Chemoselective Dual Labeling of Native and Recombinant Proteins

Agrawalla, Bikram Keshari; Wang, Tao; Riegger, Andreas; Domogalla, Matthias P.; Steinbrink, Kerstin; Dörfler, Thilo; Chen, Xi; Boldt, Felix; Lamla, Markus; Michaelis, Jens; Kuan, Seah Ling; Weil, Tanja

doi:10.1021/acs.bioconjchem.7b00675

Cited by 17 publications

(16 citation statements)

References 32 publications

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“…While only alkyne 4 c was evaluated in this case, the excellent results obtained with such a strategy should easily give access to a plethora of dually functionalized conjugates by simply varying the alkyne component. This strategy thus joins the limited existing group of site‐selective dual conjugation methods applicable to native proteins, and, most notably, to our knowledge, represents the first to not target cysteine residues [15, 43, 44] …”

Section: Resultsmentioning

confidence: 87%

“…This strategy thus joins the limited existing group of site-selective dual conjugation methods applicable to native proteins, and, most notably,t oo ur knowledge, represents the first to not target cysteiner esidues. [15,43,44] Having screened various isocyanides and investigated the diversity of payloads that could be incorporated at the play stage of our "plug-and-play"s trategy,w es et out to study the aldehydes cope of this transformation, utilising 2i as am odel isocyanide. The previously mentioned TAMRA aldehyde 1a and commercially availablea ldehydes 1c-r were thus evaluated and as trong influence of stereoelectronic effects on average DoC and conversion values were observed (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

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Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

Sornay

Hessmann

Erb

et al. 2020

Chemistry A European J

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Site-selective modificationo fp roteins hasb een the object of intense studies over the past decades, especially in the therapeutic field. Prominent resultsh ave been obtained with recombinant proteins,f or which site-specific conjugation is made possible by the incorporation of particular aminoa cid residues or peptides equences. In parallel, methods for the site-selective and site-specific conjugation of native andn atural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues.P ursuingt he efforts in this field, we planned to develop an ew typeo fs ite-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasonedt hat this should give higher chances of developing as ite-selective strategy compared to the great majority of existing methods that solely target as ingle residue. We opted for the Ugi four-centre three-component reaction to implement this idea, with the aim of conjugating the sidechain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein,w es how that this strategyc an give access to valuable antibody conjugates bearings everald ifferent payloads;f urthermore, the approach limits the potential conjugation sites to only six on the model antibody trastuzumab.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

Sornay

Hessmann

Erb

et al. 2020

Chemistry A European J

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“…(a) Cysteine and methionine sites [59] . (b) Cysteine and disulfide sites [89] …”

Section: Synthetic Strategies For Dual Functionalization Of Proteinsmentioning

confidence: 99%

“…An alternative strategy for site‐selective protein dual modification is based on the differences in the reactivity of cysteines in their free (thiol) and oxidized (disulfide) forms [89] . Disulfide bonds could be considered as protected thiols, which require activation to form the reduced free thiols for subsequent functionalization.…”

Section: Synthetic Strategies For Dual Functionalization Of Proteinsmentioning

confidence: 99%

Contemporary Approaches for Site‐Selective Dual Functionalization of Proteins

Kuan

Weil

2021

Angewandte Chemie

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Site‐selective protein functionalization serves as an invaluable tool for investigating protein structures and functions in complicated cellular environments and accomplishing semi‐synthetic protein conjugates such as traceable therapeutics with improved features. Dual functionalization of proteins allows the incorporation of two different types of functionalities at distinct location(s), which greatly expands the features of native proteins. The attachment and crosstalk of a fluorescence donor and an acceptor dye provides fundamental insights into the folding and structural changes of proteins upon ligand binding in their native cellular environments. Moreover, the combination of drug molecules with different modes of action, imaging agents or stabilizing polymers provides new avenues to design precision protein therapeutics in a reproducible and well‐characterizable fashion. This review aims to give a timely overview of the recent advancements and a future perspective of this relatively new research area. First, the chemical toolbox for dual functionalization of proteins is discussed and compared. The strengths and limitations of each strategy are summarized in order to enable readers to select the most appropriate method for their envisaged applications. Thereafter, representative applications of these dual‐modified protein bioconjugates benefiting from the synergistic/additive properties of the two synthetic moieties are highlighted.

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“…In principle, the site-selective chemical modification strategies mentioned are also applied to introduce SLs to proteins of interest 61. Dual functionalization strategies have also been developed in a site-directed fashion, for example by capitalizing on reactivity variations of different cysteine residues71,72 or in combination with N-terminal protein modification 73. By the careful selection of the PB and the chemical modification method, it will be possible to attach two different recognition motif in a defined spatial orientation.…”

Section: Design Principles Of Supramolecular Protein Nanostructures (mentioning

confidence: 99%