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. 2024 Oct 23;146(44):30009–30013. doi: 10.1021/jacs.4c12210

Halogenase-Assisted Alkyne/Aryl Bromide Sonogashira Coupling for Ribosomally Synthesized Peptides

Nirmal Saha †, F N U Vidya †, Ramon Xie †, Vinayak Agarwal ‡,§,*
PMCID: PMC11544707  PMID: 39441838

Abstract

graphic file with name ja4c12210_0005.jpg

We describe the enzymatic bromination of ribosomally synthesized peptides and develop protocols for Sonogashira coupling of peptidic aryl bromides with a panel of alkynes. Using this workflow, entirely new chemical handles are introduced onto ribosomal peptides, including but not limited to terminal alkynes, which enable further diversification via alkyne–azide click chemistry. Regiospecific enzymatic installation of the aryl bromide circumvents genetic code expansion and passivation of other reactive handles on the peptide chain, representing the applicability of biocatalysts in peptide modification chemistry.

Chemical modification of peptides and proteins is essential to expand their structural and functional novelty and fully exploit their myriad of pharmaceutical applications. Various means to introduce reactive handles in polypeptides—beyond the ones available to the proteinogenic amino acids—have been developed.1−3 Among these are amino acid building blocks with halogenated side chains. While halogenation is one of the most versatile C–H functionalization strategies and is ubiquitous in chemical synthesis, regiospecific halogenation of peptides and proteins is outside the purview of chemical halogenation catalysts; the site for halogenation is usually governed by substrate reactivity rather than by the catalyst itself. Thus, to introduce halogens into peptides and proteins, entirely new strategies in chemical biology are used. Genetic code expansion allows for the incorporation of halogenated nonproteinogenic amino acids in polypeptide chains.4 Reactive side chains for proteinogenic amino acids, such as cysteine thiols, can be conjugated to halogen-bearing handles after passivation of other similarly reactive residues.5 The de novo synthesis of peptides and proteins with halogenated handles has also been realized.6 Taking a leaf out of the chemical synthesis handbook, each of these halogenation strategies has been combined with transition-metal-assisted chemical derivatization reactions, such as the Suzuki-Miyaura cross-coupling, to derivatize peptides and proteins (Figure 1A).

Figure 1.

Figure 1

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(A) Aryl iodide introduction into proteins by genetic code expansion (top), ligation to a side chain Cys thiol (middle), and preinstallation into synthetic peptides (bottom) enable Pd-catalyzed Suzuki-Miyaura cross-coupling reactions with boronic acids. (B) In this study, enzymatic regiospecific bromination of the C-terminal Trp side chain indole allows for Sonogashira coupling of alkynes with a ribosomally synthesized peptide.

Enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs) offer an alternate route for biocatalytic introduction of novel modifications and functionalities into peptides.7 While RiPP modification enzymes indeed suffer from poor atom economy (substrate recognition is dependent on an N-terminal leader region of the peptide that in itself is not modified and is dispensed with after the enzymatic transformation), they do offer exquisite regiocontrol. Case in point are the recently discovered RiPP halogenases. Of all RiPP halogenases and small molecule halogenases that accommodate peptidic substrates, the flavin-dependent RiPP halogenase SrpI brominates only the C-terminal Trp residue of the SrpE substrate peptide at the indole-6 position; other Trp residues in the peptide substrate are not modified.8−10 Furthermore, SrpI is strictly selective for bromination with no contaminating chlorination activity.11,12

In this study, we sought to determine the optimal substrate peptide sequence for SrpI and develop protocols for the copper-free Sonogashira coupling of terminal alkynes to SrpI-delivered brominated ribosomal peptides. As a tool for modifying amino acids, the Sonogashira cross-coupling reaction has found diverse applications such as in fluorescence tagging, biotinylation, and installing 18F handles for imaging.13−15 However, Sonogashira coupling for ribosomally derived peptides and proteins has typically involved the introduction of a peptide-alkyne or peptide-iodide using the chemical strategies illustrated in Figure 1A.16,17 In this study, we leverage the regiospecificity and obligate bromination activity of SrpI to generate peptidic aryl bromide substrates for Sonogashira coupling (Figure 1B). With a view toward palladium-assisted C–C bond forming reactions, bromination is particularly desirable because it opens up avenues for these reactions to proceed at milder conditions as compared to chlorinated substrates. Specifically, reaction temperatures required for Sonogashira coupling using aryl chlorides are prohibitive (>100 °C) for application to peptides and proteins.18,19 Hence, the bromination activity of SrpI provides a unique opportunity to interface a peptide-modifying biocatalyst with chemical methodology development. Peptide iodination using RiPP biosynthetic enzymes is currently out of reach.

