Recent breakthroughs in synthetic small molecules targeting SARS-CoV-2 M^pro from 2022 to 2024

Among the identified targets for developing anti-coronavirus therapies, SARS-CoV-2 M^pro stands out as one of the most promising due to its crucial role in viral replication and its low mutability across various coronaviruses, making it a potential broad-spectrum target. Currently, although the approved drugs targeting M^pro are peptidomimetic inhibitors with an adequate efficacy, they exhibit relatively poor pharmacokinetic properties commonly associated with peptide-based compounds. On the contrary, using non-peptidic small-molecules M^pro inhibitors can offer many advantages, including reduced off-target toxicity, improved metabolic stability and drug-like properties more appropriate for oral administration. This topic has sparked interest in the scientific community, leading to the publication of numerous studies in recent years. In this review, we summarize the most recent progress over the past two years in the identification and development of synthetic small-molecule inhibitors of SARS-CoV-2 M^pro.