Ternatin-4 for COVID-19

ABSTRACT 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.

This review aims to describe and discuss the different functions of the endolysosomal system, from homeostasis to its vital role during viral infections. We will initially describe endolysosomal system’s main functions, presenting recent data on how its compartments are essential for host defense to explore later how SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) and other coronaviruses subvert these organelles for their benefit. It is clear that to succeed, pathogens’ evolution favored the establishment of ways to avoid, escape, or manipulate lysosomal function. The unavoidable coexistence with such an unfriendly milieu imposed on viruses the establishment of a vast array of strategies to make the most out of the invaded cell’s machinery to produce new viruses and maneuvers to escape the host’s defense system.

ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.