Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development

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Publication Details

Journal
Angewandte Chemie International Edition
Published
2026-09-16
DOI
https://doi.org/10.1002/anie.202523959
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development

Brett VanVeller, Rahul Jain, Komal Sharma, Kamya Rao et al.
Angewandte Chemie International Edition
Chemical Synthesis and Analysis
article

Beyond Nature's Blueprint: Macrocyclic Peptides Containing Unnatural Amino Acids in Therapeutic Development

Brett VanVeller, Rahul Jain, Komal Sharma, Kamya Rao, Anku Sharma, Krishna K. Sharma
article en

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.

Angewandte Chemie International Edition
East Tennessee State University (US), Iowa State University (US), National Institute of Pharmaceutical Education and Research (IN)
Foundation for the National Institutes of Health, East Tennessee State University, Iowa State University, National Institutes of Health
No poverty
Openalex Percentile: Top 18%
Chemical Synthesis and Analysis
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