Coronaviral therapeutic target mutagenesis platform for communal treatment evaluation and the development of pan-coronavirus inhibitors

From the onset in December 2019, the world has been struggling with a pandemic of COVID -19 disease. The pathogen responsible for the disease is a single-stranded (+ssRNA) positive sense RNA virus from the Coronaviridae family called SARS-CoV-2. The virulence of the pathogen is responsible for the fact that most cases present with mild symptoms. However, a variable percentage of patients develop pneumonia and multiorgan failure that can lead to death, especially without medical assistance. Combined with the high rate of infection, this can cripple the public health system and spiral towards a condition that is difficult to control. After more than three years of battling the situation, the public is well aware of SARS-CoV-2 pathogen, yet this is not the first time we have encountered coronaviral pathogens. Outbreaks of highly pathogenic beta and alpha coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have occurred before, and similar viruses are widespread in animal host pools and cause high morbidity in livestock (Swine Acute Diarrhea Syndrome Coronavirus or SADS-CoV). Our main concern is 'host jumping', where coronaviruses 'jump' from animal pools to the human host and potentially infect humans, as well as evolutionary selection, which produces mutations and new viral variants with higher virulence and/or transmissibility. Examination of the coronaviral proteome reveals structurally related potential therapeutic targets common to several viral strains. With the emergence of new viral variants, it is evident that a variant-agnostic and, moreover, a pan-coronaviral approach to small molecule drug development for similar situations in the future will be very valuable. Moreover, a quick and informative approach to study prospective viral mutations before they occur in the population, would be of immense value. The proposed project therefore invests heavily in developing experimentally supported in silico viral mutagenesis platform. The goal is to highlight the current viral mutation impact on the action of antiviral compounds and study the effect of future yet-to-be seen viral mutations on potential viral therapeutic targets and consequently on antiviral drugs. Using all the conglomerated and systematized data, the project will proceed to antiviral medicinal chemistry, focusing on three prominent therapeutic targets. The project will develop novel coronaviral main- as well as papain-like protease inhibitors, with a focus on the activity against multiple coronaviruses. Last but not least, the proposed research project will investigate spike protein binding of SARS-CoV-2 variants from a human host cell perspective, looking at the neuropilin-1 coreceptor as a potential target for inhibitor and molecular probe design. The developed compounds will be biologically evaluated in vitro on isolated proteins as well as studied on infected cell lines.