Thiazoles in Peptides and Peptidomimetics

Abstract

The natural occurrence of the thiazole ring in chemistry and biology has inspired its widespread use in synthetic peptidomimetics as structural templates, biological probes, and pharmaceuticals. Thiazole can be viewed as a dehydrated cyclized derivative of cysteine, incorporated into peptide sequences through chemical synthesis or ribosomal biosynthesis. Thiazoles are planar heterocycles and valuable synthetic templates with a strong hydrogen bond accepting nitrogen, a sulfur atom with extended lone pair electron orbitals, and an aromatic $π$-cloud. These properties can influence molecular conformation and direct interactions with proteins, leading to development of thiazole-containing peptidomimetics as protein mimicking scaffolds, modulators of cell surface proteins like G protein-coupled receptors (GPCRs), inhibitors of enzymes, and agonists or antagonists of protein--protein interactions. The thiazole ring is the most common five-membered heterocycle present in pharmaceuticals. This perspective article describes important properties of thiazoles in synthetic peptidomimetics and highlights key examples, including some from the last 5 years.