Montalbán-López M, Scott TA, Ramesh S, Rahman IR, van Heel AJ, Viel JH, et al. New developments in RiPP discovery, enzymology and engineering. Nat Prod Rep. 2021;38:130–239. https://doi.org/10.1039/D0NP00027B.

Article  PubMed  Google Scholar 

Süssmuth RD, Mainz A. Nonribosomal peptide synthesis—principles and prospects. Angew Chem Int Ed. 2017;56:3770–821. https://doi.org/10.1002/anie.201609079.

Article  CAS  Google Scholar 

Cao L, Goreshnik I, Coventry B, Case JB, Miller L, Kozodoy L, et al. De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science. 2020;370:426–31. https://doi.org/10.1126/science.abd9909.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cunningham AD, Qvit N, Mochly-Rosen D. Peptides and peptidomimetics as regulators of protein–protein interactions. Curr Opin Struct Biol. 2017;44:59–66. https://doi.org/10.1016/j.sbi.2016.12.009.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang H, Dawber RS, Zhang P, Walko M, Wilson AJ, Wang X. Peptide-based inhibitors of protein–protein interactions: biophysical, structural and cellular consequences of introducing a constraint. Chem Sci. 2021;12:5977–93. https://doi.org/10.1039/D1SC00165E.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cao R, Li J, Liao Q, Shao M, Zhang Q, Zhang Y, et al. Enhanced bioactivity of natural products by halogenation: a database survey and quantum chemistry calculation study. J Med Chem. 2025;68:10486–96. https://doi.org/10.1021/acs.jmedchem.5c00944.

Article  CAS  PubMed  Google Scholar 

Gribble GW. A survey of recently discovered naturally occurring organohalogen compounds. J Nat Prod. 2024;87:1285–305. https://doi.org/10.1021/acs.jnatprod.3c00803.

Article  CAS  PubMed  Google Scholar 

Böhringer N, Kramer J-C, de la Mora E, Padva L, Wuisan ZG, Liu Y, et al. Genome- and metabolome-guided discovery of marine BamA inhibitors revealed a dedicated darobactin halogenase. Cell Chem Biol. 2023;30:943–52.e7. https://doi.org/10.1016/j.chembiol.2023.06.011.

Article  CAS  PubMed  Google Scholar 

Maffioli SI, Iorio M, Sosio M, Monciardini P, Gaspari E, Donadio S. Characterization of the Congeners in the Lantibiotic NAI-107 Complex. J Nat Prod. 2014;77:79–84. https://doi.org/10.1021/np400702t.

Article  CAS  PubMed  Google Scholar 

Cruz JC, Iorio M, Monciardini P, Simone M, Brunati C, Gaspari E, et al. Brominated variant of the lantibiotic NAI-107 with enhanced antibacterial potency. J Nat Prod. 2015;78:2642–7. https://doi.org/10.1021/acs.jnatprod.5b00576.

Article  CAS  PubMed  Google Scholar 

Pinchman JR, Boger DL. Investigation into the functional impact of the vancomycin C-ring aryl chloride. Bioorg Med Chem Lett. 2013;23:4817–9. https://doi.org/10.1016/j.bmcl.2013.06.080.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pinchman JR, Boger DL. Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues. J Med Chem. 2013;56:4116–24. https://doi.org/10.1021/jm4004494.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gerhard U, Mackay JP, Maplestone RA, Williams DH. The role of the sugar and chlorine substituents in the dimerization of vancomycin antibiotics. J Am Chem Soc. 1993;115:232–7. https://doi.org/10.1021/ja00054a033.

Article  CAS  Google Scholar 

Lin Y-C, Schneider F, Eberle KJ, Chiodi D, Nakamura H, Reisberg SH, et al. Atroposelective total synthesis of Darobactin A. J Am Chem Soc. 2022;144:14458–62. https://doi.org/10.1021/jacs.2c05892.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nesic M, Ryffel DB, Maturano J, Shevlin M, Pollack SR, Gauthier DR Jr., et al. Total synthesis of Darobactin A. J Am Chem Soc. 2022;144:14026–30. https://doi.org/10.1021/jacs.2c05891.

