The Search for Therapeutic Agents against COVID-19

Posted on 2020-05-04

The emerging outbreak of COVID-19 continues to spread worldwide. Although the long-term strategy to overcome the pandemic remains focused on the development of a specific vaccine, the virus’ inherent complex nature and ability to mutate has directed research towards more immediate therapeutic treatment. Such approaches intend to interfere with the viral life cycle, including essential processes that mediate membrane fusion and replication.

SARS-CoV-2, the causative agent of COVID-19, is classified alongside the severe acute respiratory syndrome (SARS) virus (SARS-CoV) and Middle East respiratory syndrome (MERS) virus (MERS-CoV), as a betacoronavirus. Research into potential therapeutic agents requires understanding of the SARS-CoV-2 life cycle and how the virus interacts with host cell proteins,. This is explored in combination with existing and effective antiviral strategies against genetically similar strains.

The viral genome encodes several structural proteins, including a glycosylated spike (S) protein. Studies have identified that the S protein facilitates host cell invasion, through binding to the receptor protein angiotensin-converting enzyme 2 (ACE2) located on the host cell surface membrane. This interaction is of significant interest to researchers, as it marks the initiation of infection. Recent findings also suggest that this invasion process requires S protein priming, mediated by a host cell-produced serine protease, TMPRSS211 – another potential candidate for therapeutic agents.

Several non-structural proteins are also encoded: the coronavirus main protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and papain-like protease (PLpro). Upon entry into host cells, the virus exploits host cell translational machinery to translate the single-stranded positive RNA genome into viral polyproteins; 3CLpro and PLpro both function in the proteolysis of viral polyproteins into functional units. PLPro also exhibits deubiquitinase action; it has the potential to contribute to immune suppression through the deubiquination of host cell proteins such as IF-3 and NF-kappaB. RdRp functions to replicate the viral genome. In understanding viral processes and host-virus interactions, candidate targets for therapeutic agents can be identified.

Additionally, well-documented antiviral agents that have proven to be effective against genetically and functionally similar viruses, provide a strong foundation for research into drugs and strategies against a novel strain.

For example, Lopinavir/ritonavir (LPV/RTV) are antiretroviral protease inhibitors used in combination for the treatment of Human Immunodeficiency Virus (HIV), since 2000. Studies have shown that it acts against 3CLpro, and exhibits promising results against SARS-CoV and MERS-CoV. Remdesivir (RDV), an antiviral drug initially developed for the treatment of Ebola virus disease, is an adenosine nucleotide analogue that inhibits RdRps, disrupting viral replication through the premature termination of RNA transcription. Studies have highlighted this antiviral drug to be effective against SARS-CoV, which opens up promising routes of investigation for SARS-CoV-2 treatment. Similarly, Favipiravir (FPV) is a guanine analogue that selectively inhibits RdRP of RNA viruses, and has been used to effectively treat the novel influenza virus since 2004. Existing antiviral strategies can be analysed to direct research into tackling the novel SARS-CoV-2

In the global fight against COVID-19 it is crucial to understand host-virus interactions, essential virus life cycle processes, and to explore existing antiviral agents against genetically similar strains. Abbexa is proud to offer an extensive range of products to support such research into SARS-CoV-2.

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Further Reading:

Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases