Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development
- 1Department of Chemistry East Tennessee State University Johnson City Tennessee USA
- 2Department of Medicinal Chemistry National Institute of Pharmaceutical Education and Research Punjab India
- 3Department of Chemistry Iowa State University Ames Iowa USA
Abstract
Macrocyclic peptides have emerged as a compelling class of therapeutics, combining the modularity and synthetic accessibility of small molecules with the high affinity and target selectivity of biologics. Their ability to engage challenging and traditionally “undruggable” protein targets—including protein–protein interactions and allosteric sites—has generated widespread interest. However, pharmacokinetic limitations such as poor oral bioavailability, metabolic instability, and low membrane permeability continue to hinder clinical translation. The strategic incorporation of unnatural amino acids (UAAs) has proven critical for overcoming these challenges, enabling fine‐tuning of key physicochemical and pharmacological properties. In this review, we highlight recent clinical advances—including motixafortide and zilucoplan—and examine how UAAs are deployed to optimize drug‐like characteristics across diverse therapeutic areas. We discuss emerging strategies, illustrative case studies, and design principles that collectively support the development of next‐generation macrocyclic peptide drugs.
Related
- Development of the First Integrated Silver Nitrate-Containing In Vitro Regeneration Approach for the Endangered Tulipa montana var. chrysantha.
- Polymerase-Mediated Incorporation of Unnatural Alkynylated Purine–Pyridazine Base Pairs
- Decoding Stability and Selectivity in Unnatural DNA Base Pairs with Spatially Separated Recognition Interfaces.
- Nitrene generation and transfer for unnatural biosynthesis in living cells
- Discovery of an NRAS isoform and activation-state selective macrocyclic peptide
BibTeX
@article{sharma2026beyond,
title = {{Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development}},
author = {Krishna K. Sharma and Komal Sharma and Anku Sharma and Kamya Rao and Rahul Jain and Brett VanVeller},
journal = {Angewandte Chemie (International Ed. in English)},
year = {2026},
month = sep,
doi = {10.1002/anie.202523959},
url = {https://doi.org/10.1002/anie.202523959},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development
AU - Krishna K. Sharma
AU - Komal Sharma
AU - Anku Sharma
AU - Kamya Rao
AU - Rahul Jain
AU - Brett VanVeller
PY - 2026
DA - 2026/09/16
JO - Angewandte Chemie (International Ed. in English)
DO - 10.1002/anie.202523959
UR - https://doi.org/10.1002/anie.202523959
AB - Macrocyclic peptides have emerged as a compelling class of therapeutics, combining the modularity and synthetic accessibility of small molecules with the high affinity and target selectivity of biologics. Their ability to engage challenging and traditionally “undruggable” protein targets—including protein–protein interactions and allosteric sites—has generated widespread interest. However, pharmacokinetic limitations such as poor oral bioavailability, metabolic instability, and low membrane permeability continue to hinder clinical translation. The strategic incorporation of unnatural amino acids (UAAs) has proven critical for overcoming these challenges, enabling fine‐tuning of key physicochemical and pharmacological properties. In this review, we highlight recent clinical advances—including motixafortide and zilucoplan—and examine how UAAs are deployed to optimize drug‐like characteristics across diverse therapeutic areas. We discuss emerging strategies, illustrative case studies, and design principles that collectively support the development of next‐generation macrocyclic peptide drugs.
SN - 1433-7851
SN - 1521-3773
ER -