时间：2018-07-19 15:26:43 阅读数：0
Hierarchical Strategies to Transform Native Peptides into Drug Candidates
Peptide oral bioavailability remains elusive, although what was once thought to be the exceptional case of cyclosporine A is changing as a result of a deeper analysis of macrocyclic peptides to understand the relationship of the structural and conformational impact of backbone modifications, ring size and side-chain lipophilicity to passive transport (see later).Consequently, a majority of marketed peptide therapeutics leverage subcutaneous and injectable routes of administration. Such modified peptides and peptidomimetics exemplify classic hierarchical strategies to achieve an effective combination of high affinity to target and proteolytic stability, including (i) backbone amide N-alkylation; (ii) backbone amide replacement with non-hydrolyzable surrogates; (iii) amino acid Cα-stereoinversion and/or Cα-alkylation; (iv) β-amino acids; (v) cyclic α-/β-amino acids; (vi) dipeptide replacements that mimic canonical secondary structural motifs such as α-helix, β-strand/β-sheet or β-/γ-turns; and (vii) macrocyclization designed to stabilize α-helical, β-strand/β-sheet, β-/γ-turns and/
or other conformationally restricted peptide/peptidomimetic chemotypes (e.g., monocyclic or multicyclic). A few examples of the pioneering and contemporary chemistry that has contributed to modified peptides and peptidomimetics are described below.
For receptor-targeted peptide therapeutics, long-lasting exposure levels in vivo have been achieved using varying approaches, including both chemical conjugation (e.g., fatty acids, polyethylene glycol, antibodies and related recombinant proteins and serum albumin) and sustained-release formulations applicable to parenteral routes of administration (e.g., subcutaneous). Specific examples include the palmitoyl-modified glucagon-like peptide-1 (GLP-1) agonist liraglutide,28 a pegylated GLP-1 agonist/glucagon antagonist hybrid peptide,29 the pegylated granulocyte colony-stimulating fact.