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The discovery of GPAs continues, with new type IIa and V GPAs, the kineomicins, the rimomycins, and corbomycin, being recently identified. Despite this larger repertoire of GPA scaffolds and crosslinking types, limitations remain with the in vitro exploration of the cytochrome P450 enzymes that install the essential crosslinks between the aromatic side chain residues of GPAs. While the chemoenzymatic synthesis of the more hydrophilic type I GPAs like vancomycin has aided our understanding of GPA crosslinking pathways, type II\u2013V GPAs remain underexplored. This is due to the hydrophobic nature of these GPAs that makes access to peptidyl\u2010CoA substrates difficult and reduces in vitro crosslinking activity. Here, we explore the use of modified Knorr\u2010pyrazole chemistry to provide access to hydrophobic peptidyl\u2010CoA substrates of the type II\/IIa GPAs, kineomicin and actinoidin, and the type IV GPA, teicoplanin. Yields of peptidyl\u2010CoAs were improved 3\u20137\u2010fold through careful tuning of reaction solvents and the arylthiol used for displacement of the pyrazole. The type II\/IIa GPA scaffolds explored in this study displayed the highest in vitro OxyC activity seen to date, likely due to both improved synthesis and their structural properties.<\/jats:p>","DOI":"10.1002\/cmdc.70487","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T03:04:15Z","timestamp":1788663855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of Glycopeptide Antibiotic Peptide Substrates Using Knorr\u2010Pyrazole Chemistry"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8259-0464","authenticated-orcid":false,"given":"Jemma","family":"Gullick","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The Monash Biomedicine Discovery Institute Monash University  Clayton Victoria Australia"},{"name":"ARC Centre of Excellence for Innovations in Peptide and Protein Science  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-6114","authenticated-orcid":false,"given":"W. 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