SARS-CoV-2 Treatment Approaches: Numerous Options, No Certainty for a Versatile Virus

Abstract

SARS-CoV-2 is the most recent coronavirus which crossed the species barrier in 2019 and provoked a still ongoing and dangerous pandemic known as coronavirus disease 2019 (COVID-19). The SARS-CoV-2 infection has triggered an impressive amount of clinical and experimental studies to identify an effective and safe therapy to stop the pandemic spread. Hence, numerous trials and studies have scrutinized the analogies between SARS-CoV-2 and other corona viruses or the host-virus interactions and their similarities with immune system disorders. Still, the pathogenic mechanisms behind SARS-CoV-2 have been partially deciphered and the current therapies have not yet met the initial enthusiastic expectations. So far COVID-19 therapies have targeted various pathogenic mechanisms, namely the neutralization of ACE2 receptors or SARS-CoV-2 spike protein epitopes, the disruption of the endocytic pathways using hydroxychloroquine, arbidol, or anti-Janus kinase inhibitors, the inhibition of RNA-dependent RNA polymerase using nucleotide analogues such as remdesivir, immunosuppressive drugs or molecules acting on the immune response (corticoids, interferons, monoclonal antibodies against inflammatory cytokines, mesenchymal stem cells) and convalescent plasma administration together with numerous drugs with unproven effect against SARS-CoV-2 but with potential antiviral activities (antiretrovirals, antimalarial drugs, antibiotics, etc.). Nevertheless, these therapies have been associated with side effects and contradictory results. At the same time a specific SARS-CoV-2 vaccine is a long-term solution requiring clinical validation and important investments together with appropriate strategies to promote the confidence in the safety of the new vaccine. The article revises the current state of SARS-CoV-2 therapeutic options but advises towards a more cautious and individualized treatment approach centred on the clinical features, immune particularities, and the risk-benefit balance.

Keywords: SARS-CoV-2; angiotensin-converting enzyme 2 receptors; endocytosis; immune response; mesenchymal stem cells; monoclonal antibodies; therapeutic targets; vaccine.

Figure 1

SARS-CoV-2 life cycle and potential therapeutic targets. ISGs, interferon-stimulated genes; IL6R, Interleukin 6 receptor; TLR 7,8, Toll-like receptors 7,8; TMPRSS, transmembrane protease serine 2 (); mTORC1, mammalian target of rapamycin complex 1 (); RLR, RIG-I-like receptors; ACE2, angiotensin converting enzyme 2 receptor (); RTC, replication/transcription complex; 3CLpro, 3C-like protease; PLpro, Papain like Protease; RdRP, RNA-dependent RNA polymerase (); Nsp, nonstructural protein. SARS-Cov-2 life cycle and pathogenesis include: the interaction between the spike protein and ACE2 receptor on host cells (1); clathrin-mediated endocytosis (2); the fusion of the virus with cell membranes facilitated by transmembrane protease serine 2 (TMPRSS) (3); autophagy and RNA release in the presence of the mammalian target of rapamycin complex 1 protein (rapamycin complex 1) (mTORC1) (4); RNA translation , polyprotein synthesis and cleavage with the help of 3C-like protease (3CLpro) and papain like protease (PLpro) (5); genomic RNA transcription catalysed by thr RNA-dependent RNA polymerase (RdRP) in the Replication/Transcription Complex (RTC) (6); translation of viral proteins (7); assembly of viral proteins and RNA into a mature virion in the Golgi (8) ; the virion is released by exocytosis (9). Recognition of viral RNA by endosomal RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs) allows the activation of type I interferon (IFNs) response, that up-regulates the expression of interferon-stimulated genes (ISGs) and activate the antiviral response. The elimination of SARS-Cov2 requires a coordinated response which should include: the cytokine release, Th1/2 immunity and synthesis of neutralizing antibodies by LB/plasma cells SARS- Cov-2 potential therapeutic targets encompass the following steps: blocking ACE2 receptors (monoclonal antibodies); TMPRSS inhibition which prevents endosomal fusion (arbidol, hidroxyclorochine); mTORC1inhibition and the controlul of autophagy and RNA transcription (remdesivir); inhibition of 2Clpro and PLpro viral proteases involved in polyprotein fragmentation (protease inhibitors namely lopinavir, darunavir, ritonavir); Nsp-12-RdRp inhibition with an essential role in the activity of the replicase RNA transcription complex (favipiravir, remdesivir); suppression of cytokine release (hydroxiclorochine, baricitinib), blocking the IL6R (tocilizumab) or Th1 response (gimsilumab); blocking the virus through the administration of neutralizing antibodies from the plasma of COVID-19 convalescents.