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Small molecule-peptide conjugates formed from three building blocks and eleven encoding amino acids provide a suitable scaffold for the implementation of diversity-oriented reactions. (A) The small molecule formed from three building blocks is linked to the encoding peptide through a short aliphatic linker, a branching lysine, and an oxidatively cleavable linker. (B) Three reactions have been optimized to achieve high purity with a diverse sets of building blocks. The corresponding histograms show the distribution of purities obtained from coupling of different building blocks. (C) Selected examples demonstrate the scope of the optimized coupling reactions. (D) Synthesis rehearsal implementing optimized reactions with three building blocks afforded crude products with high purity after 45 steps. (E) Two PELs including C-C or C-N cross-coupling reactions generate collections of small molecules with drug-like properties (MW molecular weight, cLogP calculated partition coefficient, HBA hydrogen bond acceptor, HBD hydrogen bond donor).
Source publication
Information storage in DNA forms the fundamental basis of cellular life, but inherent limitations of information stability and density hamper innovative applications such as data storage or drug discovery. Here, we establish abiotic peptides for next-generation information storage and apply them for the encoding of diverse small molecule synthesis....
Contexts in source publication
Context 1
... established a molecular scaffold which features two loci for orthogonal synthetic elaboration (Fig 3A), allowing for sequential small molecule and peptide synthesis including a fully orthogonal protecting group strategy. The scaffold is bound to a polystyrene bead via a Rink amide linker cleavable under strongly acidic conditions which also result in global deprotection of the conjugate. ...
Context 2
... chemical stability of protected peptides and synthetic utility of solid-phase synthesis allowed the implementation of powerful palladium-mediated cross-coupling reactions (Fig 3B). Palladium-catalyzed formation of carbon-carbon and carbon-nitrogen bonds represent two of the most frequently utilized reactions in medicinal chemistry. ...
Context 3
... Under these optimized conditions, 41 anilines and 11 aryl bromides were found to undergo cross-coupling with more than 70% purity (see SI section 2.8 for scope). Notably, the scope and purity of these reactions outperform recent examples of palladium cross-couplings in the presence of DNA,(31-33) allowing for the cross-coupling of diverse heterocycles prevalent in drugs (selected examples shown in Fig 3C, for full scope see SI). Additionally, 60 carboxylic acids were found to be competent substrates for amide coupling using HATU and DIPEA in DMF (see SI section 2.9). ...
Context 4
... libraries are mixtures of compounds and thus not suitable for purification or purity assessments, high-yielding reaction sequences are imperative to robust downstream applications. To confirm the viability of the synthetic sequence in our library design, we first synthesized individual library members under the synthetic conditions applicable to library synthesis (Fig 3D). We found that following 45 synthetic manipulations according to the library design, including global deprotection and resin cleavage, afforded the desired products resulting from C-C and C-N cross-coupling in crude purities of >70%. ...
Context 5
... the efficiency of solid-phase synthesis enables such multistep library synthesis to be carried out in less than a week. Quantitative estimation of drug-likeness(35) of the individual library members showed that the majority exhibit molecular properties advantageous for lead drug candidates (Fig 3E). (36) Affinity selection of PELs afforded small molecules with nanomolar affinity for their target protein. ...
Citations
... [35] A recent work used the sequences of a series of 18-mer peptides to store a 848-bit text file and a 13,752-bit music file, where the information-bearing peptides are composed by 8 kinds of selected standard amino acids each representing 3 bits of information. [36] More recently, unnatural peptides and proteins, such as the mirror-image proteins [37] and peptide-small molecule conjugates, [38] were reported promising for data storage with higher density and durability compred to biopolymers. Until now, the decoding and sequencing of these informational peptides and proteins were mainly performed by mass spectrometry. ...
Sequence‐defined polymer is one of the most promising alternative media for high‐density data storage. It could be used to alleviate the problem of insufficient storage capacity of conventional silicon‐based devices for the explosively increasing data. To fulfil the goal of polymer data storage, suitable methods should be developed to accurately read and decode the information‐containing polymers, especially for those composed by a combination of the natural and unnatural monomers. Nanopore‐based approaches have become one of the most competitive analysis and sequencing techniques, which are expected to read both natural and synthetic polymers with single‐molecule precision and monomeric resolution. Herein, this work emphasizes the advances being made in nanopore reading and decoding of information stored in the man‐made polymers and DNA nanostructures, and discusses the challenges and opportunities towards the development and realization of high‐density data storage.
