Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants
Abstract Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 year...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54487-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559217913200640 |
|---|---|
| author | Michelle R. Garnsey Yang Wang David J. Edmonds Matthew F. Sammons Benjamin Reidich Youngwook Ahn Yotam Ashkenazi Anthony Carlo Matthew A. Cerny Karen J. Coffman Jeffrey A. Culver Anne-Marie Dechert Schmitt Heather Eng Ethan L. Fisher Jemy A. Gutierrez Larry James Samantha Jordan Jeffrey T. Kohrt Melissa Kramer Erik A. LaChapelle Jack C. Lee Jisun Lee Dongmei Li Zhenhong Li Shenping Liu Jianhua Liu Thomas V. Magee Melissa R. Miller Michael Moran Deane M. Nason Nicole L. Nedoma Steven V. O’Neil Mary A. Piotrowski Jillian Racich Ruth F. Sommese Lucy M. Stevens Ann S. Wright Jun Xiao Liying Zhang Dahui Zhou Ornella Barrandon Michelle F. Clasquin |
| author_facet | Michelle R. Garnsey Yang Wang David J. Edmonds Matthew F. Sammons Benjamin Reidich Youngwook Ahn Yotam Ashkenazi Anthony Carlo Matthew A. Cerny Karen J. Coffman Jeffrey A. Culver Anne-Marie Dechert Schmitt Heather Eng Ethan L. Fisher Jemy A. Gutierrez Larry James Samantha Jordan Jeffrey T. Kohrt Melissa Kramer Erik A. LaChapelle Jack C. Lee Jisun Lee Dongmei Li Zhenhong Li Shenping Liu Jianhua Liu Thomas V. Magee Melissa R. Miller Michael Moran Deane M. Nason Nicole L. Nedoma Steven V. O’Neil Mary A. Piotrowski Jillian Racich Ruth F. Sommese Lucy M. Stevens Ann S. Wright Jun Xiao Liying Zhang Dahui Zhou Ornella Barrandon Michelle F. Clasquin |
| author_sort | Michelle R. Garnsey |
| collection | DOAJ |
| description | Abstract Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables the development of potent and selective sulfonamide-based 17B-HSD13 inhibitors. In order to probe their inhibitory potency in endogenous expression systems like primary human hepatocytes, inhibitors are transformed into synthetic surrogate substrates with distinct selectivity advantages over substrates previously published. Their application to cells endogenously expressing 17B-HSD13 enables quantitative measures of enzymatic inhibition in primary human hepatocytes which has never been reported to date. Application to multiple cellular systems expressing the protective human variants reveals that the most prevalent IsoD variant maintains NAD-dependent catalytic activity towards some but not all substrates, contradicting reports that the truncation results in loss-of-function. |
| format | Article |
| id | doaj-art-6c4e53ca0d4f4ff0a1accd310f25ebee |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6c4e53ca0d4f4ff0a1accd310f25ebee2025-01-05T12:40:20ZengNature PortfolioNature Communications2041-17232025-01-0116111010.1038/s41467-024-54487-5Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variantsMichelle R. Garnsey0Yang Wang1David J. Edmonds2Matthew F. Sammons3Benjamin Reidich4Youngwook Ahn5Yotam Ashkenazi6Anthony Carlo7Matthew A. Cerny8Karen J. Coffman9Jeffrey A. Culver10Anne-Marie Dechert Schmitt11Heather Eng12Ethan L. Fisher13Jemy A. Gutierrez14Larry James15Samantha Jordan16Jeffrey T. Kohrt17Melissa Kramer18Erik A. LaChapelle19Jack C. Lee20Jisun Lee21Dongmei Li22Zhenhong Li23Shenping Liu24Jianhua Liu25Thomas V. Magee26Melissa R. Miller27Michael Moran28Deane M. Nason29Nicole L. Nedoma30Steven V. O’Neil31Mary A. Piotrowski32Jillian Racich33Ruth F. Sommese34Lucy M. Stevens35Ann S. Wright36Jun Xiao37Liying Zhang38Dahui Zhou39Ornella Barrandon40Michelle F. Clasquin41Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Pfizer, Inc.Abstract Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables the development of potent and selective sulfonamide-based 17B-HSD13 inhibitors. In order to probe their inhibitory potency in endogenous expression systems like primary human hepatocytes, inhibitors are transformed into synthetic surrogate substrates with distinct selectivity advantages over substrates previously published. Their application to cells endogenously expressing 17B-HSD13 enables quantitative measures of enzymatic inhibition in primary human hepatocytes which has never been reported to date. Application to multiple cellular systems expressing the protective human variants reveals that the most prevalent IsoD variant maintains NAD-dependent catalytic activity towards some but not all substrates, contradicting reports that the truncation results in loss-of-function.https://doi.org/10.1038/s41467-024-54487-5 |
| spellingShingle | Michelle R. Garnsey Yang Wang David J. Edmonds Matthew F. Sammons Benjamin Reidich Youngwook Ahn Yotam Ashkenazi Anthony Carlo Matthew A. Cerny Karen J. Coffman Jeffrey A. Culver Anne-Marie Dechert Schmitt Heather Eng Ethan L. Fisher Jemy A. Gutierrez Larry James Samantha Jordan Jeffrey T. Kohrt Melissa Kramer Erik A. LaChapelle Jack C. Lee Jisun Lee Dongmei Li Zhenhong Li Shenping Liu Jianhua Liu Thomas V. Magee Melissa R. Miller Michael Moran Deane M. Nason Nicole L. Nedoma Steven V. O’Neil Mary A. Piotrowski Jillian Racich Ruth F. Sommese Lucy M. Stevens Ann S. Wright Jun Xiao Liying Zhang Dahui Zhou Ornella Barrandon Michelle F. Clasquin Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants Nature Communications |
| title | Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants |
| title_full | Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants |
| title_fullStr | Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants |
| title_full_unstemmed | Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants |
| title_short | Design and application of synthetic 17B-HSD13 substrates reveals preserved catalytic activity of protective human variants |
| title_sort | design and application of synthetic 17b hsd13 substrates reveals preserved catalytic activity of protective human variants |
| url | https://doi.org/10.1038/s41467-024-54487-5 |
| work_keys_str_mv | AT michellergarnsey designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT yangwang designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT davidjedmonds designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT matthewfsammons designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT benjaminreidich designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT youngwookahn designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT yotamashkenazi designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT anthonycarlo designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT matthewacerny designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT karenjcoffman designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jeffreyaculver designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT annemariedechertschmitt designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT heathereng designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT ethanlfisher designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jemyagutierrez designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT larryjames designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT samanthajordan designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jeffreytkohrt designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT melissakramer designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT erikalachapelle designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jackclee designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jisunlee designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT dongmeili designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT zhenhongli designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT shenpingliu designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jianhualiu designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT thomasvmagee designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT melissarmiller designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT michaelmoran designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT deanemnason designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT nicolelnedoma designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT stevenvoneil designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT maryapiotrowski designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT jillianracich designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT ruthfsommese designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT lucymstevens designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT annswright designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT junxiao designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT liyingzhang designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT dahuizhou designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT ornellabarrandon designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants AT michellefclasquin designandapplicationofsynthetic17bhsd13substratesrevealspreservedcatalyticactivityofprotectivehumanvariants |