Professor of Tsinghua University, Member of the Chinese Academy of Sciences, Member of the American Academy of Arts and Sciences，Member of the Standing Committee of the CPPCC National Committee, Member of the Presidium of Academic Divisions of CAS, Honorary President of Biophysics Society of China, Founding President of China Union of Life Science Societies. He was president of Nankai University, Director-General of the Institute of Biophysics of CAS, and President of International Biophysical Union (IUPAB).
He has revealed fundamental structure-function and mechanistic insights to the replication/transcription, assembly and host invasion of coronavirus, retrovirus, influenza virus, picornavirus, herpesvirus, Africa-Swine-Fever-virus and other disease-causing viruses, and uncovered how Mycobacterium tuberculosis achieves metabolite/energy transport and drug resistance. This has led to new therapeutic targets and innovative drug designs. To date, Zihe Rao has published more than 400 peer reviewed research papers, including 23 papers in Science, Nature and Cell, with over 25，000 citations (retrieved from Google Scholar). He also has 38 innovation patents.
Till June 2022, the pandemic of Coronavirus Disease 2019 (COVID-19) has caused over 532 million infections and over 6.3 million deaths worldwide. It has become the most devastating challenge to global health for a century. As the causative agent of COVID-19, SARS-CoV-2 encodes 16 non-structural proteins (nsp1-nsp16) that assemble a set of protein machineries, the Replication-Transcription Complexes (RTCs), that play central roles in virus replication and transcription cycle inside the host cells.
In the early of COVID-19 outbreak, we rapidly initiated the structural study of SARS-CoV-2 RTCs, aiming to dissect the key mechanisms for SARS-CoV-2 lives in human cells and provide structural information to discover potent antivirals. With great efforts from joint collaborations, we successfully determined the structure of the central RTC (C-RTC) composed by nsp12 (RNA-dependent RNA polymerase, RdRp) with cofactors nsp7 and nsp8, providing the first picture for the world to visualize this key antiviral target. We also elucidated how C-RTC catalyzes and how Remdesivir (RDV) inhibits the synthesis of RNA, through determining the structure of C-RTC in complex with template-product duplex RNA and the active form of RDV. Subsequently, we presented the structure of the elongation RTC (E-RTC), showing how nsp13 (helicase) unwinds the high-ordered structure in genome to yield the functional template for RNA synthesis in C-RTC. After that, we discovered a key intermediate state of RTC towards mRNA capping [Cap(-1)’-RTC], demonstrating the nsp12 NiRAN is indeed the key enzyme to catalyze the second capping action and presenting nsp9 is an “adaptor” for the further recruitments of capping enzymes into RTC. Very recently, we successfully assembled Cap(0)-RTC by Cap(-1)’-RTC and nsp10/nsp14 complex and determined its structures in a monomeric and a dimeric form. The monomeric Cap(0)-RTC structure shows the assembly of a co-transcriptional capping complex (CCC) to RTC for mRNA capping, while most interestingly, the dimeric form reasons an in trans backtracking mechanism for proofreading. Other RTCs responsible for key steps for SARS-CoV-2 living inside cells have also been determined. These works not only provide a basis to understand SARS-CoV-2 proliferates in the host cells through a structural biology lens, but also shed the light for antiviral development against the rapid emerging of SARS-CoV-2 variants.