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Download This Article PDF Format Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue A straightforward methodology to overcome solubility challenges for N-terminal cysteinyl Cite this: Chem. Sci.,2021,12,3194 † All publication charges for this article peptide segments used in native chemical ligation have been paid for by the Royal Society of Chemistry Skander A. Abboud, El hadji Cisse, Michel Doudeau, Hel´ `ene Ben´ edetti´ and Vincent Aucagne * One of the main limitations encountered during the chemical synthesis of proteins through native chemical ligation (NCL) is the limited solubility of some of the peptide segments. The most commonly used solution to overcome this problem is to derivatize the segment with a temporary solubilizing tag. Conveniently, the Received 1st November 2020 tag can be introduced on the thioester segment in such a way that it is removed concomitantly with the NCL Accepted 10th January 2021 reaction. We herein describe a generalization of this approach to N-terminal cysteinyl segment DOI: 10.1039/d0sc06001a counterparts, using a straightforward synthetic approach that can be easily automated from rsc.li/chemical-science commercially available building blocks, and applied it to a well-known problematic target, SUMO-2. Creative Commons Attribution 3.0 Unported Licence. Introduction however, these modications will permanently remain in the synthesized protein. Traceless approaches include the use of The advent of the native chemical ligation1 (NCL) reaction has acid-labile N-2-hydroxy-4-methoxybenzyl (Hmb) groups on 8 3d,e,9 revolutionized the eld of chemical protein synthesis by backbone amides, or Ser/Thr O-acyl isopeptide known to offering a simple strategy to assemble unprotected peptide inhibit aggregation, but the most widely used strategy is the 10 segments bearing mutually-reactive C-terminal thioesters and incorporation of a temporary hydrophilic “solubilizing tag”. N-terminal cysteines with exquisite chemo- and regioselectivity. Such temporary tags are generally composed of lysines or This article is licensed under a Twenty-six years aer its discovery, NCL is still the gold stan- arginines that bear a cationic charge side chain, oen as homo- 11 dard reaction in the eld. The continuous development of many oligomers, and can be introduced either on a backbone amide, 12 13 related synthetic methodologies allowed to extend and simplify the C-terminus of the segment or the side chain of an Asn, 13 12c,14,15 13,16 13,17a 17 16 its applicability,2 and led to impressive applications in the total Asp, Cys, Gln, Glu, Lys or Thr residues. Open Access Article. Published on 11 January 2021. Downloaded 9/23/2021 5:30:22 PM. synthesis of functional proteins of more than 300 residues.3 A large variety of linkers used to attach the tag to the peptide One of the major current limitations of NCL-based protein segment and designed to be cleaved in an additional step aer synthesis is the low solubility or tendency to aggregate of some the NCL (Scheme 1A) have been reported. Cleavage conditions 11,14c,d 12b 17c of the segments. If this is anticipated when synthesizing a very include treatments with acids, bases, pH 4.5 buffer, 12c,13 17b,d hydrophobic target such as a transmembrane protein, segments sodium nitrite, nucleophiles, transition metal cata- 12c,14a,b,15,17a 16 12a from soluble hydrophilic proteins frequently prove to be prob- lysis, UV irradiation and autoproteolysis. lematic, while being oen very hard to predict. NCL is usually An advantageous alternative is the introduction of the solu- conducted under denaturing conditions, typically 6 M guani- bilizing tag on the C-terminal thioester moiety (Scheme 12b,18–20 dinium chloride, and is tolerant to the addition of organic 1B). In this case, the tag is cleaved in the course of the NCL solvents4 and detergents,5 thus substantially minimizing these reaction without needing an additional synthetic step, aer solubility/aggregation problems during the reaction itself. playing its solubilizing role during the purication, character- Nevertheless, the purication and characterization of the ization and handling of the problematic segment. This approach 18 19 segments prior to NCL regularly remains a severe bottleneck. was pioneered by Aimoto and Kent for Boc-SPPS-based thio- 20 Many synthetic strategies were developed to overcome this ester synthesis, and later extended by Tietze to Fmoc-SPPS using critical problem. For example, modication of the segment a b-mercaptoester precursor converted in situ into a thioester 21 through N-methylation of backbone amides6 or fusion with during NCL through an O / S acyl shi (a so-called peptide 22 a hydrophilic peptide,7 can dramatically increase its solubility; crypto-thioester ). If this one-pot NCL/tag cleavage approach is clearly not suited to extreme situations where the ligation product remains insoluble or prone to aggregation, it is expected to be Centre de Biophysique Mol´eculaire, CNRS UPR 4301, Rue Charles Sadron, 45071 widely applicable in the many cases when the