EconPapers    
Economics at your fingertips  
 

Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo

Natasha M. Nesbitt (), Gian Luca Araldi, Lisa Pennacchia, Natalia Marchenko, Zahra Assar, Kendall M. Muzzarelli, Rahul Raghavan Thekke Veedu, Brian Medel-Lacruz, Eunjeong Lee, Elan Z. Eisenmesser, Dale F. Kreitler and Wadie F. Bahou
Additional contact information
Natasha M. Nesbitt: JLABS@NYC
Gian Luca Araldi: JLABS@NYC
Lisa Pennacchia: JLABS@NYC
Natalia Marchenko: JLABS@NYC
Zahra Assar: Cayman Chemical
Kendall M. Muzzarelli: Cayman Chemical
Rahul Raghavan Thekke Veedu: Stony Brook University
Brian Medel-Lacruz: Parc Científic de Barcelona (PCB)
Eunjeong Lee: University of Colorado
Elan Z. Eisenmesser: University of Colorado
Dale F. Kreitler: Brookhaven National Laboratory
Wadie F. Bahou: Stony Brook University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening of unique small molecules retaining the capacity for selective BLVRB inhibition as a novel platelet-enhancing strategy. Two distinct classes of molecules are identified, and NMR spectroscopy and co-crystallization studies confirm binding modes within the BLVRB active site and ring stacking between the nicotinamide moiety of the NADP+ cofactor. A diazabicyclo derivative displaying minimal off-target promiscuity and excellent bioavailability characteristics promotes megakaryocyte speciation in biphenotypic (erythro/megakaryocyte) cellular models and synergizes with TPO-dependent megakaryocyte formation in hematopoietic stem cells. Upon oral delivery into mice, this inhibitor expands platelet recovery in stress thrombopoietic models with no adverse effects. In this work, we identify and validate a cellular redox inhibitor retaining the potential to selectively promote megakaryocytopoiesis and enhance stress-associated platelet formation in vivo distinct from TPO receptor agonists.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58497-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58497-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58497-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().

 
Page updated 2025-05-10
Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58497-9