Stable Analogs of Peptide and Polypeptide Therapeutics

A proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has an amino acid sequence including a proteinase substrate sequence that is cleaved under physiological conditions by a target post-proline cleaving proteinase, wherein said analog has an amino acid sequence corresponding to said peptide or polypeptide factor where the P′1 residue of said proteinase substrate sequence is replaced with a non-naturally occurring amino acid analog of Formula I:

• wherein
• R1 and R2 are independently selected from lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, carboxyl, carboxamide, carbonyl, halogen, hydroxyl, amine, or cyano, or R1 and R2 taken together form a ring of 4-7 atoms;
• R3 is selected from lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, alkoxyl, halogen, carboxyl, carboxamide, carbonyl, cyano, thioalkyl, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamido, —(CH2)m—R4, —(CH2)mOH, —(CH2)mCOOH, —(CH2)mO-lower alkyl, —(CH2)mO-lower alkenyl, —(CH2)mO(CH2)m—R4, —(CH2)mSH, —(CH2)mS-lower alkyl, —(CH2)mS-lower alkenyl, —(CH2)nS(CH2)m—R4;
• —(CH2)mNH2, —(CH2)mN—C(═NH)NH2, —(CH2)mC(═O)NH2, or —(CH2)mNH2;
• R4 represents, independently for each occurrence, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• m is 0, 1, or 2;
• and
• n is 0, 1, or 2.

A proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:

• (SEQ ID NO:
• 35)
• HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
• wherein X is a non-naturally occurring amino acid analog of Formula II:
• wherein
• R1 and R2 are independently selected from a lower alkyl or a halogen;
• R3 is selected from lower alkyl, aryl, hydroxyl group, —(CH2)m—COOH, —(CH2)m—NH2, —(CH2)m—N—C(═NH)NH2, —(CH2)m—C(═O)NH2, —SH, or —(CH2)m—S—CH3;
• and
• m is 0, 1, or 2.

A method for treating or preventing a disease or condition in which administration of a proteinase-resistant analog would be beneficial, comprising administering a proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:

• (SEQ ID NO:
• 35)
• HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
• wherein X is a non-naturally occurring amino acid analog of Formula II:
• wherein
• R1 and R2 are independently selected from a lower alkyl or a halogen;
• R3 is selected from lower alkyl, aryl, hydroxyl group, —(CH2)m—COOH, —(CH2)m—NH, —(CH2)m—N—C(═NH)NH2, —(CH2)m—C(═O)NH2, —SH, or —(CH2)m—S—CH3;
• and
• m is 0, 1, or 2.

A method for the modification of glucose metabolism, comprising administering a proteinase-resistant analog of a biologically active peptide or polypeptide factor, which peptide or polypeptide factor has the following amino acid sequence:

• (SEQ ID NO:
• 35)
• HAXGTFTSDVSSYLEGQAAKEFIAWLVKGRPSSGAPPPS-NH2
• wherein X is a non-naturally occurring amino acid analog of Formula II:
• wherein
• R1 and R2 are independently selected from a lower alkyl or a halogen;
• R3 is selected from lower alkyl, aryl, hydroxyl group, —(CH2)m—COOH, —(CH)m—NH2, —(CH2)m—N—C(═NH)NH2, —(CH2)m—C(═O)NH2, —SH, or —(CH2)m—S—CH3;
• and
• m is 0, 1, or 2.