Abstract
Natural and nonnatural amino acids represent important building blocks for the development of peptidomimetic scaffolds, especially for targeting proteolytic enzymes and for addressing protein–protein interactions. Among all the different amino acids derivatives, proline is particularly relevant in chemical biology and medicinal chemistry due to its secondary structure’s inducing and stabilizing properties. Also, the pyrrolidine ring is a conformationally constrained template that can direct appendages into specific clefts of the enzyme binding site. Thus, many papers have appeared in the literature focusing on the use of proline and its derivatives as scaffolds for medicinal chemistry applications. In this review paper, an insight into the different biological outcomes of d-proline and l-proline in enzyme inhibitors is presented, especially when associated with matrix metalloprotease and metallo-β-lactamase enzymes.
Highlights
More than 500 amino acids are present in nature
D-amino acids were long considered to have only a minor function compared to their enantiomers, many peptides that contain d-amino acids have been found in nature correlated to specific biological functions [1]
Among all the different amino acids derivatives, proline is relevant in chemical biology and medicinal chemistry due to the stabilizing properties and the conformational restriction of Symmetry 2019, 11, 558; doi:10.3390/sym11040558
Summary
More than 500 amino acids are present in nature. d-amino acids were long considered to have only a minor function compared to their enantiomers, many peptides that contain d-amino acids have been found in nature correlated to specific biological functions [1]. Proline racemase is a potential drug target against this parasite, and the development of its to the formation of several D-proline-rich peptides that showed a resistance against host proteolytic inhibitors can be used in the treatment of Chaga disease [32]. The binding mode of the two captopril stereoisomers to IMP-1 has been determined by crystallography (Figure 5) [45] In both cases, the two Zn2+ ions in the active site are located at the end of the two β-sheets; one is chelated by three histidines, while the other one is coordinated by an aspartic acid, a histidine, and a cysteine.
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