)-;
• (II)
• wherein
• a is 1;
• polymer is cellulose, poly(ethylene glycol) (PEG), methoxy poly(ethylene glycol) (MPEG), poly(lactic-co-glycolic acid), poly(N-vinyl pyrrolidone), or a derivative thereof;
• Y is:
• a 1-10 amino acid residue or peptide sequence, wherein each amino acid residue is independently selected from lysine (K), arginine (R), glycine (G), alanine (A), glutamic acid (E), and aspartic acid (D);
• a non-amino acid linker comprising an ester, an amide, a thioether, an ether, a thioether, a carbamate moiety, or a combination thereof;
• an amino acid residue-containing linker, wherein the amino acid residue is covalently attached to (polymer)a;
• or
• a peptide linker different from the 1-10 amino acid residue or peptide sequence;
• wherein the composition does not decrease blood pressure by more than 15% of a baseline blood pressure measurement;
• and
• wherein the composition increases plasma cyclic-GMP level at from 1 hour to 12 hours of a baseline plasma cyclic-GMP level, and the baseline plasma cyclic-GMP level is an average plasma cyclic-GMP level prior to administration of the composition or the average plasma cyclic-GMP level of a healthy subject.

A composition comprising a long acting CNP derivative of comprising a formula U-CFGLKLDRIGSxSGLGC [SEQ ID NO. 30], wherein

• x is a natural or unnatural amino acid residue, provided that x is not a methionine residue;
• and
• U has is a moiety of Formula (I):
• (aliphatic)a-(X)-;
• (I)
• wherein a is 1;
• aliphatic is an optionally substituted C4-24 chain (e.g., an optionally substituted C10-24 chain, an optionally substituted C12-18 chain), covalently bound to X via a chemical linkage, such as a carbonyl (e.g., as part of an amide or an ester linkage), a thioether, an ether, a thioether, a carbamate moiety, a bond, or the like with X;
• preferably via a carbonyl as part of an amide or an ester linkage;
• or more preferably via a carbonyl as part of an amide linkage with X;
• X is a linker (γE)m-(B)n wherein B is 1-8 amino acid residue or peptide sequence wherein each amino acid residue is independently selected from 2-[2-(2-aminoethoxy)ethoxy]acetic acid residue, Gly, Ala, Leu, Ser, Arg, and Lys;
• m is 0, 1, 2, or 3;
• n is 0, 1, 2, or 3;
• and the sum of m and n is at least 1.