Crippling life support for SARS-CoV-2 and other viruses through synthetic lethality

Abstract

With the rapid global spread of SARS-CoV-2, we have become acutely aware of the inadequacies of our ability to respond to viral epidemics. Although disrupting the viral life cycle is critical for limiting viral spread and disease, it has proven challenging to develop targeted and selective therapeutics. Synthetic lethality offers a promising but largely unexploited strategy against infectious viral disease; as viruses infect cells, they abnormally alter the cell state, unwittingly exposing new vulnerabilities in the infected cell. Therefore, we propose that effective therapies can be developed to selectively target the virally reconfigured host cell networks that accompany altered cellular states to cripple the host cell that has been converted into a virus factory, thus disrupting the viral life cycle.

Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality

“…GBF1 depletion is known to induce an unfolded protein response in the ER (Citterio et al, 2008). Thus, putative SLs of GBF1 are likely functionally redundant with GBF1, an attribute of the genetic interactions between SLs that offers buffering in the event of a loss of function of one of the SL genes (Hartman IV et al, 2001; Mast et al, 2020). As evident by a PPI network, the 53 GBF1 -SLs and the 17 GBF1 suppressors are functionally related and can be grouped into a few distinct functional clusters (Fig.…”

“…In summary, viral-host protein-protein interactions that result in the functional attenuation of the host factor offer a promising avenue for therapeutics based on the principle of synthetic lethality (Mast et al 2020). In this context, the infected cell becomes selectively dependent upon the otherwise nonessential SL partner of the vi-induced hypomorph.…”

“…Thus, although viral genomes drift, they often maintain reliance on the same subset of host factors (Gordon et al, 2020a; Heaton, 2019). The idea of exploiting this over-reliance on their host to develop host-directed antivirals to interfere with host cell factors that are required by the virus, or to more broadly influence immune responses is gaining traction (Gordon et al, 2020b; Kaufmann et al, 2018; Mast et al, 2020; Prussia et al, 2011).…”

“…The principle of synthetic lethality offers an opportunity for selectively targeting virus infected cells by drugging synthetic lethal (SL) interactors of virus-targeted multifunctional protein hubs (Mast et al, 2020). Synthetic lethality occurs between two genes when a loss-of-function mutation in either gene has little impact on cell viability, but becomes detrimental when paired together resulting in cell death (Dobzhansky, 1946; Hartwell et al, 1997) (Fig.…”

“…Infected cells exhibit altered metabolic requirements (Thaker et al, 2019), signaling pathways (Gaur et al, 2011), intracellular transport pathways (Belov et al, 2007) and other morphological and molecular characteristics relative to the noninfected cells. In such situations, infected cells may depend on a different complement of proteins than their uninfected counterparts (Mast et al, 2020). This state-specific vulnerability may be a target for host-based therapeutics based on the well-established principle of synthetic lethality.…”