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This conversion process is central to disease progression. However, due to difficulties in producing functional PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  molecules that can be selectively modified with chemical probes, many aspects of PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  biology cannot be directly studied. To overcome this limitation, we substituted p-azido-L-phenylalanine (AzF), a small click chemistry-reactive amino acid, for tryptophan residue 99 of PrP\n                  <jats:sup>C<\/jats:sup>\n                  . W99AzF PrP\n                  <jats:sup>C<\/jats:sup>\n                  substrate can efficiently and faithfully propagate either infectious or non-infectious PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  conformers\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Critically, W99AzF PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  amyloid fibrils remain amenable to click chemistry by various ligands after the prion conversion process. Through the combination of site-specific substitution, the modularity of click chemistry, and the functional diversity of click labels, a multitude of modified prions can now be produced to ask targeted questions about the biochemical and biological basis of prion infectivity.\n                <\/jats:p>\n                <jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"717205v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:p>","DOI":"10.64898\/2026.04.08.717205","type":"posted-content","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T01:10:31Z","timestamp":1775869831000},"source":"Crossref","is-referenced-by-count":0,"title":["Generation of Infectious Prions Amenable to Site-specific Click Chemistry"],"prefix":"10.64898","author":[{"given":"Ryan G.","family":"Campbell","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolene N.","family":"Iseler","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail M.","family":"Schwind","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surachai","family":"Supattapone","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA"},{"name":"Medicine,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041313501887000_2026.04.08.717205v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6801762"},{"key":"2026041313501887000_2026.04.08.717205v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13363"},{"key":"2026041313501887000_2026.04.08.717205v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/39057"},{"key":"2026041313501887000_2026.04.08.717205v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1995.tb00576.x"},{"key":"2026041313501887000_2026.04.08.717205v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad5169"},{"key":"2026041313501887000_2026.04.08.717205v1.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199104183241604"},{"key":"2026041313501887000_2026.04.08.717205v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.08.011"},{"issue":"6","key":"2026041313501887000_2026.04.08.717205v1.8","doi-asserted-by":"crossref","first-page":"e1010594","DOI":"10.1371\/journal.ppat.1010594","article-title":"Pathogenic prion structures at high resolution","volume":"18","year":"2022","journal-title":"PLoS Pathog"},{"key":"2026041313501887000_2026.04.08.717205v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010947"},{"issue":"1","key":"2026041313501887000_2026.04.08.717205v1.10","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1038\/s41467-022-30458-6","article-title":"Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains","volume":"13","year":"2022","journal-title":"Nature communications"},{"issue":"1","key":"2026041313501887000_2026.04.08.717205v1.11","doi-asserted-by":"crossref","first-page":"4004","DOI":"10.1038\/s41467-022-30457-7","article-title":"2.7 A cryo-EM structure of ex vivo RML prion fibrils","volume":"13","year":"2022","journal-title":"Nature communications"},{"key":"2026041313501887000_2026.04.08.717205v1.12","doi-asserted-by":"crossref","unstructured":"Manka, S. 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