Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency
Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule “...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , , , , , , , , |
| منشور في: |
2024
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| _version_ | 1852025869180076032 |
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| author | Lara N. Gechijian (19865698) |
| author2 | Giovanni Muncipinto (712719) T. Justin Rettenmaier (1503352) Matthew T. Labenski (1971112) Victor Rusu (19865701) Lea Rosskamp (19865704) Leslie Conway (262028) Daniel van Kalken (19277907) Liam Gross (19865707) Gianna Iantosca (19865710) William Crotty (19865713) Robert Mathis (19865716) Hyejin Park (331233) Benjamin Rabin (14000694) Christina Westgate (19865719) Matthew Lyons (19865722) Chloe Deshusses (19865725) Nicholas Brandon (2105707) Dean G. Brown (1261668) Heather S. Blanchette (19865728) Nicholas Pullen (19865731) Lyn H. Jones (465244) Joel C. Barrish (1429858) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Lara N. Gechijian (19865698) Giovanni Muncipinto (712719) T. Justin Rettenmaier (1503352) Matthew T. Labenski (1971112) Victor Rusu (19865701) Lea Rosskamp (19865704) Leslie Conway (262028) Daniel van Kalken (19277907) Liam Gross (19865707) Gianna Iantosca (19865710) William Crotty (19865713) Robert Mathis (19865716) Hyejin Park (331233) Benjamin Rabin (14000694) Christina Westgate (19865719) Matthew Lyons (19865722) Chloe Deshusses (19865725) Nicholas Brandon (2105707) Dean G. Brown (1261668) Heather S. Blanchette (19865728) Nicholas Pullen (19865731) Lyn H. Jones (465244) Joel C. Barrish (1429858) |
| author_role | author |
| dc.creator.none.fl_str_mv | Lara N. Gechijian (19865698) Giovanni Muncipinto (712719) T. Justin Rettenmaier (1503352) Matthew T. Labenski (1971112) Victor Rusu (19865701) Lea Rosskamp (19865704) Leslie Conway (262028) Daniel van Kalken (19277907) Liam Gross (19865707) Gianna Iantosca (19865710) William Crotty (19865713) Robert Mathis (19865716) Hyejin Park (331233) Benjamin Rabin (14000694) Christina Westgate (19865719) Matthew Lyons (19865722) Chloe Deshusses (19865725) Nicholas Brandon (2105707) Dean G. Brown (1261668) Heather S. Blanchette (19865728) Nicholas Pullen (19865731) Lyn H. Jones (465244) Joel C. Barrish (1429858) |
| dc.date.none.fl_str_mv | 2024-10-17T19:34:28Z |
| dc.identifier.none.fl_str_mv | 10.1021/acschembio.4c00571.s001 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Novel_Corrector_for_Variants_of_SLC6A8_A_Therapeutic_Opportunity_for_Creatine_Transporter_Deficiency/27252103 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Cancer Mental Health Plant Biology Chemical Sciences not elsewhere classified selected missense alleles linked intellectual disability irreversible covalent analogs heterozygous female mice endogenous setting using defined variant knocked cftr ion channel 10 – 20 transformational therapeutic impact identify reversible drug novel chemoproteomic technology potential therapeutic approach like small molecules could stabilize slc6a8 identify small molecules mutant slc6a8 variants identify small therapeutic opportunity novel corrector slc6a8 locus revealed molecules vivo proof profiled across potential treatment photoaffinity handles patient mutations p544l patient orally bioavailable mutated versions molecule fragments medicinal chemistry ligand discovery functional assays cystic fibrosis current treatments crispr knock could promote cellular environment cell surface |
| dc.title.none.fl_str_mv | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule “correctors” for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD. We leveraged a novel chemoproteomic technology for ligand discovery, reactive affinity probe interaction discovery, to identify small-molecule fragments with photoaffinity handles that bind to SLC6A8 in a cellular environment. We synthesized a library of irreversible covalent analogs of these molecules to characterize in functional assays, which revealed molecules that could promote the trafficking of mutant SLC6A8 variants to the cell surface. Further medicinal chemistry was able to identify reversible drug-like small molecules that both promoted trafficking of the transporter and also rescued creatine uptake. When profiled across the 27 most prevalent SLC6A8 missense variants, we found that 10–20% of patient mutations were amenable to correction by our molecules. These results were verified in an endogenous setting using the CRISPR knock-in of selected missense alleles. We established in vivo proof-of-mechanism for correctors in a novel CTD mouse model with the P544L patient-defined variant knocked in to the SLC6A8 locus, where treatment with our orally bioavailable and brain penetrant tool corrector increased brain creatine levels in heterozygous female mice, validating correctors as a potential therapeutic approach for CTD. |
| eu_rights_str_mv | openAccess |
| id | Manara_539f00cd42fc8940fe993bb97eb1027c |
