Principles and applications of small molecule peptidomimetics

Peptidomimetic chemistry is a well-established approach for the generation of small-molecule-based drugs acting as enzyme inhibitors or receptor ligands. Since the introduction of this concept in the 1990s, this approach is still relevant in drug discovery, given the significance and importance of developing drugs starting from bioactive peptides. In fact, the generation of small molecule peptidomimetics consists of reducing the conformational flexibility and the peptide character to improve the potency and selectivity, and to achieve hit compounds with improved bioactivity and pharmacokinetics profile. The synthetic approaches toward peptidomimetics have evolved over the years, spanning from combinatorial chemistry to solid-phase synthesis and heterocyclic chemistry. This chapter aims to give an overview of peptidomimetics and their classification based on common structural features, and to discuss the key synthetic approaches to achieve bioactive compounds of “peptidomimetic nature.” Also, the case study of HIV protease inhibitors is to document the relevance of peptidomimetics in drug discovery.