Abstract
Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) a can cause major safety concerns due to the enrichment of ERa in female tissues and certain malignancies. In contrast, ERb is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ERb agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERa activation. Here, we report the design and of small molecule conjugates containing selective non-steroid ERb agonists 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 ERb conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ERb-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.
https://doi.org/10.1016/j.apsb.2024.01.014
2211-3835 ª 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese
Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
