Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery  

作　　者：Tarik Zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang 

机构地区：[1]Naomi Berrie Diabetes Center,Columbia University,New York,NY 10032,USA [2]Department of Molecular Pharmacology and Therapeutics,Columbia University,New York,NY 10032,USA [3]Department of Pharmaceutical Sciences,College of Pharmacy,University of Tennessee Health Science Center,Memphis,TN 38163,USA [4]Drug Discovery Center,College of Pharmacy,University of Tennessee Health Science Center,Memphis,TN 38163,USA [5]Division of Digestive and Liver Diseases,Columbia University,New York,NY 10032,USA [6]Center for Human Development,Columbia University,New York,NY 10027,USA [7]Department of Pathology and Cell Biology,Columbia University,New York,NY 10032,USA [8]Department of Medicine,Columbia University,New York,NY 10032,USA

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2137-2152,共16页药学学报（英文版）

基　　金：This work was supported by the Columbia University startup packages(Li Qiang and Jianwen Que)and the University of Tennessee College of Pharmacy Drug Discovery Center(Wei Li).

摘　　要：Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关 键 词：Estrogen receptorβ Aging METABOLISM Skin injury Muscle metabolism Small molecule conjugates Regeneration ADIPOSITY 

分 类 号：R914[医药卫生—药物化学]