Therapies using non-natural amino acids and polypeptides

A method for treating a growth hormone deficiency, comprising administering to a subject in need thereof a therapeutically effective amount of human growth hormone (hGH), having at least one non-natural amino acid in the B-C loop, the A-B loop, the C-D loop, proximal to helix A, or distal to the final helix of human growth hormone (hGH), wherein the at least one non-natural amino acid has the structure:

• wherein:
• A is phenylene;
• B is a bond;
• R is alkyl;
• R3 and R4 are H;
• R1 is H, an amino protecting group, or at least one amino acid of human growth hormone (hGH);
• and
• R2 is OH, an ester protecting group, or at least one amino acid of human growth hormone (hGH);
• R5 is L—X, where
• X is a polyalkylene glycol;
• and
• L is optional, and when present is a linker selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —O-(alkylene or substituted alkylene)-, —S-(alkylene or substituted alkylene)-, —S(O)k(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O—N═CR′—, -(alkylene or substituted alkylene)-C(O)NR′-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S(O)k-(alkylene or substituted alkylene)-S—, -(alkylene or substituted alkylene)-S—S—, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N—N═, —C(R′)2—N═N—, and —C(R′)2—N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl;
• and
• k is 1 or 2.