ABSTRACT
The development of peptide drugs and potential applications of peptides as immunogens or as immunomodulators are often impaired by their high susceptibility to enzymatic degradation and their rapid clearance from the circulation. Moreover, the bioactive conformations of peptides are often poorly defined as a result of their inherent flexibility. With the aim of circumventing these problems, intense research has been focused in the past 20 years on chemical modifications of the peptide backbone [1], i.e., "backbone chemistry. " Enhanced biological lifetime and stabilization of secondary structures can be achieved through the incorporation of D-amino acids, N-alkyl-aamino acids, or other nonnatural constrained amino acid derivatives. Alternatively, the introduction of nonhydrolyzable peptide bond surrogates (denoted ljJ[ ] according to Spatola's nomenclature for pseudopeptides [1]) or the replacement of the caH group by a nitrogen (azapeptides) also proved useful in converting biologically active peptides into more stable molecules with similar or even enhanced biological activity, with improved selectivity, or with antagonist properties [1-7]. Methylene amino ljJ[CH2NH] [8,9], retro-inverso ljJ[NHCO] [10-13], (E)- or (Z)-alkene ljJ[CH=CH] [14,15], carba ljJ[CHzCHz] [16,17], hydroxyethy1ene ljJ[CHOHCH2] [18-20], methyleneoxy ljJ[CH20] [21-24], and ketomethylene ljJ[COCHz] [25,26], are the most popular amide bond replacements found in the literature. Although most syn-
thetic routes to these modifications have been developed in solution, successful approaches to the solid-phase synthesis of l/I[NHCO] [27] and l/I[CHzNH] [28] pseudopeptides were proposed as early as 1983 and 1987, respectively, allowing the rapid generation of large and diverse sets of pseudopeptides for biological testing. Since these pioneering works, the synthesis of several other peptide bond surrogates has been made accessible on solid supports, including (E)-alkene [29], aza(-azXaa-) [30-32], iminoaza (-Xaa l/I[CH=NH]azXbb-) [32], reduced aza (-Xaa l/I[CHzNH]azXbb-) [32], carbaza (-Xaa l/I[CHzCHz]azXbb-) [33], N-hydroxyamide l/I[CONOH] [34], and depsipeptide l/I[COO] [35]. In addition, important synthetic efforts have been made to synthesize on the solid phase protease inhibitors incorporating stable transition state mimics such as hydroxyethylene, hydroxyethyleneamine [36-38], and diamino diol [39].
