A variety of peptides active in biological pathways have been identified e.g. receptor antagonists or inhibitors
of protein–protein interactions and several peptide or peptide-derived compounds are on the drug market or in clinical trials.
Through the rational design or the combinatorial preparation and High-throughput screening of arrays of compounds,
peptides play a pivotal role for the rapid identification of ligands, but, despite these favorable properties, they often present
poorer bioavailability and lower metabolic stability respect to traditional drugs. The process of conversion of a peptide
in a small molecule provides the reduction of the peptide to the minimum active sequence (MAS) testing truncated
peptides from the C- and N- termini alternatively. Then the influence of individual amino acid on the biological activity is
determined by systematically replacing each residue in the peptide with specific amino acids. After structure–activity
relationship (SAR) of each amino acid in the sequence has been assessed, the bioactive conformational flexibility is
reduced by introducing constraints at various positions. These features are used for the design of a pharmacophore model
in which functional groups crucial for activity are pre-positioned. Here we propose a panoramic review of the common
principles for the conversion of peptides into small organic molecules and the most interesting findings in peptide-based
leads of the last decades.
Keywords: Peptides as drugs, small molecules, molecular Interaction.
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