Page - (000253) - in Biomedical Chemistry: Current Trends and Developments

and a high intestinal permeability barrier (Woodley, 1994). Table 3.1.4: Lead peptide chemical optimization (adapted from Vlieghe, 2010). Lead Attribute 1 Blocking N- or C-terminal ends by N-acylation, N-pyroglutamate, C-amidation and so on, or addition of carbohydrate chains (glycosylation: glucose, xylose, hexose and so on) to increase plasma stability (notably, resistance towards exopeptidases) 2 Search for the minimum active sequence (MAS) from N- and/or C-terminal truncated analogues 3 Simplification and/or optimization of the structure after alanine scanning (Ala-scan) and/or D-scanning (D-scan) to eliminate potential sites of cleavage (notably by endopeptidases) and to determine important functional groups involved in the interaction with the target of interest 4 Isosteric, or not, amide bond replacement between two amino acids: NH-amide alkylation, the carbonyl function of the peptide bond can be replaced by CH2 (reduced bond: -CH2-NH-), C(S) (endothio-peptide, -C(S)-NH-) or PO2H (phosphonamide, -P(O)OH- NH-). NH-amide bond can be exchanged by O (depsipeptide, -CO-O-), S (thioester, -CO-S- ) or CH2 (ketomethylene, -CO-CH2-). The peptide bond can also be modified: retro- inverso bond (-NH-CO-), methyleneoxy bond (-CH2-), thiomethylene bond (-CH2-S-), carba bond (-CH2-CH2-), hydroxyethylene bond (-CHOH-CH2-) and so on, to increase plasma stability of the peptide sequence (notably towards endopeptidases) 5 Cyclization of the peptide sequence (between side chains or ends of the peptide sequence: head to tail, N-backbone to N-backbone, end to N-backbone, end to side chain, side chain to N-backbone, side chain to side chain) through disulfides (disulfide- bond cyclization scan), lanthionine, dicarba, hydrazine or lactam bridges, to decrease the conformational flexibility of linear peptides and reduce hydrogen bonding, enhance membrane permeability, and most importantly to increase their stability against proteolysis by endo- and exopeptidases 6 Substitution of a natural amino acid residue by an unnatural amino acid (D- configuration), an N-methyl-α-amino acid, a non-proteogenic constrained amino acid or a β-amino acid, to increase plasma stability (e.g. resistance to endopeptidases) of the peptide and/or affinity (activity) for its target 7 Deletion of one or more consecutive amino acid(s) and combinatorial deletion with two or more positions omitted independently throughout the sequence