Peptidomimetics

Peptides are open-chain polymers composed of amino acids linked by amide bonds. The side chains branch off from the main chain at the Cα-atoms and have a high degree of flexibility. When such a polymer contains up to 30-50 amino acids, it is called a peptide; beyond this limit, it is called a protein. Peptides are responsible for a wide range of biological functions. However, their applicability as drugs is limited by their size, polarity, and poor proteolytic stability. Because of their multiple functions, peptides are attractive to be mimicked with smaller, similarly binding, and metabolically stable peptidomimetics. Peptidomimetic design begins with the identification of the minimal peptide sequence responsible for a biological effect. This is followed by the successive replacement of each amino acid in the chain with an alanine to reveal the side chains that are responsible for the activity. Finally, individual amino acids are replaced with nonproteinogenic or similar chemical building blocks. Several surrogates for amino acid side chains have been developed. They can be tested to reveal better binding and more stable peptidomimetics. When not involved in direct binding, main-chain amide bonds can be replaced by a variety of substitutes that achieve similar geometry. Peptides are flexible and can adopt multiple conformations. If a particular fold is adopted for the correct orientation of interacting side chains, the peptide backbone can be replaced by a completely different scaffold that correctly positions the essential interacting groups. By means of specific turns, peptides fold on themselves. These turns stabilize a desired conformation. They can be chemically replaced by rigid structural surrogates that freeze a particular turn conformation. Proteins communicate with each other through the formation of large, shared surface areas. Small molecules that are designed to bind to such flat surfaces can antagonize the formation of protein-protein complexes and disrupt the communication between proteins. Depressions on the surface that accommodate spatial patterns such as turns or helical portions of the penetrating contact surface of the partner protein are exploited in the design of small molecules to block protein-protein interface formation. Peptides bind to receptors primarily through side chains, and the backbone provides the scaffold for their attachment. Computer programs can be used to search structural databases for alternative scaffolds that can orient substituents in very similar ways. https://sn.pub/b19kz8