Concepts of Catalysis in Site-Selective Protein Modifications

Isenegger, Patrick G.; Davis, Benjamin G.

doi:10.1021/jacs.8b13187

Cited by 93 publications

(84 citation statements)

References 69 publications

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“…57,84,85 Chemical methodologies for protein labelling have vastly diversied and improved in recent years, showing ne-tuned reactivity and biocompatibility with labelling achieved within live cells. [86][87][88][89][90][91][92][93][94] One can anticipate that efficient articial enzymes can be made by adapting these novel technologies.…”

Section: Site-selective Chemical Modication Of Proteinsmentioning

confidence: 99%

Enabling protein-hosted organocatalytic transformations

et al. 2020

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Section: Site-selective Chemical Modication Of Proteinsmentioning

confidence: 99%

Enabling protein-hosted organocatalytic transformations

et al. 2020

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“…Since EcDHFR and human DHFR are important targets in infectious diseases and cancer (Raimondi et al, 2019), exploitation of this site might provide an alternative route to design new inhibitors. Other low abundant amino acids such as tryptophan, methionine, tyrosine and histidine are also pursued in genetically engineered systems for which rational positioning within the protein target permit sites for unique chemical handles (Hoyt et al, 2019;Isenegger and Davis, 2019). On the other hand, modification approaches targeting naturally occurring residues offer more advantages to selected bioconjugation strategies since they avoid the genetic engineering required to arrive at suitable bioconjugation conditions (Spicer and Davis, 2014;Koniev and Wagner, 2015;Matos et al, 2018).…”

Section: Site-selective Protein Modificationmentioning

confidence: 99%

Unveiling Druggable Pockets by Site-Specific Protein Modification: Beyond Antibody-Drug Conjugates

2020

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Site-specific modification approaches have been extensively employed in the development of protein-based technologies. In this field, stability and activity integrity are the envisioned features of chemically modified proteins. These methods are especially used in the design of antibody-drug conjugates (ADCs). Nevertheless, a biochemical feature of the target protein in these reactions is often overlooked, residue specificity. Usually, in the course of developing chemical probes to modify a protein of interest (POI), specific amino acids are selected due to their reactivity. It is not critical which residue is modified as long as its modification does not compromise the POI's activity. However, no attention is paid as to why certain residues are preferentially modified over others. Physicochemical and structural constraints are often involved in the reactivity of the residue and account for the preferential modification. We propose that site-specific protein modification approaches can be applied beyond the development of ADCs or protein-drug conjugates, and used as a tool to reveal functionally relevant residues. By preferentially modifying certain side chains in the POI, chemical probes can uncover new binding motifs to investigate. Here we describe methods for protein modification, and how some pitfalls in the field can be turned into tools to reveal and exploit druggable pockets. Thus, allowing the design of innovative inhibitors against disease-relevant POIs. We discuss methodologies for site-specific modification of lysine, tryptophan, cysteine, histidine and tyrosine and comment on instances where the modified residues were used as targets for functionalization or drug design.

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“…Site-and chemoselective modification of proteins and peptides is becoming recognized as an important tool for probing structure-function relationship and accessing new therapeutic leads. [1][2][3][4] Significant advances have been made over the past decade to modify peptides using heteroatom conjugation with cysteine or lysine, [5][6][7][8][9][10] site specific C-H functionalization of aromatic rings in tryptophan, histidine, or phenylalanine, [11][12][13] radical functionalization, 14,15 and decarboxylative couplings of C-terminal amino acids or side chains functionalities in aspartic and glutamic acids. [16][17][18][19][20] In addition to the diversification strategies, 21 natural peptides with posttranslational modifications are gaining increasing importance due to their translational potential.…”

Section: Introductionmentioning

confidence: 99%

Organometallic AlaM Reagents for Umpolung Peptide Diversification

Zhu¹,

Powell²,

Jing³

et al. 2021

Preprint

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Selective modification of peptides and proteins is emerging as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potential. While many methods to perform direct bioconjugation rely on reactions with dehydroalanine, an alternative strategy capitalizing on polarity reversal at the β carbon in amino acids can open access to a new type of diversification reactions characterized by absolute control of regio- and stereoselectivity. Here, we report that alanine carbastannatranes AlaSn can serve as a universal synthon in various C-C and C-heteroatom bond-forming reactions demonstrated in over 50 diverse examples. These reagents are compatible with peptide and protein manipulation techniques and undergo chemoselective conjugation in minutes when promoted by Pd(0). Despite their increased nucleophilicity and propensity to transfer the alkyl group, AlaSn operate at room temperature under buffered conditions (pH 6.5-8.5). We also show that AlaSn can be easily transformed into several canonical L- and D-amino acids in arylation, acylation, and etherification reactions. Furthermore, AlaSn can partake in macrocyclizations exemplified by the synthesis of medium size cyclic peptides with various topologies (7-13 membered macrocycles). Taken together, metalated alanine AlaSn demonstrate unparalleled scope and represent a new type of umpolung reagents suitable for structure-activity relationship studies and peptide diversification.

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Concepts of Catalysis in Site-Selective Protein Modifications

Cited by 93 publications

References 69 publications

Enabling protein-hosted organocatalytic transformations

Enabling protein-hosted organocatalytic transformations

Unveiling Druggable Pockets by Site-Specific Protein Modification: Beyond Antibody-Drug Conjugates

Organometallic AlaM Reagents for Umpolung Peptide Diversification

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