New Insights into Bioactive Peptides: Design, Synthesis, Structure–Activity Relationship

In recent decades, peptides have attracted significant attention not only from Academia but also from big Pharma as novel potential therapeutic compounds. Peptides are made up of amino acids and only differ from proteins in terms of their smaller size (up to ~50 residues). Contrarily to small molecules, peptides do not generally obey to “Lipinski’s rule of five” (also known as “Pfizer’s rule of five”) for orally bioactive drugs. However, medicinal chemistry efforts have lately allowed researchers to establish novel synthetic routes so that peptide drug-like features can now be largely improved. For example, peptides translated into peptidomimetics or peptoids with unusual backbones, unnatural amino acids or peculiar cyclic organizations can be provided with specific secondary structure elements and become more resistant to proteolytic cleavage or even acquire better membrane permeability, resulting in improved drug-like characteristics for therapeutic applications. Despite their poor pharmacokinetics, in comparison with small molecules, peptides are characterized by great pharmacodynamic properties. In fact, peptides can be designed ad hoc to modulate specific “undruggable” protein–protein interactions and achieve desired in-cell biological effects. Their larger size in comparison with small molecules allows peptides to establish many different interactions with target macromolecules and achieve high affinity, specificity and efficacy that produce fewer sideand off-target effects for applications in the therapeutic field. Peptides also have some advantages with respect to other therapeutic biologics (like antibodies, therapeutic proteins and vaccines), including decreased immunogenicity and lower production-associated costs. In the biomedical field, peptides can be employed as original therapeutics but also be implemented as drug-delivery tools to distribute drugs to specific cells that overexpress certain receptors on their surfaces, or as theragnostic compounds, for example, by exploiting their self-assembly properties and/or linking them to contrast agents for employment in magnetic resonance imaging. Considering primarily the impact of peptides in the biomedical field and the variety of their applications, in the framework of this Special Issue, we invited authors to submit research and review articles centered on the design and characterization of bioactive peptides, with a particular focus on crucial structure–activity data that could promote the understanding of their mechanisms of action within the cell. This Special Issue includes 10 research and 2 review articles.