7O4D

QR2 inhibitor from a novel sulfanamide series to tackle age related oxidative stress and cognitive decline

Summary for 7O4D

• Entry DOI: 10.2210/pdb7o4d/pdb
• Descriptor: Ribosyldihydronicotinamide dehydrogenase [quinone], ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: inhibitors, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 58530.49

Authors

Gould, N.L.,Scherer, G.R.,Carvalh, S.,Shurrush, K.,Edry, E.,Elkobi, A.,David, O.,Dym, O.,Albeck, S.,Peleg, Y.,Germain, N.,Babaev, I.,Sharir, H.,Lefker, B.,Subramanyam, C.,Barr, H.,Rosenblum, K. (deposition date: 2021-04-06, release date: 2022-08-17, Last modification date: 2024-02-28)

Primary citation

Gould, N.L.,Scherer, G.R.,Carvalho, S.,Shurrush, K.,Kayyal, H.,Edry, E.,Elkobi, A.,David, O.,Foqara, M.,Thakar, D.,Pavesi, T.,Sharma, V.,Walker, M.,Maitland, M.,Dym, O.,Albeck, S.,Peleg, Y.,Germain, N.,Babaev, I.,Sharir, H.,Lalzar, M.,Shklyar, B.,Hazut, N.,Khamaisy, M.,Levesque, M.,Lajoie, G.,Avoli, M.,Amitai, G.,Lefker, B.,Subramanyam, C.,Shilton, B.,Barr, H.,Rosenblum, K.
Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.
J.Clin.Invest., 133:-, 2023

PubMed Abstract: Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs.

PubMed: 37561584
DOI: 10.1172/JCI162120

Experimental method

X-RAY DIFFRACTION (2.249 Å)