Guided by binding to the substrate peptide’s N-terminal leader region, SrpI is permissive for diverse C-terminal core peptides as long as the Trp residue—the side chain of which is brominated at the indole-6 position—is positioned at the C-terminus.20 Though SrpI can (di)brominate a Tyr side chain phenoxyl, the physiological substrate is the Trp indole.11 Ribosomally synthesized core peptides ranging from 3 to 11 residues, appended to the SrpE leader, were tested as substrates for in vitro bromination by SrpI using the NAD(P)H-generating phosphite dehydrogenase PTDH and the flavin-reductase RebF as partner enzymes (Figure 2A, Table S1).12 While the core sequences of these susbtrate peptides are quite divergent from the native azoline-containing native substrates for SrpI, bromination still proceeds as long as the Trp residue is present at the C-terminus.11,20 Product yields were determined using liquid chromatography/mass spectrometry (LC/MS). In the core peptides used in this study, the Pro residue preceding the terminal Trp residue (which gets brominated by SrpI) provides a diagnostic MS2 fragmentation signature due to the labile nature of the prolyl amide bond allowing for any modifications on the Trp residue to be tracked (vide infra).21 Using a panel of substrate peptides with a conserved leader sequence but different core sequences, we discerned that the penta- and hexapeptides offered maximal productivity for SrpI, with the yield falling off at either end of the range (Figures 2B and S1–S15, Table S2). Product MS2 fragmentation spectra demonstrated that the C-terminal Trp was brominated (Figure 2C). Henceforth, the hexapeptide LTVLPW is used as the core peptide for bromination by SrpI. The in vitro bromination strategy developed herein allowed for large volume reactions. The core peptide was excised from the proteusin leader by proteolytic digestion by Glu-C to afford a undecapeptide brominated product in multimilligram scale (Figure S16). With the brominated undecapeptide in hand, we were well positioned to explore reaction conditions that afford Sonogashira coupling of alkynes to a ribosomally synthesized peptide.

Figure 2.

Figure 2

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(A) Scheme for SrpI-catalyzed in vitro bromination. The leader peptide is shown in cartoon representation. (B) Product yields for different core peptides. Means and standard deviations from three independent reactions are plotted. All reactions were conducted under identical conditions (see Supporting Information for details). (C) MS2 fragmentation spectra corresponding to the brominated undecapeptide demonstrate the characteristic Pro-Trp product ion. The undecapeptide [M+2H]2+ parent ion is illustrated by the blue diamond. Digestion by endoproteinase Glu-C furnishes an undecapeptide product, of which the underlined five amino acids are derived from the SrpE leader.

Buchwald reported the development of the hydrophilic sulfonated ligand sXPhos for copper-free Sonogashira coupling of small molecule aryl bromides with alkynes using a water/acetonitrile biphasic solvent system and bisPdCl2(CH3CN)2 as the catalyst.22 Subsequently, Goss reported the use of this catalyst/ligand pair, and microwave/100 °C reaction conditions for Sonogashira coupling of alkynes to bromoindoles, bromotryptophans, and synthetic tripeptides.23 However, under the optimized reaction conditions reported therein for simple aryl bromides, no product formation was observed for the brominated peptidic substrates developed in this study (Table S3, entry 1). Using phenylacetylene (1) as the model alkyne, we were also unsuccessful in achieving product formation by changing the temperature alone with higher temperatures effecting substrate degradation (Table S3, entry 2). Thus, a comprehensive evaluation of reaction conditions was undertaken to reveal that at an intermediate temperature of 65 °C, a higher catalyst and the ligand loading were necessary for the Sonogashira coupling to be affected upon the longer, ribosomally derived peptide (Figure 3A, Table S3, entry 3). The observation that higher ligand and catalyst loading were necessary for the derivatization of peptides and proteins is not without precedent.17 We noted that increasing the temperature from 65 to 80 °C (Table S3, entry 5) led to abolition of product formation likely due to substrate degradation, suggesting that 65 °C is the optimal temperature for this reaction.

Figure 3.

