In the ever-evolving landscape of peptide therapeutics, the quest for molecules that exhibit not only potent biological activity but also improved chemical diversity and conformational complexity remains a pivotal challenge. Traditionally, the discovery of peptides with therapeutic potential has heavily relied on the screening of massive libraries—sometimes comprising trillions of members—to identify ligands that bind specifically to clinically relevant targets. These libraries predominantly consist of ribosomally synthesized peptides, often incorporating non-canonical amino acids and sophisticated macrocyclic architectures designed to enhance stability and affinity. Yet, despite advances in library design and screening technologies, the chemical space explored by such peptides remains significantly narrower than that spanned by natural products and small-molecule drugs, which often display intricate frameworks and stereochemical complexities.
The research unveiled by Knudson, Dover, Dilworth, and colleagues represents a transformative stride in bridging this gap. By integrating chemical synthesis principles with ribosomal peptide production, their work introduces a novel methodology that endows peptides with enhanced chemical complexity and conformational control. At the heart of their strategy lies the incorporation of reactive N-terminal keto amides—specifically β-keto and γ-keto amides—into linear peptides during ribosomal synthesis. This modification primes the peptides for subsequent intramolecular Friedländer reactions, enabling the seamless generation of quinoline-peptide hybrid structures, some of which exhibit remarkable atropisomerism through stable biaryl axes.
The implications of embedding quinoline moieties directly within peptide backbones are profound. Quinoline derivatives are well established in medicinal chemistry for their rich pharmacological profiles and capacity to engage in diverse molecular interactions. By harnessing Friedländer condensation—a classic synthetic reaction that forms quinoline rings through cyclization involving amino ketones and carbonyl compounds—the researchers establish a robust chemical handle for post-translational peptide diversification. Notably, these Friedländer macrocyclizations proceed under conditions sufficiently mild to be conducted on unprotected peptides, including those generated in vitro by ribosomes. This breakthrough allows direct incorporation of complex heterocycles into peptide frameworks without the need for protecting group manipulations, which are often cumbersome and limiting in peptide chemistry.
One of the striking features of this approach is the formation of atropisomeric biaryl axes in the resultant peptide-quinoline hybrids. Atropisomerism arises due to restricted rotation around a bond connecting two aromatic rings, creating stereoisomers that are stable and display distinct three-dimensional shapes. This conformational rigidity can endow peptides with enhanced receptor selectivity and binding affinity by reducing entropic penalties upon binding and locking the molecule into biologically relevant conformations. The ability to generate atropisomeric peptides ribosomally—traditionally achieved only through arduous synthetic routes—opens a new frontier in peptide drug design by merging the precision of ribosomal synthesis with nuanced chemical complexity.
Moreover, the researchers demonstrate that these Friedländer macrocyclizations can be utilized not only to decorate linear peptides but also to initiate cyclization reactions that generate macrocycles embedding quinoline units within their backbone. Macrocyclic peptides are highly valued for their enhanced stability, membrane permeability, and selective target engagement. Embedding pharmacophores like quinolines directly into macrocyclic backbones represents a paradigm shift in how peptide macrocycles can be designed to mimic complex natural products, which often feature heterocyclic linkages critical to their activity.
The study also emphasizes the genetic encodability of the N-terminal keto amide motifs, a feature that empowers the ribosomal machinery to produce synthetic peptide precursors poised for these chemical transformations. This genetic encoding facilitates high-throughput generation of diverse peptide libraries with built-in chemical handles, transforming post-translational modification from a random, unpredictable event into a programmable and orthogonal process. Such programmable synthesis could enable the tailored design of peptide-based materials and therapeutics with functionalities that were previously inaccessible through either biological or chemical synthesis alone.
In practical terms, the authors’ method addresses a fundamental bottleneck in peptide ligand discovery. While screening vast peptide libraries can yield initial leads, these often exhibit suboptimal potency or physicochemical properties and require extensive medicinal chemistry optimization. By embedding chemically diverse quinoline moieties and introducing atropisomeric axes, this approach inherently biases peptide libraries toward structures with improved drug-like properties, potentially reducing the need for exhaustive synthetic modifications downstream.
From a mechanistic perspective, the ability to carry out Friedländer reactions efficiently on unprotected peptides illustrates the exquisite compatibility of classical synthetic chemistry with modern ribosomal peptide synthesis and in vitro translation platforms. This compatibility surmounts traditional challenges associated with chemoselectivity and functional group tolerance, showcasing a sophisticated interplay between biological and chemical methodologies.
Furthermore, the research highlights new opportunities for exploring peptide-based materials that combine the modularity and programmability of ribosomal synthesis with the conformational diversity and pharmacophoric richness of small-molecule natural products. Such hybrid molecules could find applications not only in therapeutics but also in diagnostics, molecular recognition, and biomaterials science.
Looking ahead, this conceptual framework could be extended by incorporating alternative post-translational modifications that embed other aromatic or heterocyclic pharmacophores, further expanding the repertoire of genetically encodable, chemically elaborated peptides. The biaryl atropisomers generated in this study may also inspire further exploration into stereochemically complex peptides, potentially providing access to novel ligand classes targeting challenging protein-protein interactions and other biomolecular interfaces.
Another exciting prospect lies in integrating this chemical approach with machine learning-guided peptide design and high-throughput screening, accelerating the iterative cycle of peptide optimization and lead compound discovery. The programmable nature of keto amide incorporation, combined with post-translational Friedländer cyclizations, establishes a versatile platform for discovering next-generation peptide therapeutics that outperform traditional leads in specificity, stability, and bioavailability.
In conclusion, Knudson and colleagues’ pioneering work eloquently demonstrates how classical organic reactions can be harnessed in synergy with ribosomal machinery to produce complex, conformationally restricted peptide macrocycles featuring embedded quinoline pharmacophores. This innovative fusion of chemical and biological synthesis paves the way for programmable construction of peptide-derived materials with unprecedented structural diversity, potentially revolutionizing the field of peptide drug discovery and beyond. As the demand for peptide therapeutics with enhanced drug-like properties continues to rise, such strategies stand to redefine the boundaries of chemical space accessible through ribosomal synthesis and post-translational modification.
Subject of Research: Chemical and ribosomal synthesis of peptides incorporating N-terminal keto amides enabling Friedländer reaction-based generation of quinoline-embedded, atropisomeric, and macrocyclic peptide hybrid structures.
Article Title: Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines.
Article References:
Knudson, I.J., Dover, T.L., Dilworth, D.A. et al. Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01935-4
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