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. 2023 Mar 29;28(7):3042.
doi: 10.3390/molecules28073042.

Activation-Free Sulfonyl Fluoride Probes for Fragment Screening

László Petri  1   2 , Péter Ábrányi-Balogh  1   2   3 , Noémi Csorba  1   2   3 , Aaron Keeley  1 , József Simon  1   4 , Ivan Ranđelović  5 , József Tóvári  6 , Gitta Schlosser  7 , Dániel Szabó  8 , László Drahos  8 , György M Keserű  1   2   3
Affiliations

Activation-Free Sulfonyl Fluoride Probes for Fragment Screening

László Petri et al. Molecules. .

Abstract

SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Accordingly, sulfonyl fluorides label multiple nucleophilic amino acid residues, making these reagents popular in both chemical biology and medicinal chemistry applications. The reactivity of sulfonyl fluorides nominates this warhead chemotype as a candidate for an external, activation-free general labelling tag. Here, we report the synthesis and characterization of a small sulfonyl fluoride library that yielded the 3-carboxybenzenesulfonyl fluoride warhead for tagging tractable targets at nucleophilic residues. Based on these results, we propose that coupling diverse fragments to this warhead would result in a library of sulfonyl fluoride bits (SuFBits), available for screening against protein targets. SuFBits will label the target if it binds to the core fragment, which facilitates the identification of weak fragments by mass spectrometry.

Keywords: chemical probe; covalent fragment; electrophilic warhead; fragment screening; sulfonyl fluoride; targeted covalent inhibitor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Members of the aryl sulfonyl fluoride library. Blue atoms are the attachment points between the warhead and the variable fragment. Red and green groups are electron donating (OMe) or electron withdrawing groups (NO2) to reveal their possible impact on reactivity.
Figure 2
Figure 2
(A) Representative chemical reaction of the intrinsic reactivity assay with representative linear regression resulting in a k value for the 6→21 transformation and (B) representative HPLC chromatograms of the 6→21 reaction.
Figure 3
Figure 3
(A) Fluorogenic reaction of the DPF sensor molecule in the presence of fluoride ions; (B) calibration of assay sensitivity with NaF solutions and (C) the measured activity as relative fluorescence unit (RFU) for compounds 1–20 and compared to the tyrosine labelling conversion obtained by the nonapeptide assay.
Figure 4
Figure 4
Nonapeptide conversion and amino acid labelling (selectivity/promiscuity) data for the phenyl-derived sulfonyl fluorides (1–20).
Figure 5
Figure 5
Correlation between nonapeptide conversion and amino acid labelling percentage (Tyr—blue, Lys—green).
Figure 6
Figure 6
Correlation between calculated (left) and experimental (right) 13C NMR shifts and nonapeptide conversion. Orange: 1–5, blue: 12–17, green: 6–11.
Figure 7
Figure 7
MS/MS spectrum (enlarged) of the KRasG12D 150–161 tryptic peptide modified with covalent probe 12. Modified fragments are labelled with ∗. Note that only the most intensive sequence fragments are assigned.
Figure 8
Figure 8
(A) SuFBit-C5-TAMRA (22) as a fluorescent derivative of probe 12, and (B) SDS-PAGE confirmation of proteome-wide fluorescent labelling with SuFBit-C5-TAMRA (22).
See this image and copyright information in PMC

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