{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:54:32Z","timestamp":1787032472205,"version":"build-2736575974"},"posted":{"date-parts":[[2026,1,8]]},"group-title":"Biophysics","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01GM067260"],"award-info":[{"award-number":["R01GM067260"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01GM135158"],"award-info":[{"award-number":["R01GM135158"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL157566"],"award-info":[{"award-number":["R01HL157566"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Immunoglobulin light chains, a component of antibodies, can misfold and aggregate to cause systemic AL amyloidosis. Aggregation, including amyloid fibril formation, requires unfolding of the full-length light chain from its native state, and in most cases aberrant proteolysis. Small molecules that bind to the native state of light chains to stabilize them against conformational excursions and proteolysis are under development as drug candidates for AL amyloidosis. Since each patient has a unique light chain sequence, a challenge for candidate stabilizer drugs is to bind multiple light chains and suppress their dynamics. Here, we used hydrogen-deuterium exchange measured by mass spectrometry to characterize the binding of six small molecule stabilizers to eleven different \u03bb light chain proteins. Despite structural and dynamic differences among the light chains, the binding of the most efficacious stabilizer molecule led to increased protection from hydrogen exchange, consistent with reduced local and global unfolding. Protection upon binding was most prominent in residues within complementarity determining region 3 and framework region 4 of the light chain variable domains, which undergo major conformational changes enabling amyloid formation. Stabilizer binding also reduced the rate at which all light chains were cleaved by protease. These data show that these stabilizers suppress the range of conformational dynamics associated with light chain aggregation, supporting their therapeutic potential.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Small-molecule kinetic stabilizers suppress conformational dynamics and aberrant proteolysis of diverse amyloidogenic full-length \u03bb light chains.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>HDX-MS indicates conserved protection in regions forming the interface between the two variable domains of the light chain dimer, corresponding to residues that form the core of patient-derived amyloid fibrils.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>PLIMSTEX binding titrations show coupled binding, dimerization and stabilization at sub-micromolar kinetic stabilizer concentrations.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Small molecule kinetic stabilization across different \u03bb sequences supports kinetic stabilizers as a promising therapeutic strategy for AL amyloidosis.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.07.698275","type":"posted-content","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T01:35:18Z","timestamp":1767922518000},"source":"Crossref","is-referenced-by-count":1,"title":["Small molecule stabilization of diverse amyloidogenic immunoglobulin light chains revealed by hydrogen-deuterium exchange mass spectrometry"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9960-1054","authenticated-orcid":false,"given":"Daniele","family":"Peterle","sequence":"first","affiliation":[{"name":"Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-550X","authenticated-orcid":false,"given":"Nicholas L.","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0254-0550","authenticated-orcid":false,"given":"Elena S.","family":"Klimtchuk","sequence":"additional","affiliation":[{"name":"Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-5689","authenticated-orcid":false,"given":"Thomas E.","family":"Wales","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-4824","authenticated-orcid":false,"given":"Olga","family":"Gursky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8943-3395","authenticated-orcid":false,"given":"Jeffery W.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6918-9476","authenticated-orcid":false,"given":"John R.","family":"Engen","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1275-2010","authenticated-orcid":false,"given":"Gareth J.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"},{"name":"Section of Hematology and Medical Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026010923351015000_2026.01.07.698275v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"2026010923351015000_2026.01.07.698275v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16390"},{"key":"2026010923351015000_2026.01.07.698275v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.750323"},{"key":"2026010923351015000_2026.01.07.698275v1.4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705347200"},{"key":"2026010923351015000_2026.01.07.698275v1.5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804822200"},{"key":"2026010923351015000_2026.01.07.698275v1.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-12-618108"},{"key":"2026010923351015000_2026.01.07.698275v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2015.07.005"},{"key":"2026010923351015000_2026.01.07.698275v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2017.08.011"},{"key":"2026010923351015000_2026.01.07.698275v1.9","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b00090"},{"key":"2026010923351015000_2026.01.07.698275v1.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.585638"},{"key":"2026010923351015000_2026.01.07.698275v1.11","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2024.2405948"},{"key":"2026010923351015000_2026.01.07.698275v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2021.11.009"},{"key":"2026010923351015000_2026.01.07.698275v1.13","doi-asserted-by":"publisher","DOI":"10.3109\/13506129.2015.1063485"},{"key":"2026010923351015000_2026.01.07.698275v1.14","doi-asserted-by":"publisher","DOI":"10.1021\/bi7013773"},{"key":"2026010923351015000_2026.01.07.698275v1.15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1203425"},{"key":"2026010923351015000_2026.01.07.698275v1.16","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-anchem-062011-143113"},{"key":"2026010923351015000_2026.01.07.698275v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.11.005"},{"key":"2026010923351015000_2026.01.07.698275v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0915166107"},{"key":"2026010923351015000_2026.01.07.698275v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5446"},{"key":"2026010923351015000_2026.01.07.698275v1.20","unstructured":"Kabat, E. A. , T. T. Wu , M. Reid-Miller , H. Perry , and K. Gottesman . 