Figure 3

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(A) Optimized Sonogashira reaction scheme with reaction conditions as follows: 1 mg of Br-peptide (1 equiv), 10 eq. terminal alkyne, 6.2 eq. Cs2CO3, degassed water (0.1 mL), MeCN (0.1 mL), [PdCl2(CH3CN)2] (15 mol %), ligand sXPhos (18 mol %), 65 °C, 2 h; all solvents purged with argon. Reactions were quenched by the addition of mercaptopropionic acid. (B) Yields for Sonogashira coupling of alkynes 1–14 with the SrpI-brominated peptide. Also illustrated are MS2 fragmentation spectra for each coupling product, wherein the diagnostic prolyl-(modified)Trp ion can be visualized. The [M+2H]2+ parent ions are illustrated by blue diamonds.

In line with Davis’ finding, scavenging the palladium by the addition of mercaptopropionic acid facilitated reaction monitoring by LC/MS.24 Using these optimized conditions, product yields using a panel of alkynes 1–14 were evaluated to establish the broad substrate scope of the Sonogashira coupling reaction conditions developed in this study. As before, reaction products were characterized using the Pro-(modified)Trp MS2 fragmentation ions (Figures 3B and S17–S44, Table S4).

Excellent product yields for a majority of aryl alkynes were observed. Using the cross-coupling strategy, we were able to introduce fluoro, cyano, and thiophene handles onto the ribosomal peptide, in addition to simple arenes with moderate to excellent yields (Figure 3B). In general, electron withdrawing groups on the aryl rings were associated with higher yields, likely due to higher acidity of the terminal alkyne hydrogen. Yields for coupling of long chain and branched aliphatic alkynes 11 and 12 were perhaps challenged by substrate solubility; the cross-coupling reactions with 13 and 14 proceeded with high yields.

In addition to querying the reaction scope, we explored whether aliphatic and aryl diynes could be coupled to the brominated peptide, with the motivation that the other unreacted alkyne terminus could serve as an additional reactive handle for a second round of bioorthogonal peptide derivatization. Moderate to excellent yields for the coupling of 1,4-diethynylbenzene (8) and 1,7-octadiyne (10) were observed to produce terminal alkyne bearing peptides 15 and 16, respectively. Steric complexity in coordinating with the Pd complex could have compromised the yield for 1,3-diethynylbenzene (9) (Figure 3B).

Pursuant to the above-mentioned motivation of exploring diyne substrates for the Sonogashira cross-coupling reaction, we investigated if simple aryl and aliphatic azides could be coupled to 15 and 16 using the traditional copper-catalyzed alkyne–azide click reaction (CuAAC) to yield triazole products. In the single-pot reaction scheme thus devised, the Sonogashira reaction was not quenched by the addition of mercaptopropionic acid. Rather, the copper salt and ligand THPTA were introduced at the end of the Sonogashira reaction period. The CuAAC coupling was allowed to proceed at room temperature, followed by quenching by mercaptopropionic acid and analysis by LC/MS. Gratifyingly, the appropriate triazole products were observed representing hypermodified ribosomal peptides in excellent yields (Figures 4B and S45–S50, Table S5).

Figure 4.

Figure 4

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(A) Scheme for CuAAC coupling of azides to modified peptides 15 and 16. (B) MS2 fragmentation spectra for the triazole products with characteristic MS2 fragmentation ions labeled. The [M+2H]2+ parent ions are illustrated by blue diamonds.

Taken together, these data establish the applicability of the RiPP halogenase SrpI and the Sonogashira reaction to extend the chemistry of ribosomally derived peptides. A ribosomal peptide with multiple other Trp and Tyr residues is regiospecifically brominated in high yield by SrpI; no passivation by mutagenesis of these other Trp and Tyr residues is required. While well-developed derivatization reactions for Cys, Lys, Tyr, and His side chains are now available, strategies for late-stage derivatization of the Trp side chain, particularly at the indole-4–7 positions, are rarified.25−28 Biocatalytic reactions can fill this void, particularly as applications are extended to long peptides and proteins that have multiple reactive handles and require mild and aqueous reaction conditions. At present, the reaction conditions herein perhaps limit applications to small peptides and thermostable proteins. Regardless, indole derivatization is exceptionally well represented in natural products and in medicinal chemistry.29 It is thus noteworthy that late-stage peptidic Trp-modifying enzymes are usually derived from natural product biosynthetic gene clusters exemplifying the applicability of natural product biosynthetic enzymes in biocatalytic applications.30

Acknowledgments

The authors are thankful to the National Institutes of Health (1R35GM142882 to V.A.) for their support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c12210.

  • Comprehensive description of materials and methods used in this study, synthetic schemes, compound characterization data, and descriptions of enzyme reaction outcomes (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja4c12210_si_001.pdf (5MB, pdf)

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Supplementary Materials

ja4c12210_si_001.pdf (5MB, pdf)

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