low-solubility/ Orl´eans Cedex 2, France. E-mail: [email protected] † Electronic supplementary information (ESI) available. See DOI: aggregation behavior is associated with a single isolated 10.1039/d0sc06001a segment of the protein. Indeed, the additional segment ligated to 3194 | Chem. Sci.,2021,12,3194–3201 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Edge Article Chemical Science Scheme 1 Synthetic strategies for solubilization of peptide segments used in NCL-based protein synthesis using temporary solubility tags (blue ovals) that are removed either after (A) or concomitantly (B and C) with the NCL reaction. the problematic one can further play the role of solubility tag, strategy. Ideally, this linker should be (1) introduced through an strikingly demonstrated by the synthesis of fragments of trans- automation-friendly solid phase step using commercially membrane proteins using these techniques.18,20 However, the available materials, (2) bear a primary aliphatic amine or Creative Commons Attribution 3.0 Unported Licence. strategy is inherently limited to thioester segments and not suited a suitable precursor for further Fmoc-SPPS elongation of for N-terminal cysteinyl counterparts.23 a hydrophilic peptide sequence and (3) be stable to the Fmoc- In a closely related context, Valiyaveetil24 proposed the idea to SPPS conditions, including elongation and TFA-based cleavage. introduce a solubility tag linked through a disulde to the N- Considering these requirements, we reasoned that incorpo- terminal Cys of a cysteinyl segment synthesized by Boc-SPPS, ration of the N-terminal cysteinyl residue through the coupling the disulde bond being cleaved in a rst additional reduction of Boc-Cys(Npys)-OH would be ideal. The Npys group27 (S-3- step prior to NCL. In this case, the tag (Arg–Arg–Arg–Cys–NH2)was nitro-2-pyridinesulfenyl) is classically used for the directed introduced in solution through air oxidation-mediated formation formation of a mixed disulde on an N-terminal cysteine either 28 This article is licensed under a of a mixed disulde with the crude segment. This resulted in on solid support or in solution, through reaction with a thiol. a very low yield in the tagged segment due to both insolubility of The simplest solution for automated synthesis would be the non-tagged segment and the non-directed formation of the a reaction on solid support with an amino-thiol. We selected disulde leading to complex mixtures. Nevertheless, the authors two commercially available candidates: cysteamine (2-amino- Open Access Article. Published on 11 January 2021. Downloaded 9/23/2021 5:30:22 PM. succeeded in the highly demanding semi-synthesis of ion chan- ethane-1-thiol, 1), and 2-amino-1,1-dimethyl-ethane-1-thiol (2). nels through expressed protein ligation25 (EPL) with a recombi- Preliminary experiments with a model tripeptide (see ESI p. S5– nant thioester, demonstrating the feasibility of the approach. S11†) showed that disulde formation was quantitative through We thought that devising a straightforward methodology for simple incubation in NMP for 1 h with an excess (10 equiv.) of 2 the introduction of such a disulde-linked solubilizing tag on as its hydrochloride salt. We also demonstrated that the disul- N-terminal cysteinyl segments, and extending the concept of de was stable to a long piperidine treatment mimicking the concomitant NCL/tag cleavage could be extremely valuable and repeated Fmoc deprotection conditions needed for the SPPS generally applicable in chemical protein synthesis (Scheme 1C). elongation of a hydrophilic peptide tag. Contrastingly, reaction Indeed, disuldes are readily cleaved under standard NCL with 1 was much less clean, and the resulting disulde was not conditions generally including reducing agents (e.g. TCEP) and stable to the piperidine treatment. These results are in accor- a large excess of aromatic thiols like 4-mercaptophenylacetic dance with the known higher stability of tertiary thiol disuldes acid (MPAA).26 derivatives of cysteine like S-StBu towards Fmoc-SPPS condi- We herein describe a straightforward methodology for the tions as compared to simple non-hindered primary thiol introduction of such a tag through Fmoc-SPPS, which can be disuldes.29 easily automated on a standard peptide synthesizer, and Having in hand a robust method for the solid phase intro- exemplied the utility of this method through the synthesis of duction of the linker (referred hereaer as Ades, 2-amino-1,1- SUMO-2, a previously reported difficult target.12c dimethylethyl-1-sulfanyl), we applied it to two different long peptides, followed by the automated introduction of a (Lys)6 Results and discussion hydrophilic tag through repeated couplings of Fmoc-Lys(Boc)- OH under standard conditions (Scheme 2). We started with The disulde-based linker bridging the N-terminal cysteinyl a 41 amino acids (aa) model sequence devoid of any solubility 30 segment and the solubilizing tag is the cornerstone of the problem, derived from the human mucin MUC1 variable © 2021 The Author(s).
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