Designing short peptides: A Sisyphean task?

Over the last few years, short peptides have become a powerful tool in basic and applied research, with different uses like diagnostic, antimicrobial peptides, human health promoters or bioactive peptides, therapeutic treatments, templates for peptidomimetic design, and peptide-based vaccines. In this endeavor, different approaches and technologies have been explored, such as bioinformatics, large-scale peptide synthesis, omics sciences, structure-activity relationship studies, and a biophysical approach, among others, seeking to obtain the shortest sequence with the best activity. The advantage of short peptides lies in their stability, ease of production, safety, and low cost. There are many strategies for designing short peptides with biomedical and industrial applications (targeting the structure, length, charge, or polarity) or as a starting point for improving their properties (sequence data base, de novo sequences, templates, or organic scaffolds). In peptide design, it is necessary to keep in mind factors such as the application (peptidomimetic, immunogen, antimicrobial, bioactive, or protein-protein interaction inhibitor), the expected target (membrane cell, nucleus, receptor proteins, or immune system), and particular characteristics (shorter, conformationally constrained, cycled, charged, flexible, polymerized, or pseudopeptides). This review summarizes the different synthetic approaches and strategies used to design new peptide analogs, highlighting the achievements, constraints, and advantages of each.