This invention relates to methods for preparing cyclic peptides and
peptidomimetic compounds in solution and bound to solid supports, and to
cyclic peptide or peptidomimetic libraries for use in drug screening
programs. In particular, the invention relates to a generic strategy for
synthesis of cyclic peptides or peptidomimetics that enables the
efficient synthesis under mild conditions of a wide variety of desired
compounds. Two approaches were evaluated for their improvements in
solution and solid phase synthesis of small cyclic peptides: positioning
reversible N-amide substituents in the sequence; and applying native
ligation chemistry in an intramolecular sense. Systematic investigation
of the effects of preorganising peptides prior to cyclisation by using
peptide cyclisation auxiliaries, and developing new linkers and peptide
cyclisation auxiliaries to aid cyclic peptide synthesis gives surprising
improvements in both yields and purity of products compared to the prior
art methods. The combination of these technologies provides a powerful
generic approach for the solution and solid phase synthesis of small
cyclic peptides. The ring contraction and N-amide substitution technology
of the invention provide improved methods for the synthesis of cyclic
peptides and peptidomimetics. When used in conjunction with linker
strategies, this combination provides solid-phase avenues to cyclic
peptides and peptidomimetics.