A research team led by Professor Zhang Ge, Director of the Technology Development Division and Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases; Professor Lyu Aiping, Dean of Chinese Medicine and Dr. Kennedy Y.H. Wong Endowed Professor in Chinese Medicine; and Professor Zhang Baoting, Assistant Director of the School of Chinese Medicine at The Chinese University of Hong Kong, has developed a novel drug discovery strategy for the virtual screening of natural products for microRNAs (miRNAs). The findings of their research were recently published in the world-renowned journal Advanced Science (https://onlinelibrary.wiley.com/doi/10.1002/advs.201903451).
The miRNA is a ribonucleic acid (RNA) molecule with a length of 21 to 23 nucleotides that is widely present in eukaryotes and can regulate gene expression. A large number of studies have confirmed that miRNA plays an important role in many pathophysiological processes. Through the analysis of miRNA databases of different species, the team found that miRNA and messenger RNA (mRNA) can form a unique loop structure during the interaction process. This loop structure is very close to the spatial position of the Argonuate (AGO) protein it guides. The complex composed of miRNA, mRNA and AGO protein has a high degree of structure-based drug target. Therefore, the team proposed to combine the structure-based and knowledge-based approaches to perform virtual drug screening for miRNA targets. After clarifying the virtual screening strategy, it is necessary to consider the source of small molecule compounds for screening. It is very promising to select lead compounds that can target a complex composed of miRNA and mRNA and AGO protein from a vast array of traditional Chinese medicines and natural products.
The team found two sets of small molecules from the vast database of traditional Chinese medicines and natural products, which can target the miRNA214-ATF4-AGO complex and miRNA214-TRAF3-AGO complex. Through a series of in vitro cell activity validation experiments, a small-molecule natural product OB-4 was singled out. The team further used a previously designed osteoblast targeted delivery system (Zhang G, et al. Nature Medicine 2012; Liang C, et al. Nature Medicine 2015) to deliver OB-4 to specific target osteoblasts to resist the phenotype of reduced osteogenic capacity of the osteoblast-specific miR-214 transgenic mice. At the same time, the team selected another small-molecule natural product OC-3, and employed another of its established systems (Liu J, et al. Biomaterials 2015) to deliver OC-3 to osteoclasts, which can reverse the bone phenotype of osteoclast specific miR-214 in mice with enhanced bone absorption capacity. What is interesting is that, a single miRNA214, when applied to different mRNAs (ATF4 mRNA in osteoblasts, and TRAF3 mRNA in osteoclasts), could result in a huge difference in the structure score in virtual screening, indicating that the strategy adopted by the team in the virtual screening of the natural product library is highly specific and hence will provide for a highly effective tool for drug discovery based on non-coding miRNA.
Professor Zhang Ge