Extending the Targets for Coronavirus Antivirals Beyond That of Approved Drugs: Insights From Preclinical Research

Antiviral drugs have been approved for the treatment of COVID-19. However, they present pharmacological limitations, a mixed efficacy profile and target just two coronavirus proteins. To extend the range of druggable coronavirus proteins, researchers explored small molecule N-glycan binders as inhibitors of SARS-CoV-2 spike protein interaction with the cell receptor. Other groups investigated lipopeptides as inhibitors of cell fusion by viral spikes. High throughput screening of chemical libraries yielded viral maturation inhibitors that targeted the viral M protein. Massive screening led to inhibitors of the non-structural coronavirus protein NSP14, a methyltransferase involved in viral mRNA cap synthesis. Machine learning-driven scans of chemical space revealed inhibitors of non-structural coronavirus protein NSP3, a papain-like protease subverting innate immune response to viral infection. A chimera of a nucleotide analogue coupled to an RNase L attractor bound the RNA-dependent RNA polymerase NSP12 and mediated degradation of the viral RNA. Several of these compounds showed comparable or even superior antiviral efficacy as approved COVID-19 drugs in preclinical animal tests. Parallel efforts were made to develop chemical compounds targeting host proteins needed for viral multiplication. Peptidomimetic tetrapeptides acted as inhibitors of the host protease TMPRSS2 involved in cell fusion by the viral spike protein. A repurposed TMPRSS2 inhibitor was tested in COVID-19 patients without demonstrating efficacy. A genetic screen demonstrated an enzyme involved in sphingomyelin synthesis and its inhibitor which impaired SARS-CoV-2 replication. A viral-cell protein interactome study showed 332 cellular proteins interacting with 26 coronaviral proteins. A chemoinformatic search found inhibitors for the interaction of NSP9 with host elongation factor eIF4A and for NSP13 with elongation factor eEF1A. Plitidepsin, a clinically used eEF1A inhibitor, was tested in human clinical trials with COVID-19 patients demonstrating in vivo antiviral activity and a trend for clinical amelioration in an underpowered phase 3 clinical trial.