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A Chemoselective Strategy for Late Stage Functionalization of Complex Small Molecules with Polypeptides and Proteins

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A Chemoselective Strategy for Late Stage Functionalization of Complex Small Molecules with Polypeptides and Proteins A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Cohen, Daniel T. et al. "A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins." Nature Chemistry 11, 1 (November 2018): 78–85 © 2018, The Author(s), under exclusive licence to Springer Nature Limited As Published http://dx.doi.org/10.1038/s41557-018-0154-0 Publisher Springer Science and Business Media LLC Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/123668 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Chem Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 January 01. Published in final edited form as: Nat Chem. 2019 January ; 11(1): 78–85. doi:10.1038/s41557-018-0154-0. A Chemoselective Strategy for Late Stage Functionalization of Complex Small Molecules with Polypeptides and Proteins Daniel T. Cohen*,#, Chi Zhang^, Colin M. Fadzen^, Alexander J. Mijalis, Liana Hie‡, Kenneth D. Johnson†, Zachary Shriver†, Obadiah Plante†, Scott J. Miller‡, Stephen L. Buchwald, and Bradley L. Pentelute* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA ‡Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, USA †Visterra Inc., 1 Kendall Square, Cambridge, Massachusetts 02139, USA Abstract Conjugates between proteins and small molecules enable access to a vast chemical space that is not achievable with either type of molecule alone; however, the paucity of specific reactions capable of functionalizing proteins and natural products has presented a formidable challenge for preparing conjugates. Here we report a strategy for conjugating electron-rich (hetero)arenes to polypeptides and proteins. Our bioconjugation technique exploits the electrophilic reactivity of an oxidized selenocysteine residue in polypeptides and proteins, and the electron-rich character of certain small molecules to provide bioconjugates in excellent yields under mild conditions. This conjugation chemistry enabled the synthesis of peptide-vancomycin conjugates without prefunctionalization of vancomycin. These conjugates had enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we showed that a 6 kDa affibody protein and a 150 kDa IgG antibody could be modified without diminishing bioactivity. Table of Contents Summary The preparation of conjugates between proteins and small molecules is often challenging and requires several synthetic steps to functionalize each component for conjugation. Herein, a conjugation methodology is described that leverages an electrophilic Se-S bond of selenocysteine to create bioconjugates between polypeptides and complex small molecules. *Correspondence to: [email protected], [email protected]. #Current address: AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, USA ^These authors contributed equally Contributions D.T.C and B.L.P. conceived the work and designed the experiments. D.T.C, C.Z., and C.M.F. performed the peptide and protein labeling experiments. D.T.C., C.M.F., and A.J.M. developed the seleno-affibody synthesis. L.H. and S.J.M performed the NMR characterization to assign regioselectivity for the selenocysteine conjugation. K.D.J., Z.S. and O.P. carried out the cytotoxicity and hemolysis assays on 23v analogues. D.T.C., C.Z., C.M.F., and B.L.P. wrote the manuscript, with input from all other authors. Competing interests K.D.J., Z.S. and O.P. are employees of Visterra Inc. D.T.C., C.Z., S.L.B., and B.L.P. are inventors on a patent filed by MIT-TLO to cover this work (US patent application no. 15187169). Cohen et al. Page 2 Synthesizing covalent conjugates of a peptide or protein and a complex small molecule is Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author often challenging with available chemical tools. However, such conjugates may have clinical value as they can direct small molecule toxins to certain tissues, widen therapeutic windows, and tune pharmacokinetic and pharmacodynamic properties often beyond the capabilities of each component alone.1 For example, a conjugate of the highly cytotoxic agent emtansine (DM1) with trastuzumab, a HER2 selective antibody, is used clinically to treat late stage breast cancer.2 Early antibody-drug conjugates (ADCs) were prepared in a heterogeneous fashion, usually by linking exposed lysine residues on the antibody with N-hydroxysuccinimide ester derivatives of the small molecule payload.3–5 Alternatively, cysteine