Crippling Life Support for SARS-CoV-2 Through Synthetic Lethality

Significance of paper
This paper authored by a group of scientists from the Center for Global Infectious Disease Research at Seattle Children’s Research Institute presents a promising concept for disrupting the life cycle of a virus using synthetic lethality. When viruses infect cells they alter the state of their host cell making these host cells vulnerable to treatments to which they would otherwise be insensitive. We are suggesting that you can identify and target these vulnerabilities in virally-infected host cells. If you can kill the host cell, you can kill the “factory” that is responsible for replicating the virus, thereby disabling the virus while leaving the healthy cells alone.

Synthetic lethality has been successful in cancer therapies where drugs are designed to attack specific alterations in the cancer cell. However, the strategy is largely unused to combat viral infections. The authors on this paper come from a variety of backgrounds – immunology, cell biology, systems and synthetic biology, proteomics, and virology – and that has allowed us to think about this concept in a new way with respect to viral diseases.

The targets revealed using synthetic lethality can be compared to an airplane at the gate versus one that is midflight. The vulnerabilities for an airplane sitting on the ground are very different from when it is in the air. The same is true for a host cell – there are very different vulnerabilities when it is working normally versus when it is under attack by a virus. We believe we can disrupt the viral life cycle by exploiting those vulnerabilities.

Future directions and next steps
First, we are working to demonstrate that the synthetic lethality concept is viable in viral diseases – that selectively disrupt the virally-infected host cell and eradicate the virus by specifically targeting the identified vulnerabilities. Once we establish proof of concept, we can then apply synthetic lethality to develop targeted and selective therapeutics to address viruses like SARS-CoV-2.

With synthetic lethality, we expect to uncover many more alterations we can potentially target with drugs than when we only look at the virus itself. Readily available computational tools can then help us mine for drugs capable of targeting the alteration and inhibiting the host cells from producing virus. We believe existing data sets, reexamined using synthetic lethality, may very likely hold answers that can help develop more effective therapies against SARS-CoV-2 or other deadly viruses. We may also find therapies that slow infection, offering possible preventive measures.  

Looking at the bigger picture, we hope our efforts will expose common host functions used by many viruses. By working now to develop synthetic lethal drug approaches based on these shared targets, we can more quickly and comprehensively counter future global outbreaks.

Crippling Life Support for SARS-CoV-2 and other Viruses Through Synthetic Lethality
Fred D. Mast, Arti T. Navare, Almer M. van der Sloot, Jasmin Coulombe-Huntington, Michael P. Rout, Nitin S. Baliga, Alexis Kaushansky, Brian T. Chait, Alan Aderem, Charles M. Rice, Andrej Sali, Mike Tyers, and John D. Aitchison

Published in the Journal of Cell Biology, August 2020