Peptidomimetics That Mimic the Tertiary Structures of Peptides

Abstract

In the previous chapter, peptidomimetics of secondary structures involving stapled peptides are described. This chapter introduces peptidomimetics of tertiary structures of peptides, which are also useful for the development of inhibitors of protein–protein interactions. The HIV-1 gp41 ectodomain contains N-terminal heptad repeat (NHR) (heptad repeat 1; HR1) and C-terminal heptad repeat (CHR) (heptad repeat 2; HR2) domains, both of which have helical structures. N36 or C34 is an NHR- or CHR-derived helical peptide, respectively. A three-helical bundle mimetic corresponding to the equivalent trimeric form of N36 was designed and synthesized. As a result, mice immunized with this N36 trimer mimetic induced neutralizing antibodies with higher binding affinity for the N36 trimer than that for the corresponding monomer. Furthermore, a three-helical bundle mimicking the equivalent trimeric form of C34 and the C34 dimer mimetic was designed and synthesized. As a result, the HIV-1 inhibitory potencies of the C34 trimer and dimer mimetics are one hundred times higher than that of the corresponding monomer. The NHR region is more suitable as a vaccine target than the CHR region while the CHR region is more suitable as an inhibitor target. In each case, the assembly of triple (or double)-helical peptides using a C 3-symmetric template is effective to remodel and mimic the natural tertiary structures of the proteins.