Peptidomimetic therapeutics: scientific approaches and opportunities

Abstract

Natural endogenously occurring peptides exhibit desirable medicinal properties, but are often limited in application by rapid proteolysis and inadequate membrane permeability. However, editing naturally occurring peptide sequences to develop peptidomimetic analogs created a promising class of therapeutics that can augment or inhibit molecular interactions. Here, we discuss a variety of chemical modifications, including l to d isomerization, cyclization, and unnatural amino acid substitution, as well as design strategies, such as attachment to cell-penetrating peptides, which are used to develop peptidomimetics. We also provide examples of approved peptidomimetics and discuss several compounds in clinical trials.

FIGURE 1

Peptidomimetic therapeutics approved for American, European, and/or Japanese pharmaceutical markets that were mentioned in this study (also see Table 1, main text). Compounds are organized by corresponding modifications: (a) L to D amino acid substitution; (b) incorporation of unnatural amino acids; and (c) and cyclization.

FIGURE 1

Peptidomimetic therapeutics approved for American, European, and/or Japanese pharmaceutical markets that were mentioned in this study (also see Table 1, main text). Compounds are organized by corresponding modifications: (a) L to D amino acid substitution; (b) incorporation of unnatural amino acids; and (c) and cyclization.