Toward the next generation of sclerostin inhibitors: validation of molecular targets and computation-based virtual screening of small molecule compounds
Postmenopausal osteoporosis commonly coexists with obesity (AM Inzerillo, et al.,2004). Humanized therapeutic antibody against sclerostin (romosozumab) for postmenopausal osteoporosis was approved by US-FDA and European Medicines Agency (EMA) in 2019 with a warning on increased risk of cardiovascular safety concern (FDA Press Announcements,2019; EMA Documents,2019). Moreover, obese patients themselves are at high risk of cardiovascular disease (B Cepeda-Valery, et al.,2011). Therefore, it is desirable to develop a new generation of sclerostin inhibitors with low cardiovascular risk for not only promoting bone anabolic potential but also normalizing fat metabolism disorders in postmenopausal osteoporosis coexisting with obesity.
The applicants found that loop3 in sclerostin played an important role in inhibiting osteogenic potential, while the protective effect of sclerostin on cardiovascular system was independent of loop3. We screened and obtained an optimized sclerostin loop3-specific aptamer, aptscl56, which could promote bone anabolism, while maintain loop3-independent cardiovascular protective effect of sclerostin. The Peglatd-aptscl56 was firstly granted US-FDA orphan drug designation in Hong Kong.
Moreover, we further identified the role of sclerostin loop3 in promoting adipogenic potential and lipid deposition in a mouse preadipocyte-like cell line, 3T3-L1 cell, in vitro.
In the proposal, we have the following two specific aims:
- To investigate the role of sclerostin loop3 in promoting adipogenic potential and lipid deposition in a human preadipocyte-like cell line (HPA-V cells) in vitro.
- To perform computation-based virtual screening of small molecule compounds targeting sclerostin loop3.
Students with either molecular cell biology or computational background.