{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:37:34Z","timestamp":1768513054620,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,22]]},"group-title":"Biochemistry","reference-count":76,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington\u2019s disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington\u2019s disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)\n                  <jats:sup>exp<\/jats:sup>\n                  . The RNA folds into a hairpin structure with a periodic array of 1\u00d71 nucleotide UU loops (5\u2019C\n                  <jats:underline>U<\/jats:underline>\n                  G\/3\u2019G\n                  <jats:underline>U<\/jats:underline>\n                  C; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function. Here, we report NMR-refined structures of single 5\u2019C\n                  <jats:underline>U<\/jats:underline>\n                  G\/3\u2019G\n                  <jats:underline>U<\/jats:underline>\n                  C motifs in complex with three different small molecules, a diguandinobenzoate (\n                  <jats:bold>1<\/jats:bold>\n                  ), a derivative of\n                  <jats:bold>1<\/jats:bold>\n                  where the guanidino groups have been exchanged for imidazole (\n                  <jats:bold>2<\/jats:bold>\n                  ), and a quinoline with improved drug-like properties (\n                  <jats:bold>3<\/jats:bold>\n                  ). These structures were determined using nuclear magnetic resonance (NMR) spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds\n                  <jats:bold>1<\/jats:bold>\n                  ,\n                  <jats:bold>2<\/jats:bold>\n                  , and\n                  <jats:bold>3<\/jats:bold>\n                  formed stacking and hydrogen bonding interactions with the 5\u2019C\n                  <jats:underline>U<\/jats:underline>\n                  G\/3\u2019G\n                  <jats:underline>U<\/jats:underline>\n                  C motif. Compound\n                  <jats:bold>3<\/jats:bold>\n                  also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)\n                  <jats:sup>exp<\/jats:sup>\n                  . As the first ever reported structures of RNA r(CUG) repeats bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted\n                  <jats:italic>de novo<\/jats:italic>\n                  design.\n                <\/jats:p>","DOI":"10.1101\/2024.06.21.600119","type":"posted-content","created":{"date-parts":[[2024,6,23]],"date-time":"2024-06-23T02:10:13Z","timestamp":1719108613000},"source":"Crossref","is-referenced-by-count":2,"title":["NMR structures of small molecules bound to a model of an RNA CUG repeat expansion"],"prefix":"10.64898","author":[{"given":"Jonathan L.","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amirhossein","family":"Taghavi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander 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