{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:22:29Z","timestamp":1785424949991,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,4]]},"group-title":"Pharmacology and Toxicology","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL167046"],"award-info":[{"award-number":["R01HL167046"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"award":["T32GM149371"],"award-info":[{"award-number":["T32GM149371"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  More than 1,200 variants of the cystic fibrosis transmembrane conductance regulator gene (\n                  <jats:italic>CFTR<\/jats:italic>\n                  ) are associated with cystic fibrosis (CF), an autosomal recessive pulmonary disease affecting over 100,000 people. Most people with CF bear a common\n                  <jats:italic>CFTR<\/jats:italic>\n                  variant (F508del) that can be treated with therapeutics containing \u201ccorrectors\u201d that suppress the misfolding of the CFTR chloride channel. However, the pharmacological responsiveness of other rare CF variants can vary tremendously. The approval of VX-121, a VX-445 analog that serves as a key component of Alyftrek\n                  <jats:sup>TM<\/jats:sup>\n                  , potentially provides a new therapeutic option for those with rare CF variants. Nevertheless, it remains unclear whether VX-121 offers superior rescue across the entire spectrum of rare CF variants. In this work, we use deep mutational scanning (DMS) to survey the impact of VX-121 on the plasma membrane expression of 232 rare CF variants. Our results show that VX-121 generally enhances CF variant expression more than VX-445 and is most potent towards variants with mutations in the first membrane spanning domain (MSD1). However, we identify one variant (Y1032C) with diminished proteostatic and functional selectivity for VX-121 relative to VX-445. Computational docking suggests that the native Y1032 side chain forms favorable interactions with VX-121 that are disrupted by this mutation in a manner that alters its coordination. Finally, using photo-crosslinking, we show that VX-121 avoids a key off-target interaction of VX-445. Together, our findings provide new insights into the similarities and differences between current approved CF therapeutics.\n                <\/jats:p>","DOI":"10.64898\/2026.06.01.729306","type":"posted-content","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T22:40:22Z","timestamp":1780612822000},"source":"Crossref","is-referenced-by-count":0,"title":["Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121"],"prefix":"10.64898","author":[{"given":"Ashish R.","family":"Jhangiani","sequence":"first","affiliation":[{"name":"The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"John A.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"},{"name":"Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Tedman","sequence":"additional","affiliation":[{"name":"The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Foye","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"name":"Center for Cystic Fibrosis and Airways Disease Research, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JaNise J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"name":"Center for Cystic Fibrosis and Airways Disease Research, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlyn G.","family":"Winters","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"name":"Center for Cystic Fibrosis and Airways Disease Research, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janiyah A.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"name":"Center for Cystic Fibrosis and Airways Disease Research, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Perfetti","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Abell","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crissey D.","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liudmyla","family":"Arifova","sequence":"additional","affiliation":[{"name":"Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN, USA"},{"name":"Department of Biochemistry, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Corman","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Paul","family":"Robinson","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles P.","family":"Kuntz","sequence":"additional","affiliation":[{"name":"The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3791-7392","authenticated-orcid":false,"given":"Kaitlyn V.","family":"Ledwitch","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-193X","authenticated-orcid":false,"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"},{"name":"Center for Structural Biology, Vanderbilt University, Nashville, TN, USA"},{"name":"Institute for Drug Development, Leipzig University, Leipzig, SAC, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-7006","authenticated-orcid":false,"given":"Kathryn E.","family":"Oliver","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"name":"Center for Cystic Fibrosis and Airways Disease Research, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Plate","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN, USA"},{"name":"Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0955-7633","authenticated-orcid":false,"given":"Jonathan P.","family":"Schlebach","sequence":"additional","affiliation":[{"name":"The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061108300661000_2026.06.01.729306v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2745"},{"key":"2026061108300661000_2026.06.01.729306v2.2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-04-0935"},{"key":"2026061108300661000_2026.06.01.729306v2.3","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1080\/17460441.2025.2490250","article-title":"Recent developments in cystic fibrosis drug discovery: where are we today?","volume":"20","year":"2025","journal-title":"Expert Opin. 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