Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis

Rössler, Simon L.; Grob, Nathalie M.; Buchwald, Stephen L.; Pentelute, Bradley L.

doi:10.1126/science.adf1354

Cited by 22 publications

(16 citation statements)

References 51 publications

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“…In this aspect, end-capping of reactive termini of sequence-defined polymers and catalyst-assisted depolymerization could be examined. Furthermore, sequence-defined polymers with chemically diverse functional groups combined with on-demand depolymerization behavior are also promising for use as tags or libraries to discover therapeutics and biochemical ligands …”

Section: Discussionmentioning

confidence: 99%

Emerging Trends in the Chemistry of End-to-End Depolymerization

Deng,

Gillies

2023

JACS Au

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Over the past couple of decades, polymers that depolymerize end-to-end upon cleavage of their backbone or activation of a terminal functional group, sometimes referred to as "self-immolative" polymers, have been attracting increasing attention. They are of growing interest in the context of enhancing polymer degradability but also in polymer recycling as they allow monomers to be regenerated in a controlled manner under mild conditions. Furthermore, they are highly promising for applications as smart materials due to their ability to provide an amplified response to a specific signal, as a single sensing event is translated into the generation of many small molecules through a cascade of reactions. From a chemistry perspective, end-to-end depolymerization relies on the principles of self-immolative linkers and polymer ceiling temperature (T c ). In this article, we will introduce the key chemical concepts and foundations of the field and then provide our perspective on recent exciting developments. For example, over the past few years, new depolymerizable backbones, including polyacetals, polydisulfides, polyesters, polythioesters, and polyalkenamers, have been developed, while modern approaches to depolymerize conventional backbones such as polymethacrylates have also been introduced. Progress has also been made on the topological evolution of depolymerizable systems, including the introduction of fully depolymerizable block copolymers, hyperbranched polymers, and polymer networks. Furthermore, precision sequence-defined oligomers have been synthesized and studied for data storage and encryption. Finally, our perspectives on future opportunities and challenges in the field will be discussed.

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Section: Discussionmentioning

confidence: 99%

Emerging Trends in the Chemistry of End-to-End Depolymerization

Deng,

Gillies

2023

JACS Au

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“…DELs need to be built utilizing DNA compatible chemical transformations, while OBOC libraries, in theory, have higher tolerability toward “harsh” reaction conditions. Roessler et al tested and summarized some transformation that work on solid phase particles, but are incompatible with DNA . In practice, however, the DEL community has established an impressive number of DNA compatible chemical transformations, leading to a broad accessible chemical space .…”

Section: Discussion and Future Perspectivementioning

confidence: 99%

“…As described above, automated peptide sequencing software has been a crucial technology for enabling advanced AS–MS/MS. A first important step toward drug-like molecule discovery has been the peptide encoded library (PEL) technology . However, the largest PEL reported by Roessler et al contained only ∼40 thousand members.…”

Section: Discussion and Future Perspectivementioning

confidence: 99%

“…Roessler et al leveraged the high sensitivity de novo peptide sequencing capabilities to develop a new type of encoded small molecule discovery platform . The authors assembled small druglike molecules on a solid support, and, connected via a cleavable linker (seramox), they built up a peptide tag encoding the identity of the small molecule.…”

Section: Success Stories Of Hit Discovery With As–ms/msmentioning

confidence: 99%

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Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries

Mata,

van der Nol,

Pomplun

2023

J. Am. Chem. Soc.

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Discovering new bioactive molecules is crucial for drug development. Finding a hit compound for a new drug target usually requires screening of millions of molecules. Affinity selection based technologies have revolutionized early hit discovery by enabling the rapid screening of libraries with millions or billions of compounds in short timeframes. In this Perspective, we describe recent technology breakthroughs that enable the screening of ultralarge synthetic peptidomimetic libraries with a barcode-free tandem mass spectrometry decoding strategy. A combination of combinatorial synthesis, affinity selection, automated de novo peptide sequencing algorithms, and advances in mass spectrometry instrumentation now enables hit discovery from synthetic libraries with over 100 million members. We provide a perspective on this powerful technology and showcase success stories featuring the discovery of high affinity binders for a number of drug targets including proteins, nucleic acids, and specific cell types. Further, we show the usage of the technology to discover synthetic peptidomimetics with specific functions and reactivity. We predict that affinity selection coupled with tandem mass spectrometry and automated de novo decoding will rapidly evolve further and become a broadly used drug discovery technology.

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“…As is widely acknowledged, the employment of palladium-catalyzed Suzuki–Miyaura cross-coupling conditions may have deleterious effects on DNA . To verify whether DNA would be damaged under the standard conditions of this reaction, we performed several validation experiments.…”

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confidence: 99%

DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis

Zhang,

Wang,

et al. 2023

Org. Lett.

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A DNA-compatible reaction has been developed for the cyanomethylation of (hetero)aryl halides or triflates via a tandem process involving palladium-mediated Suzuki–Miyaura coupling and base-promoted isoxazole fragmentation. This one-pot protocol employs easily accessible starting materials, exhibits a wide substrate scope, and results in no significant DNA damage. Additionally, the resulting (hetero)arylacetonitriles can be converted into the corresponding carboxylic acids, which may be utilized for the synthesis of DNA-encoded chemical libraries.

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Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis

Cited by 22 publications

References 51 publications

Emerging Trends in the Chemistry of End-to-End Depolymerization

Emerging Trends in the Chemistry of End-to-End Depolymerization

Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries

DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis

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