More than 6.8 million people have already died as a result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is to blame for the ongoing coronavirus disease 2019 (COVID-19) pandemic.
A recent study published in Nature Signal Transduction and Targeted Therapy showed that a novel Mpro inhibitor (SY110) may have antiviral properties against SARS-CoV-2 Omicron and its sublineages. Moreover, it was discovered to be effective against additional human coronaviruses, including Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) (MERS-CoV).
Despite the fact that there are a number of COVID-19 vaccinations that are commercially accessible, their effectiveness has decreased as a result of the ongoing development of new COVID-19 variations like the Alpha, Beta, Delta, and the most recent Omicron. Many SARS-CoV-2 variations are capable of evading immunological reactions brought either by vaccination or unintentional infection. There is a significant chance that SARS-CoV-2 will persist for a very long time, according to previous data. Thus, there is an urgent need for new antivirals against present and future SARS-CoV-2 variations in addition to more potent COVID-19 vaccines.
SARS-CoV-2 is a member of the Coronaviridae family of the coronavirus genus. This virus has 14 open reading frames (ORFs), which code for two large polyproteins, pp1a and pp1ab, as well as four structural proteins and nine auxiliary proteins. Using two cysteine proteases, specifically, the polyproteins break into sixteen non-structural proteins (NSPs).
Considering all attributes of Mpro, it can be a potential target for developing antivirals. Several small molecules, such as Remdesivir, Molnupiravir, and Paxlovid, have been approved as antiviral agents. Nirmatrelvir, Ensitrelvir, and Simnotrelvir are inhibitors of SARS-CoV-2 Mpro. However, these antivirals have some toxicity-related issues, suboptimal potency, and imperfect pharmacokinetic (PK) properties, such as poor oral bioavailability, poor oral bioavailability, and modest stability in human liver microsomes (HLM).
Notably, SARS-CoV-2 variants that contain Q192S/T/V, E166N/V, G143S, H172F/Q/Y, Q189E, M165T or A173V, have shown resistance to Nirmatrelvir treatment. Therefore, developing next-generation antivirals effective against SARS-CoV-2 variants is urgently needed.
