Within the last two decades, three highly pathogenic human coronaviruses have emerged and caused global economic and public health crises. The Yang Lab strives to elucidate the structures and dynamics of the coronavirus replication-transcription machinery and how they are modulated by various viral and host factors. Through the integration of structural, biochemical, cell biological, and computational approaches, we are revealing the mechanisms and regulation of SARS-CoV-2 RNA synthesis and developing antivirals to battle COVID-19 and potential outbreaks of deadly coronaviruses in the future.
Structures and dynamics of the SARS-CoV-2 replication-transcription machinery
Coronavirus genome replication and transcription are carried out by a multi-subunit replication-transcription complex (RTC). RTC represents a promising target for anti-coronavirus treatments due to its essential role in the virus life cycle. However, many fundamental aspects of coronavirus genome replication and transcription remain largely uncharacterized, which greatly hinder the development of specific and highly effective antivirals targeting the viral RTC. We aim to delineate the molecular details underlying a series of key events during the SARS-CoV-2 genome replication-transcription pathway, such as proofreading during viral RNA synthesis, template switch process, and co-transcriptional 5' capping of viral messenger RNAs.
Develop novel SARS-CoV-2 antivirals
SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, is resistant to most nucleotide analog-based antivirals because of its unique, conserved, but poorly understood, proofreading mechanism. Guided by the mechanistic insight gained from our lab's recent study on the SARS-CoV-2 proofreading enzyme, we aim to develop novel therapeutic agents that can resist mismatch excision activity of its proofreading enzyme. The platform will be also applied to our future efforts on emerging coronaviruses.