RS-102895 for COVID-19

Abstract Coronaviruses constitute a significant threat to the human population. Severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, is a highly pathogenic human coronavirus that has caused the coronavirus disease 2019 (COVID-19) pandemic. It has led to a global viral outbreak with an exceptional spread and a high death toll, highlighting the need for effective antiviral strategies. 3-Chymotrypsin-like protease (3CLpro), the main protease in SARS-CoV-2, plays an indispensable role in the SARS-CoV-2 viral life cycle by cleaving the viral polyprotein to produce 11 individual non-structural proteins necessary for viral replication. 3CLpro is one of two proteases that function to produce new viral particles. It is a highly conserved cysteine protease with identical structural folds in all known human coronaviruses. Inhibitors binding with high affinity to 3CLpro will prevent the cleavage of viral polyproteins, thus impeding viral replication. Multiple strategies have been implemented to screen for inhibitors against 3CLpro, including peptide-like and small molecule inhibitors that covalently and non-covalently bind the active site, respectively. In addition, allosteric sites of 3CLpro have been identified to screen for small molecules that could make non-competitive inhibitors of 3CLpro. In essence, this review serves as a comprehensive guide to understanding the structural intricacies and functional dynamics of 3CLpro, emphasizing key findings that elucidate its role as the main protease of SARS-CoV-2. Notably, the review is a critical resource in recognizing the advancements in identifying and developing 3CLpro inhibitors as effective antiviral strategies against COVID-19, some of which are already approved for clinical use in COVID-19 patients.

A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, M pro , is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to M pro . High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science , this issue p. 642

In this study, we present the highly efficient and rapid synthesis of substituted dihydropyrimidinone derivatives through an ultrasound-accelerated approach. We utilize copper ferrite (CuFe2O4) magnetic nanoparticles as heterogeneous catalysts, employing the well-known Biginelli reaction, under solvent-free conditions. The impact of the solvent, catalyst amount, and catalyst type on the reaction performance is thoroughly investigated. Our method offers several notable advantages, including facile catalyst separation, catalyst reusability for up to three cycles with the minimal loss of activity, a straightforward procedure, mild reaction conditions, and impressive yields, ranging from 79% to 95%, within short reaction times of 20 to 40 min. Furthermore, in the context of fighting COVID-19, we explore the potential of substituted dihydropyrimidinone derivatives as inhibitors of three crucial SARS-CoV-2 proteins. These proteins, glycoproteins, and proteases play pivotal roles in the entry, replication, and spread of the virus. Peptides and antiviral drugs targeting these proteins hold great promise in the development of effective treatments. Through theoretical molecular docking studies, we compare the binding properties of the synthesized dihydropyrimidinone derivatives with the widely used hydroxychloroquine molecule as a reference. Our findings reveal that some of the tested molecules exhibit superior binding characteristics compared to hydroxychloroquine, while others demonstrate comparable results. These results highlight the potential of our synthesized derivatives as effective inhibitors in the fight against SARS-CoV-2.