Structural biology of SARS-CoV-1/SARS-CoV-2 main protease

Abstract

The SARS-CoV-1/SARS-CoV-2 main protease cleaves the nascent viral polyproteins into biologically functional molecules, which are essential for viral reproduction inside the host cell. With more than 500 crystal structures available, it is one of the most heavily researched coronavirus proteins and a popular drug target. This review focuses on putting the function and structure of the main protease into a historical perspective, highlighting the structure-based design of inhibitors of the main protease and discussing potential future research directions.

KEYWORDS:

• COVID-19
• main protease
• inhibitors
• ligand screening
• SARS-CoV-2

Acknowledgements

We thank Rosemary Wilson for proofreading. All figures are courtesy of the Coronavirus Structural Task Force (insidecorona.net) which retains copyright for both the text and the figures.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the German Federal Ministry of Education and Research [grant number 05K19WWA], [grant number 05K22GU5] and Deutsche Forschungsgemeinschaft [project TH2135/2-1]. N.M.P recognizes funding from a Veni Fellowship [no. VI.Veni.192.143] from the .

Notes on contributors

Yunyun Gao

Yunyun Gao is a method developer for strategies of analysing data from biomacromolecules and solid-state materials. He have been working on SAXS/WAXS of polymers and proteins. During his PhD study, he developed new methods for the analysis of SAXS data from biomacromolecules, including correctness-state score (CSS) and cumulative first-ranked singular-values correlation map (CSV-CORMAP). He is interested in improving objectivity and reliability of data analysis. He is currently extending the functionality of AUSPEX. He is also the repository manager and validation pipeline developer for the Coronavirus Structural Task Force.

Johannes Kaub

Johannes Kaub studied chemistry at RWTH Aachen University, with a focus on solid-state physical chemistry. At the Max Planck Instiute for the Structure and Dynamics of Matter, he took a dive into cellular biology and laser physics. He supported the Coronavirus Structural Task Force as a scientific coordinator with his organizing ability and his talent for solving problems. Other than science, his greatest passion is the written word, and due to this he is also a member of the editorial board on the most well-known German table top RPG.

Gianluca Santoni

Gianluca Santoni is a scientist at the European Synchrotron radiation facility. His work is focused on the development of methods for synchrotron serial crystallography, from the comparison of datasets for multi-crystal data collection methods to the implementation of new measurement techniques at synchrotron beamlines. He got his PhD in structural biology studying the structure of acetylcholinesterase in complex with organophosphate nerve agents, applying a mixture of crystallography and computational methods. More recently he has been involved in the data strategies implementation for open science, participating in activities concerning the storage of experimental metadata, the distribution of raw data along with publication according to FAIR principle, and the definition of the Gold standard format for protein diffraction data. His work with the coronavirus structural taskforce has been focused on the implementation of routines to evaluate the quality of both deposited datasets and models.

Nicholas Pearce

Nicholas Pearce is a computational method developer in macromolecular X-ray crystallography and cryo-EM. He developed the PanDDA method for identifying fragments in crystallographic fragment screens, and the ECHT model for analysing disorder in macromolecular atomic models. His group at Linköping university works on methods for modelling and analysing disorder in macromolecular structural data, with a focus on extracting protein dynamics.

Andrea Thorn

Andrea Thorn is a specialist for structure solution by crystallography and Cryo-EM, having contributed to programmes like SHELX, ANODE and PHASER in the past. Her group at the University of Hamburg develops AI-based methods in crystallography such as the diffraction diagnostics tool AUSPEX and a neural network for secondary structure annotation of Cryo-EM maps (HARUSPEX). Her methods enable other scientists to solve new structures and to answer challenging biological questions. Andrea is very passionate about structural biology and good at bringing people together. She started and leads the Coronavirus Structural Task Force.