| identifier_str_mv | 10.1021/acschembio.4c00571.s001 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/27252103 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter DeficiencyLara N. Gechijian (19865698)Giovanni Muncipinto (712719)T. Justin Rettenmaier (1503352)Matthew T. Labenski (1971112)Victor Rusu (19865701)Lea Rosskamp (19865704)Leslie Conway (262028)Daniel van Kalken (19277907)Liam Gross (19865707)Gianna Iantosca (19865710)William Crotty (19865713)Robert Mathis (19865716)Hyejin Park (331233)Benjamin Rabin (14000694)Christina Westgate (19865719)Matthew Lyons (19865722)Chloe Deshusses (19865725)Nicholas Brandon (2105707)Dean G. Brown (1261668)Heather S. Blanchette (19865728)Nicholas Pullen (19865731)Lyn H. Jones (465244)Joel C. Barrish (1429858)BiophysicsBiochemistryMedicineCell BiologyGeneticsMolecular BiologyNeurosciencePharmacologyCancerMental HealthPlant BiologyChemical Sciences not elsewhere classifiedselected missense alleleslinked intellectual disabilityirreversible covalent analogsheterozygous female miceendogenous setting usingdefined variant knockedcftr ion channel10 – 20transformational therapeutic impactidentify reversible drugnovel chemoproteomic technologypotential therapeutic approachlike small moleculescould stabilize slc6a8identify small moleculesmutant slc6a8 variantsidentify smalltherapeutic opportunitynovel correctorslc6a8 locusrevealed moleculesvivo proofprofiled acrosspotential treatmentphotoaffinity handlespatient mutationsp544l patientorally bioavailablemutated versionsmolecule fragmentsmedicinal chemistryligand discoveryfunctional assayscystic fibrosiscurrent treatmentscrispr knockcould promotecellular environmentcell surfaceMutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule “correctors” for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD. We leveraged a novel chemoproteomic technology for ligand discovery, reactive affinity probe interaction discovery, to identify small-molecule fragments with photoaffinity handles that bind to SLC6A8 in a cellular environment. We synthesized a library of irreversible covalent analogs of these molecules to characterize in functional assays, which revealed molecules that could promote the trafficking of mutant SLC6A8 variants to the cell surface. Further medicinal chemistry was able to identify reversible drug-like small molecules that both promoted trafficking of the transporter and also rescued creatine uptake. When profiled across the 27 most prevalent SLC6A8 missense variants, we found that 10–20% of patient mutations were amenable to correction by our molecules. These results were verified in an endogenous setting using the CRISPR knock-in of selected missense alleles. We established in vivo proof-of-mechanism for correctors in a novel CTD mouse model with the P544L patient-defined variant knocked in to the SLC6A8 locus, where treatment with our orally bioavailable and brain penetrant tool corrector increased brain creatine levels in heterozygous female mice, validating correctors as a potential therapeutic approach for CTD.2024-10-17T19:34:28ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acschembio.4c00571.s001https://figshare.com/articles/dataset/Novel_Corrector_for_Variants_of_SLC6A8_A_Therapeutic_Opportunity_for_Creatine_Transporter_Deficiency/27252103CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/272521032024-10-17T19:34:28Z |
| spellingShingle | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency Lara N. Gechijian (19865698) Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Cancer Mental Health Plant Biology Chemical Sciences not elsewhere classified selected missense alleles linked intellectual disability irreversible covalent analogs heterozygous female mice endogenous setting using defined variant knocked cftr ion channel 10 – 20 transformational therapeutic impact identify reversible drug novel chemoproteomic technology potential therapeutic approach like small molecules could stabilize slc6a8 identify small molecules mutant slc6a8 variants identify small therapeutic opportunity novel corrector slc6a8 locus revealed molecules vivo proof profiled across potential treatment photoaffinity handles patient mutations p544l patient orally bioavailable mutated versions molecule fragments medicinal chemistry ligand discovery functional assays cystic fibrosis current treatments crispr knock could promote cellular environment cell surface |
| status_str | publishedVersion |
| title | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| title_full | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| title_fullStr | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| title_full_unstemmed | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| title_short | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| title_sort | Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency |
| topic | Biophysics Biochemistry Medicine Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Cancer Mental Health Plant Biology Chemical Sciences not elsewhere classified selected missense alleles linked intellectual disability irreversible covalent analogs heterozygous female mice endogenous setting using defined variant knocked cftr ion channel 10 – 20 transformational therapeutic impact identify reversible drug novel chemoproteomic technology potential therapeutic approach like small molecules could stabilize slc6a8 identify small molecules mutant slc6a8 variants identify small therapeutic opportunity novel corrector slc6a8 locus revealed molecules vivo proof profiled across potential treatment photoaffinity handles patient mutations p544l patient orally bioavailable mutated versions molecule fragments medicinal chemistry ligand discovery functional assays cystic fibrosis current treatments crispr knock could promote cellular environment cell surface |