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

This review traces the historical development and clinical adoption of FDA-approved drugs that incorporate d-amino acids — the non-natural mirror-image enantiomers of standard l-amino acids. The authors survey more than 20 FDA-approved drugs spanning therapeutic areas including infectious diseases, endocrine disorders, rare dermatologic conditions, and diagnostic imaging. Key examples discussed include naturally derived compounds such as gramicidin D and synthetic analogs including desmopressin, leuprolide, bremelanotide, and etelcalcetide — the latter highlighted as the first fully d-amino acid peptide to receive FDA approval. The review explains why d-amino acids are pharmacologically attractive: their resistance to proteolytic degradation, enhanced conformational rigidity, and reduced immunogenicity make them well-suited for long-acting and receptor-selective drug design. The authors also discuss enabling technologies, particularly solid-phase peptide synthesis and mirror-image phage display, that have accelerated the field. As a narrative review, the paper does not present new experimental data, conduct meta-analytic comparisons, or include a systematic literature search, which limits its ability to draw novel evidence-based conclusions. Its primary value lies in synthesizing the historical trajectory and mechanistic rationale of a growing drug class.

Why this grade: This is a narrative review that synthesizes existing literature on FDA-approved d-amino acid-containing drugs without generating new experimental or clinical data, precluding an independent evidence grade for any specific claim.