Although the inherent differences of L-peptide and its retro-inverso isomer at secondary and tertiary structure prevent the complete recapitulation of the activity of the L-peptides, the retro-inverso peptides, indeed, achieve certain binding activity in a few cases ( 8– 10). Regardless of the target, focusing only on the equivalent transformation of small molecules, the retro-inverso peptides show a great advantage in accessibility. Bearing a high degree of the topochemical equivalence of L-peptides, the retro-inverso peptides, presumably, would exhibit similar bioactivity for the corresponding L-peptides. To avoid the time-consuming synthesis of D-proteins required for mirror-image phage display, Goodman and Chorev have developed a more effective approach – retro-inverso peptides which consist of D-amino acids in the reverse sequence of the naturally occurring L-peptides – for the development of bioactive D-peptides ( 7). Despite it being costly to synthesize a D-protein, the D-peptide from such screening process, being resistant to proteolytic degradation, represents a breakthrough in manipulating D-amino acids to develop biostable inhibitors as potential therapeutics ( 5, 6). According to the mirror symmetry, the corresponding D-peptide, as the enantiomer of that specific L-peptide, should be able to specifically bind to the natural L-target with high affinity. That elegant approach allows the use of phage display to identify biologically encoded L-peptides specifically binding to the given D-protein that is the enantiomer of the native target (e.g. demonstrated the concept of mirror-image phage display, which displays genetically encoded libraries on bacteriophages, for screening D-peptides which would bind to natural protein targets that are made of L-amino acids ( 4). They have found out that the D-proteins and natural L-proteins display reciprocal chiral specificities on their substrates, from which they proposed that the L and D-enzymes have entirely mirrored structure of each other ( 3). For example, Kent and co-workers synthesized D-proteins – that is, the proteins consist of solely D-amino acids – through total chemical synthesis via native chemical ligation ( 2). The miraculous use of D-amino acids in nature also stimulates the exploration of D-amino acids for a variety of applications. One notable example of a naturally used D-amino acid is D-Ala-D-Ala, which is the stem terminal of the peptidoglycan side-chain pentapeptide found in cell walls of Gram-positive bacteria as well as the target for the microbe inhibition by antibiotics like vancomycin ( 1). While L-amino acids serve as the elements of the natural proteins translated in the ribosome, D-amino acids are found in some posttranslational modification and peptidoglycan cell walls of bacteria. Reflecting the L-amino acids by a mirror are their enantiomers, D-amino acids, which share identical chemical and physical properties of L-amino acids, except for their ability to rotate plane-polarized light in opposite directions.
At the end, we briefly mention the challenges and possible future directions.Īs the fundamental building blocks of proteins, natural L-amino acids always serve as a starting point for protein-related research. To highlight the enzymatic reactions of D-amino acids, we will describe several emerging works on the enzyme-instructed self-assembly (EISA) and their potential application in selective anti-inflammatory or anticancer therapies. Then, we discuss some works that explore the relatively underexplored interactions between the enzyme and D-amino acids and enzymatic reactions of D-amino acids. First, we will introduce some progress made in traditional application of D-amino acids to enhance biostability of peptide therapeutics. In this review, we highlight the recent progress and challenges in the exploration of D-amino acids at the interface of chemistry and life science. Previous works have demonstrated applications of D-amino acids in therapeutic development with the aid of mirror-image phage display and retro-inverso peptide synthesis. D-amino acids, the enantiomers of naturally abundant L-amino acids, bear unique stereochemistry properties that lead to the resistance towards most of the endogenous enzymes.
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