Learning the structure–activity relationship (SAR) of the Wittig reaction from genetically-encoded substrates

Yan, Kejia; Triana, Vivian; Kalmady, Sunil V.; Aku-Dominguez, Kwami; Memon, Sharyar; Brown, Alex; Greiner, Russell; Derda, Ratmir

doi:10.1039/d1sc04146k

Cited by 10 publications

(7 citation statements)

References 60 publications

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“…The resulting glycopeptides from this method resemble natural N - and O -linked glycans, giving them promise in identifying peptide ligands for lectins and other carbohydrate-binding proteins . The Derda Lab has taken advantage of this technique to guide phage-based selections toward active sites by modifying phage libraries with glycans, − sulfonamides, and biotin. , They have also combined these modifications with integration of silent barcodes downstream of the peptide library, allowing for the ability to simultaneously screen libraries containing different N-terminal modifications. In doing this, they have identified peptide ligands with low nanomolar potency for carbonic anhydrase and femtomolar peptides for streptavidin (Table S1, Peptides 34–48).…”

Section: Chemical Post-translational Modifications Of Phage-displayed...mentioning

confidence: 99%

Diversification of Phage-Displayed Peptide Libraries with Noncanonical Amino Acid Mutagenesis and Chemical Modification

Hampton,

Liu

2024

Chem. Rev.

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Sitting on the interface between biologics and small molecules, peptides represent an emerging class of therapeutics. Numerous techniques have been developed in the past 30 years to take advantage of biological methods to generate and screen peptide libraries for the identification of therapeutic compounds, with phage display being one of the most accessible techniques. Although traditional phage display can generate billions of peptides simultaneously, it is limited to expression of canonical amino acids. Recently, several groups have successfully undergone efforts to apply genetic code expansion to introduce noncanonical amino acids (ncAAs) with novel reactivities and chemistries into phage-displayed peptide libraries. In addition to biological methods, several different chemical approaches have also been used to install noncanonical motifs into phage libraries. This review focuses on these recent advances that have taken advantage of both biological and chemical means for diversification of phage libraries with ncAAs. CONTENTS 3.6. Outlook of Chemically Modified Phage Libraries 6070 4.

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Section: Chemical Post-translational Modifications Of Phage-displayed...mentioning

confidence: 99%

Diversification of Phage-Displayed Peptide Libraries with Noncanonical Amino Acid Mutagenesis and Chemical Modification

Hampton,

Liu

2024

Chem. Rev.

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“…23 Given its prominence in organic chemistry, it is not surprising that Wittig olefination has been explored for protein functionalization 24 with some applications described for cell labelling 25,26 and phage libraries display. 27,28 However, harsh reaction conditions of Wittig olefination have failed to demonstrate use beyond the limited proof-of-concept stage. 29 In organic chemistry, a well-known alternative to Wittig reactions is the related Horner-Wadsworth-Emmons (HWE) olefination (Fig.…”

Section: Introductionmentioning

confidence: 99%

Horner-Wadsworth-Emmons Olefination of Proteins and Glycoproteins

Angelastro

Barkhanskiy

Goundry

et al. 2023

Preprint

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Chemo-selective and site-specific modifications of proteins are fundamental to the advancement of biological and pharmaceutical sciences, from understanding the basis of cellular biology to development of biotherapeutics. Recent successes in bioconjugation chemistry have inspired the search for more biocompatible chemical reactions, which has prompted us to investigate Horner-Wadsworth-Emmons (HWE) olefinations, iconic reactions used widely in organic synthesis that would give rise to new selective protein olefinations. Our choice of HWE olefinations was inspired by the growing number of methods for the generation of aldehydes as transient reactive groups in proteins and the potential for mild and simple reaction conditions. Here we show that HWE on aldehydes produced by both chemical and enzymatic methods is fully compatible with physiological conditions and highly selective in small and large proteins, including therapeutic antibodies. By exploiting the wide range of easily accessible HWE reagents provided by organic chemistry, we show that the reaction kinetics can be fine-tuned over orders of magnitude by judicious use of substituents. The electrophilic nature of the HWE products can be tuned to allow for subsequent nucleophilic additions, including thiol- and phospha-Michael additions, enabling two-step dual labelling strategies. Our results demonstrate that HWE olefination of aldehydes in proteins provide efficient and selective bioconjugation chemistries that are orthogonal to existing methods.

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“…Using this generated data set, they discovered the cooperative effect of the first and second N-terminal amino acids and the effect of backbone hydrogen bonding on the reaction rate. 34 In 2022, the Jacobsen group reported an enantioselective Pictet−Spengler reaction. They screened 14 aldehyde substrates with 14 different catalysts individually and combinatorially.…”

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confidence: 99%

“…They selected a series of peptide aldehydes to test individually by HPLC to confirm that the results were consistent with the deep conversion method. Using this generated data set, they discovered the cooperative effect of the first and second N-terminal amino acids and the effect of backbone hydrogen bonding on the reaction rate …”

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Recent Progress on One-Pot Multisubstrate Screening

Fogel,

Koide

2023

Org. Process Res. Dev.

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Traditionally, new synthetic reactions have been developed using a model substrate to screen reaction conditions before testing the optimized conditions with a range of more complex substrates. In 1998, Gao and Kagan pooled multiple substrates in one pot to study the generality of an enantioselective method. Although such one-pot multisubstrate screenings may be powerful, few applications have appeared in the literature. With the advancement of various chromatography techniques, it may be time to revisit this underutilized platform. This review article discusses the applications of one-pot multisubstrate screenings as a method for developing new synthetic methods.

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Learning the structure–activity relationship (SAR) of the Wittig reaction from genetically-encoded substrates

Abstract: 160 000 peptides displayed on phage were subjected to the Wittig reaction with a biotinylated ylide. Deep-sequencing estimated the conversion rate for each sequence and unveiled the relationship between sequences and the rate of the Wittig reaction.

Cited by 10 publications

References 60 publications

Diversification of Phage-Displayed Peptide Libraries with Noncanonical Amino Acid Mutagenesis and Chemical Modification

Diversification of Phage-Displayed Peptide Libraries with Noncanonical Amino Acid Mutagenesis and Chemical Modification

Horner-Wadsworth-Emmons Olefination of Proteins and Glycoproteins

Recent Progress on One-Pot Multisubstrate Screening

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