1987. Sequences of Proteins of Immunological Interest. National Library of Medicine. https:\/\/catalog.nlm.nih.gov\/discovery\/fulldisplay\/alma997039213406676\/01NLM_INST:01NLM_INST."},{"key":"2026010923351015000_2026.01.07.698275v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/48.9.1437"},{"key":"2026010923351015000_2026.01.07.698275v1.22","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52300"},{"key":"2026010923351015000_2026.01.07.698275v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.081"},{"key":"2026010923351015000_2026.01.07.698275v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/bi101351c"},{"key":"2026010923351015000_2026.01.07.698275v1.25","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2023.2212397"},{"key":"2026010923351015000_2026.01.07.698275v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168837"},{"key":"2026010923351015000_2026.01.07.698275v1.27","doi-asserted-by":"publisher","DOI":"10.1039\/c0cs00113a"},{"key":"2026010923351015000_2026.01.07.698275v1.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-743997"},{"key":"2026010923351015000_2026.01.07.698275v1.29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.013461"},{"key":"2026010923351015000_2026.01.07.698275v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107174"},{"key":"2026010923351015000_2026.01.07.698275v1.31","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01773"},{"key":"2026010923351015000_2026.01.07.698275v1.32","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8648-4_3"},{"key":"2026010923351015000_2026.01.07.698275v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-305X(02)00039-3"},{"key":"2026010923351015000_2026.01.07.698275v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0459-y"},{"key":"2026010923351015000_2026.01.07.698275v1.35","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16182"},{"key":"2026010923351015000_2026.01.07.698275v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0034-3"},{"key":"2026010923351015000_2026.01.07.698275v1.37","doi-asserted-by":"publisher","DOI":"10.3390\/hemato2040042"},{"key":"2026010923351015000_2026.01.07.698275v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.08.021"},{"key":"2026010923351015000_2026.01.07.698275v1.39","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2024.2434899"},{"key":"2026010923351015000_2026.01.07.698275v1.40","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00579"},{"key":"2026010923351015000_2026.01.07.698275v1.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817567116"},{"key":"2026010923351015000_2026.01.07.698275v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16953-7"},{"key":"2026010923351015000_2026.01.07.698275v1.43","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1106"},{"key":"2026010923351015000_2026.01.07.698275v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167310"},{"key":"2026010923351015000_2026.01.07.698275v1.45","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.2c01446"},{"key":"2026010923351015000_2026.01.07.698275v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.168958"},{"key":"2026010923351015000_2026.01.07.698275v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.169468"},{"key":"2026010923351015000_2026.01.07.698275v1.48","unstructured":"R Core Team. 2022. \u201cR: A Language and Environment for Statistical Computing.\u201d Vienna, Austria. 2022. https:\/\/www.R-project.org\/."},{"key":"2026010923351015000_2026.01.07.698275v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09032-0"},{"key":"2026010923351015000_2026.01.07.698275v1.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817538116"},{"key":"2026010923351015000_2026.01.07.698275v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04574-y"},{"key":"2026010923351015000_2026.01.07.698275v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100334"},{"key":"2026010923351015000_2026.01.07.698275v1.53","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2304088"},{"key":"2026010923351015000_2026.01.07.698275v1.54","doi-asserted-by":"publisher","DOI":"10.1021\/bi00747a013"},{"key":"2026010923351015000_2026.01.07.698275v1.55","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.1c02155"},{"key":"2026010923351015000_2026.01.07.698275v1.56","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.8771"},{"key":"2026010923351015000_2026.01.07.698275v1.57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054175"},{"key":"2026010923351015000_2026.01.07.698275v1.58","doi-asserted-by":"crossref","unstructured":"Wagih, Omar . 2017. \u201cggseqlogo: A \u2018ggplot2\u2019 Extension for Drawing Publication-Ready Sequence Logos.\u201d https:\/\/CRAN.R-project.org\/package=ggseqlogo.","DOI":"10.32614\/CRAN.package.ggseqlogo"},{"key":"2026010923351015000_2026.01.07.698275v1.59","doi-asserted-by":"publisher","DOI":"10.1021\/ac8008862"},{"key":"2026010923351015000_2026.01.07.698275v1.60","doi-asserted-by":"publisher","DOI":"10.1021\/bi991131j"},{"key":"2026010923351015000_2026.01.07.698275v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2020.10.005"},{"key":"2026010923351015000_2026.01.07.698275v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2023.102319"},{"key":"2026010923351015000_2026.01.07.698275v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128571"},{"key":"2026010923351015000_2026.01.07.698275v1.64","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00339"},{"key":"2026010923351015000_2026.01.07.698275v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.127356"},{"key":"2026010923351015000_2026.01.07.698275v1.66","doi-asserted-by":"publisher","DOI":"10.1002\/ijch.202300002"},{"key":"2026010923351015000_2026.01.07.698275v1.67","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560020404"},{"key":"2026010923351015000_2026.01.07.698275v1.68","doi-asserted-by":"publisher","DOI":"10.1021\/ja029460d"},{"key":"2026010923351015000_2026.01.07.698275v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.jasms.2003.11.007"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.07.698275","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T07:35:20Z","timestamp":1768030520000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.07.698275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,8]]},"references-count":69,"URL":"https:\/\/doi.org\/10.64898\/2026.01.07.698275","relation":{},"subject":[],"published":{"date-parts":[[2026,1,8]]},"subtype":"preprint"}}