FDA-Approved Drugs Containing D-Amino Acids: A Historical and Developmental Perspective.

d-Amino acids, the non-natural enantiomers of l-amino acids, have emerged as powerful tools in peptide drug development due to their unique biochemical properties. Their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them especially valuable in designing long-acting and receptor-selective therapeutics. Since the mid-20th century, more than 20 FDA-approved drugs have incorporated at least one d-amino acid into their structure, spanning indications from infectious diseases and endocrine disorders to rare dermatologic conditions and diagnostic imaging. These drugs include both natural products like gramicidin D and synthetic analogs such as desmopressin, leuprolide, bremelanotide, and etelcalcetide, the latter being the first fully d-amino acid peptide to receive FDA approval. This review traces the historical development and clinical adoption of d-amino acid-containing drugs, highlighting their mechanisms of action, therapeutic relevance across disease areas, and the technological innovations, particularly solid-phase peptide synthesis and conceptual advances such as mirror-image phage display, that enabled their advancement. As peptide therapeutics continue to evolve, d-amino acids-containing drugs are poised to play a central role in the next generation of targeted, stable, and high-precision pharmaceuticals.