DC Field | Value | Language |
---|---|---|
dc.contributor.author | Patwardhan, Neeraj N. | ko |
dc.contributor.author | Ganser, Laura R. | ko |
dc.contributor.author | Kapral, Gary J. | ko |
dc.contributor.author | Eubanks, Christopher S. | ko |
dc.contributor.author | Lee, Janghyun | ko |
dc.contributor.author | Sathyamoorthy, Bharathwaj | ko |
dc.contributor.author | Al-Hashimi, Hashim M. | ko |
dc.contributor.author | Hargrove, Amanda E. | ko |
dc.date.accessioned | 2017-07-04T02:25:06Z | - |
dc.date.available | 2017-07-04T02:25:06Z | - |
dc.date.created | 2017-06-20 | - |
dc.date.created | 2017-06-20 | - |
dc.date.issued | 2017-05 | - |
dc.identifier.citation | MEDCHEMCOMM, v.8, no.5, pp.1022 - 1036 | - |
dc.identifier.issn | 2040-2503 | - |
dc.identifier.uri | http://hdl.handle.net/10203/224550 | - |
dc.description.abstract | Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)-positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST-[H-1-C-13] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule: RNA interactions. | - |
dc.language | English | - |
dc.publisher | ROYAL SOC CHEMISTRY | - |
dc.subject | BIOACTIVE SMALL MOLECULES | - |
dc.subject | MYOTONIC-DYSTROPHY TYPE-1 | - |
dc.subject | DESIGNED SMALL MOLECULES | - |
dc.subject | SEQUENCE-BASED DESIGN | - |
dc.subject | TARGETING RNA | - |
dc.subject | PLASMINOGEN-ACTIVATOR | - |
dc.subject | DRUG DISCOVERY | - |
dc.subject | RECOGNITION | - |
dc.subject | INHIBITORS | - |
dc.subject | COMPLEX | - |
dc.title | Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR | - |
dc.type | Article | - |
dc.identifier.wosid | 000402049300021 | - |
dc.identifier.scopusid | 2-s2.0-85021920955 | - |
dc.type.rims | ART | - |
dc.citation.volume | 8 | - |
dc.citation.issue | 5 | - |
dc.citation.beginningpage | 1022 | - |
dc.citation.endingpage | 1036 | - |
dc.citation.publicationname | MEDCHEMCOMM | - |
dc.identifier.doi | 10.1039/c6md00729e | - |
dc.contributor.nonIdAuthor | Patwardhan, Neeraj N. | - |
dc.contributor.nonIdAuthor | Ganser, Laura R. | - |
dc.contributor.nonIdAuthor | Kapral, Gary J. | - |
dc.contributor.nonIdAuthor | Eubanks, Christopher S. | - |
dc.contributor.nonIdAuthor | Sathyamoorthy, Bharathwaj | - |
dc.contributor.nonIdAuthor | Al-Hashimi, Hashim M. | - |
dc.contributor.nonIdAuthor | Hargrove, Amanda E. | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | BIOACTIVE SMALL MOLECULES | - |
dc.subject.keywordPlus | MYOTONIC-DYSTROPHY TYPE-1 | - |
dc.subject.keywordPlus | DESIGNED SMALL MOLECULES | - |
dc.subject.keywordPlus | SEQUENCE-BASED DESIGN | - |
dc.subject.keywordPlus | TARGETING RNA | - |
dc.subject.keywordPlus | PLASMINOGEN-ACTIVATOR | - |
dc.subject.keywordPlus | DRUG DISCOVERY | - |
dc.subject.keywordPlus | RECOGNITION | - |
dc.subject.keywordPlus | INHIBITORS | - |
dc.subject.keywordPlus | COMPLEX | - |
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