Looking beyond the Spike protein: targeting the coronavirus copy machine with antiviral drugs

17 January 2022• NEWSITEM

Due to the COVID-19 pandemic, the coronavirus particle and its spike proteins have been in the spotlight for almost 2 years. The virus particle is key in disease transmission, whereas the spike protein is the basis for all vaccines that are currently used to induce protective immunity. But are there other viral proteins that may serve as targets during our efforts to stop the coronavirus from spreading?

According to Professor Eric Professor Eric Snijder of the Leiden University Medical Center (LUMC) department of Medical Microbiology, the answer is yes. Virus entry into the host cell – which is mediated by the spike protein - is only the starting point of the coronavirus replication cycle. “At least 25 other viral proteins contribute during this process, and several of these are primary targets for newly developed anti-coronavirus drugs that will soon become available.” In collaboration with researchers from Rockefeller University (New York) and Aix-Marseille University, the Molecular Virology group of the LUMC has recently highlighted the substantial progress made in understanding the structure and function of such proteins in two Nature and Proceedings of the National Academy of Sciences of the USA (PNAS) publications.

GIF1: Coronavirus entry into the host cell mediated by the spike protein.

Coronavirus replication

A complex biological chain of events initiates following the delivery of the coronavirus’ genome (an organism’s complete genetic code) into the host cell. As a result, all viral proteins – including those needed for replication of the virus genome – are produced, ultimately leading to the assembly and release of new virus particles. Snijder explains: “In the first hours after infection, the virus hijacks the host cell’s infrastructure and this ‘hostile takeover’ reprograms the cell to generate a rapidly increasing number of viral genome copies that in turn are used to produce even more viral proteins”.

Figure: Following the delivery of the coronavirus' genome into the host cell, a complex process of virus replication is initiated.

Understanding protein structure and function

At least 8 enzymes (a special type of protein that performs biochemical reactions needed to copy the viral genome) need to work together to drive coronavirus genome synthesis in the infected cell. At the start of the COVID-19 pandemic their molecular structure and interactions were relatively poorly understood. “But with groundbreaking technological advances, such as in electron microscopy, major progress has been achieved over the past couple of years. This method has enabled us to see the molecular structure of individual enzymes and their assembly into a ‘copy machine’ that directs the production of new virus genomes”, says Snijder. Together, LUMC and Aix-Marseille researchers have now characterized the structure and function of one of them in greater detail.

GIF2: Components of the coronavirus replication machinery working together to drive viral genome synthesis in the infected cell.

Antiviral drugs underway

This knowledge is critical to further our understanding of several special features of coronavirus biology, but also to facilitate the design of small drug molecules that can block the specific function of certain enzymes and thus stop virus replication. “Such antiviral drugs will be an important additional tool to fight the COVID-19 pandemic”, Snijder notes. For example, when treating human infections in cases where vaccination was not possible or failed. “They are expected to significantly reduce the risk of developing serious disease, provided that treatment starts shortly after infection so that its impact on virus replication can be maximal. Furthermore, it is anticipated they will have broad activity against all SARS-CoV-2 variants, as well as against related coronaviruses that may emerge in the future”.

Multiple weapons against COVID-19

The first couple of drugs that will soon be available (Molnupiravir and Paxlovid) target two different coronavirus enzymes. Compounds blocking other viral functions are expected to follow within the next year. According to the professor, using a combination of such drugs is key in reducing problems associated with the (potential) emergence of drug-resistant variants. “This would be similar to the successful ‘triple therapy’ cocktail used against HIV”. Snijder also emphasizes that the use of antiviral drugs will be complementary to vaccination, and should not be considered as a replacement. “Some populational groups, such as those with inherited immune deficiencies or who use medications that suppresses the immune system, may depend on these alternatives, but preventing infections through vaccination is always a better approach. Most importantly, antiviral drugs will give us an opportunity to control outbreaks while vaccines are being developed against, for instance, the next emerging coronavirus”. 

The collaboration between LUMC and Aix-Marseille University was facilitated by the EU-funded SARS-CoV-2 research project (SCORE), which is coordinated by LUMC.

Imagery has been taken from the University of Utah’s Animation Lab. Watch the full ‘How does SARS-CoV-2 enter and replicate in cells?’ animation here.

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