conjugation is facilitated by reduction of the four interchain disulfide bonds, followed by reaction with a maleimide-linked payload.6–8 Given the varying stability and efficacy of heterogeneous ADCs, the ADC field has prioritized the development of new methods to create homogenous ADCs.9 Current methods to manufacture homogenous ADCs include leveraging the reactivity of cysteine and lysine, incorporating unnatural amino acids into the antibody, and utilizing conserved glycans on the antibody surface.9 Many of these strategies require modification of both the antibody and the small molecule in order to enable homogeneous linkage, which is frequently laborious. The direct and chemoselective conjugation of complex small molecules to peptides or proteins is a formidable task due to the presence of multiple nucleophilic and electrophilic functional groups. To achieve this conjugation with high selectivity, the reactivity of the small molecule must be complementary with the reactivity of the coupling functional group in the biopolymer. In particular, a technique for the replacement of an aromatic C–H bond of a small molecule with a biopolymer would be an especially straightforward and appealing means of coupling two complex fragments. There are several examples of using both metal- free and copper-catalyzed reactions to connect aryl thiols to arenes.10–12 Additionally, Fang et al. have demonstrated C-S and C-Se bond formation with indoles using iron-catalyzed chemistry with diaryldisulfides and diarylselenides.13 Unfortunately, these techniques often require bioincompatible solvents such as DMF and are performed between two small molecules. However, these types of reactions suggest that an electrophilic disulfide, diselenide, or mixed Se-S bond in a biopolymer may be able to be used for direct, aromatic C-H bond replacement if the conditions were milder. We recently reported the selective formation of carbon-selenium bonds in unprotected peptides containing an oxidized, electrophilic selenocysteine residue.14 This approach exploited an electrophilic selenium-sulfur (Se–S) bond in combination with a copper reagent and a boronic acid to selectively arylate the selenium of selenocysteine. Despite the elaborate scope and mild conditions, this method required the use of a boronic acid functional group to facilitate the C–Se bond formation. The need for the boronic acid hampers the overall efficiency for conjugating complex small molecules to biopolymers because additional synthetic steps are needed to install the prerequisite boronic acid.15 Having demonstrated that we can access electrophilic selenocysteine under mild biocompatible conditions, we questioned whether our electrophilic selenium reagent in combination with electron-donating arenes could be used to achieve the direct conjugation Nat Chem. Author manuscript; available in PMC 2020 January 01. Cohen et al. Page 3 of unmodified small molecules to peptides and proteins (Fig. 1). If effective, this would be a Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author general route for the conjugation of natural products and pharmaceuticals with electron-rich units to peptides and proteins. Herein we report an approach to creating peptide and protein- small molecule conjugates by matching the inherent reactivity of a small molecule with an oxidized selenocysteine residue (Sec). This strategy exploits the unique nature of electrophilic Sec in combination with the electron-rich nature of arene-containing small molecules to provide the respective conjugate (Fig. 1). Results and Discussion We began our investigations with the conjugation of vancomycin to antimicrobial peptides containing an oxidized selenocysteine residue. Vancomycin provided a good candidate for the small molecule component, as the embedded electron-rich resorcinol ring of vancomycin serves as a site for conjugation. Additionally, vancomycin is a potent antibiotic often used as first-line treatment for methicillin-resistant S. aureus.16 We hypothesized that conjugation to antimicrobial peptides may be beneficial as vancomycin is unable to penetrate the outer membrane of Gram-negative bacteria.17 Also compared with larger proteins, small antimicrobial peptides would be a lower complexity starting point for the development of our chemistry. Upon incorporation of an oxidized selenocysteine residue into various antimicrobial peptides, the conjugation reaction described herein provides a rapid and convenient single step approach to prepare a small library of antibacterial peptide- vancomycin conjugates in multi-milligram
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