More than 6.8 million people have died as a result of the continuing coronavirus disease 2019 (COVID-19) pandemic, which is caused by the extremely contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (
Although various COVID-19 vaccines are commercially available, their efficiency has decreased because of the constant appearance of new COVID-19 variations, such as Alpha, Beta, Delta, and the most recent Omicron. Several SARS-CoV-2 variations are resistant to immune responses elicited by vaccination or spontaneous infection. Based on past experience, SARS-CoV-2 has a strong chance of surviving indefinitely. As a result, in addition to more effective
vaccines, new antivirals against present and future SARS-CoV-2 variants are urgently needed.
SARS-CoV-2 is a member of the Coronaviridae family and the genus Coronavirus. This virus contains 14 open reading frames (ORFs), four of which express structural proteins, nine of which encode auxiliary proteins, and two lengthy polyproteins, pp1a, and pp1ab. Using two cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), the polyproteins are cleaved into sixteen non-structural proteins (NSPs).
Mpro- a Variation Conserved Gene
Mpro, also known as 3CLpro, is a viral and variation-conserved gene. Furthermore, this protease is found in additional deadly coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and middle east respiratory syndrome coronavirus (MERS-CoV).
Through cleaving pp1a and pp1b, Mpro is connected to the production of thirteen NSPs. Mpro detects and cleaves amino acid sequences with specificity, particularly cleavage sites at Leu-Gln sequences. Significantly, no human proteases have the same specificity.
Considering all of Mpro’s characteristics, it could be a promising target for creating antivirals. Many small compounds have been approved as antiviral medicines, including Remdesivir, Molnupiravir, and Paxlovid. Nirmatrelvir, Ensitrelvir, and Simnotrelvir are SARS-CoV-2 MPRO inhibitors. These antivirals, however, have some safety problems, inferior potency, and unsatisfactory pharmacokinetic (PK) features, such as limited oral bioavailability and modest stability in human liver microsomes (HLM).
Concluding on the Potential Drug for COVID-19
The recent investigation demonstrated SY110’s potential as a pan-coronavirus antiviral inhibitor, including SARS-CoV-2. This Mpro inhibitor had favorable PK characteristics, great oral bioavailability, and a significant safety profile when taken orally. SY110’s clinical therapeutic efficacy will need to be verified further in the future through clinical trial research. The authors expressed the possibility of further improving HLM stability for SY110.
- A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants – (https:www.nature.com/articles/s41392-023-01392-w)