藥 物 設 計 及 化 學 生 物 核 心 實 驗 室
Since the early 1950s, a wide range of physical-chemical methods have been applied to nucleic acids to determine their structures, functions, and physicochemical properties. We have used various spectroscopic methods (UV absorption, SPR, CD, fluorescence, etc.) as well as X-ray crystallography and single molecule methods to achieve this goal. Our research is mainly focused on the study of unusual DNA structures caused by repetitive sequences, slippage DNA and mismatches, which are associated with neurological disorders and cancers. In addition, we aim to elucidate the regulatory role of small molecules that interact with these unusual DNA structures. This could lead to the use of old drugs to detect and cure the above diseases. We are also studying the function and structure of coronavirus nucleocapsid proteins to develop antiviral drugs targeting nucleocapsid proteins against COVID19.
Over the past decade, we have made a significant impact on the international multidisciplinary chemistry research community. Our research results have been published in several reputed international journals with high impact factor, including JACS, PNAS, Nucleic Acids Research, Angewandte Chemie and Journal of Medicinal Chemistry, etc. Our strong research achievements in the field of nucleic acids have attracted international attention and we were invited by Prof. William Dynan, Executive Editor of Nucleic Acids Research, to write a review paper on unusual DNA duplex structures, especially those arising from base pair mismatches, repetitive sequence motifs, and ligand-induced structures (Nucleic Acids Research 2018). We have solved an unusual complex structure of a small molecule that selectively targets T:T mismatches in CTG trinucleotide DNA, inducing thymine base flipping out and an unusual four-way junction associated with neurological diseases. Our results describe novel structural features of higher-order noncanonical DNA conformations induced by a small-molecule ligand and its selective supramolecular interactions. These may have future applications in the development of drugs for neurological diseases and in DNA nanotechnology (JACS 2020). Recently, we found that the G4C2 repeat-expanded DNA motifs on the C9orf72 gene can act as a "hotspot" for selective binding of metal-anthracene complexes. The results provide a new direction for drug discovery against ALS and FTD diseases by targeting DNA with G4C2 repeat motifs (Nucleic Acids Research 2021).
PNAS 2017
Angewandte Chemie 2017
JACS 2020
NAR 2021
In addition to the field of nucleic acids, we have been interested in the development of new antiviral agents against coronaviruses targeting the N protein for more than ten years. Based on our contribution to the development of antiviral agents targeting the nucleocapsid protein of coronaviruses, we were invited by Prof. Stephen Carney to write a review article in Elsevier's Drug Discovery Today in 2016, in which we provided readers with a concise overview of the structural features of coronavirus N-proteins and suggested deep insights into structure-based development of therapeutics against coronaviruses. Recently, a closely related novel coronavirus, COVID -19, caused an outbreak of pneumonia in China, further highlighting the risk of CoVs to global public health. We first used the non-native dimer interface of the N protein as a target for antiviral drug design. We found that a compound, 5-benzyloxygramine (P3), has both antiviral and stabilizing activities on the N protein. P3 can induce abnormal oligomerization of full-length N protein in vitro and at the cellular level. We have also found that the conserve sites on the protein may provide certain advantages in the development of compounds with a broad spectrum of activity against most CoVs, including COVID -19. Recently, we found that P3 can slow down the clinical symptoms caused by a coronavirus in animal models. The results were published in March (2020) in the Journal of Medicinal Chemistry, an important international journal in the field of medicinal chemistry, and were selected as the cover of the journal.