FDA-Approved Drugs Containing D-Amino Acids: A Historical and Developmental Perspective
Tran L, Nguyen TD, Gad AG, Shaaban E, Tai TH, Tram NT, Nguyen Khanh Tran H, Le MT, +1 more
Drug Development Research (2026)
More than twenty FDA-approved drugs incorporate at least one D-amino acid; bremelanotide ([PT-141](/peptides/pt-141)) — the cyclic heptapeptide melanocortin agonist approved for hypoactive sexual desire disorder — is one of them, and the chemistry that made approval possible is the same chemistry the gray-market melanocortin landscape now leans on.
Tran and colleagues at the University of Health Sciences (Vietnam National University Ho Chi Minh City) and the Online Research Club international consortium published a historical and developmental review in Drug Development Research tracing the appearance of D-amino-acid–containing drugs in the FDA-approved pharmacopoeia from the mid-twentieth century to the present. The review is narrative rather than systematic, with no formal search protocol or PRISMA framing, but it consolidates a body of medicinal-chemistry history that is otherwise dispersed across structural-biology and peptide-synthesis literature.
The review counts more than twenty FDA-approved drugs that incorporate at least one D-amino-acid residue, including the natural product gramicidin D, and the synthetic analogues desmopressin, leuprolide, bremelanotide, and etelcalcetide — the last of which is described as the first fully D-amino-acid peptide to receive FDA approval. The biochemical rationale is shared across the class: D-amino-acid substitution confers resistance to proteolytic degradation by mammalian peptidases, increases conformational rigidity (which can sharpen receptor selectivity), and reduces immunogenicity relative to the all-L equivalents. Solid-phase peptide synthesis and the conceptual frame of mirror-image phage display are credited as the enabling technologies that turned this design strategy from theoretical advantage to manufacturable drug.
For the PT-141 / bremelanotide page on this site, the review provides regulatory and historical context that explains why bremelanotide could be developed into an approvable drug at all: the cyclic heptapeptide melanocortin agonist incorporates a D-amino-acid substitution that buys enough plasma half-life and protease resistance to make subcutaneous dosing viable. The same chemistry underlies the broader class of off-label melanocortin agonists that circulate outside regulated channels and that the Diamond, Pfaus, Kingsberg, and Simon entries in this corpus address from different angles.
This is a narrative review by a group whose primary expertise is medicinal chemistry and infectious-disease pharmacology rather than melanocortin pharmacology specifically — bremelanotide is one of several illustrative examples rather than the focus. The review does not provide a head-to-head safety or efficacy comparison across the D-amino-acid–containing peptide drugs, and it does not engage with the gray-market analogue landscape (Melanotan I, Melanotan II) where D-amino-acid chemistry has been used to extend half-life without the regulatory and clinical-trial infrastructure that produced bremelanotide.
The publication is in Drug Development Research, a Wiley journal of medicinal-chemistry-adjacent scope; the article is indexed for MEDLINE. There is no disclosed commercial sponsorship and no declared conflict of interest related to bremelanotide specifically. As a Tier 2 narrative review, the entry is useful for situating the chemistry of bremelanotide within the broader regulatory peptide landscape, but should not be cited as a primary source for melanocortin pharmacology or for clinical claims about hypoactive sexual desire disorder treatment — for those, defer to Kingsberg et al. 2019 RECONNECT and the Simon 2019 long-term safety data already in the corpus.
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