Article  CAS  PubMed  Google Scholar 

Noisier AFM, Brimble MA. C–H functionalization in the synthesis of amino acids and peptides. Chem Rev. 2014;114:8775–806. https://doi.org/10.1021/cr500200x.

Article  CAS  PubMed  Google Scholar 

Moore MJ, Qu S, Tan C, Cai Y, Mogi Y, Jamin Keith D, et al. Next-generation total synthesis of vancomycin. J Am Chem Soc. 2020;142:16039–50. https://doi.org/10.1021/jacs.0c07433.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fraley AE, Sherman DH. Halogenase engineering and its utility in medicinal chemistry. Bioorg Med Chem Lett. 2018;28:1992–9. https://doi.org/10.1016/j.bmcl.2018.04.066.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hegarty E, Büchler J, Buller RM. Halogenases for the synthesis of small molecules. Curr Opin Green Sustain Chem. 2023;41:100784. https://doi.org/10.1016/j.cogsc.2023.100784.

Article  CAS  Google Scholar 

Latham J, Brandenburger E, Shepherd SA, Menon BRK, Micklefield J. Development of halogenase enzymes for use in synthesis. Chem Rev. 2018;118:232–69. https://doi.org/10.1021/acs.chemrev.7b00032.

Article  CAS  PubMed  Google Scholar 

Crowe C, Molyneux S, Sharma SV, Zhang Y, Gkotsi DS, Connaris H, et al. Halogenases: a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation. Chem Soc Rev. 2021;50:9443–81. https://doi.org/10.1039/D0CS01551B.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Voitsekhovskaia I, Ho YTC, Klatt C, Müller A, Machell DL, Tan YJ, et al. Altering glycopeptide antibiotic biosynthesis through mutasynthesis allows incorporation of fluorinated phenylglycine residues. RSC Chem Biol. 2024;5:1017–34. https://doi.org/10.1039/D4CB00140K.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schmartz PC, Zerbe K, Abou-Hadeed K, Robinson JA. Bis-chlorination of a hexapeptide-PCP conjugate by the halogenase involved in vancomycin biosynthesis. Org Biomol Chem. 2014;12:5574–7. https://doi.org/10.1039/c4ob00474d.

Article  CAS  PubMed  Google Scholar 

Kittilä T, Kittel C, Tailhades J, Butz D, Schoppet M, Büttner A, et al. Halogenation of glycopeptide antibiotics occurs at the amino acid level during non-ribosomal peptide synthesis. Chem Sci. 2017;8:5992–6004. https://doi.org/10.1039/C7SC00460E.

Article  PubMed  PubMed Central  Google Scholar 

Yi D, Acharya A, Gumbart JC, Gutekunst WR, Agarwal V. Gatekeeping ketosynthases dictate initiation of assembly line biosynthesis of pyrrolic polyketides. J Am Chem Soc. 2021;143:7617–22. https://doi.org/10.1021/jacs.1c02371.

Article  CAS  PubMed  Google Scholar 

Jiang W, Heemstra JR Jr., Forseth RR, Neumann CS, Manaviazar S, Schroeder FC, et al. Biosynthetic chlorination of the piperazate residue in kutzneride biosynthesis by KthP. Biochemistry. 2011;50:6063–72. https://doi.org/10.1021/bi200656k.

Article  CAS  PubMed  Google Scholar 

Neumann CS, Walsh CT. Biosynthesis of (−)-(1S,2R)-Allocoronamic Acyl Thioester by an FeII-Dependent Halogenase and a Cyclopropane-Forming Flavoprotein. J Am Chem Soc. 2008;130:14022–3. https://doi.org/10.1021/ja8064667.

Article  CAS  PubMed  PubMed Central  Google Scholar