SARS-CoV-2 Omicron Variant in Medicinal Chemistry Research

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Nowadays, modern society has faced a new challenging problem, the emergence of novel SARS-CoV-2 variants of concern (VOCs). In this context, the Omicron (B.1.1.529) variant, having more than 60 mutations when compared to its ancestral wild-type virus, has infected many individuals around the world. It is rapidly spread person-to-person due to its increased transmissibility. Additionally, it was demonstrated that this newest variant and its subvariants have the capability of evading the host immune system, being resistant to neutralizing antibodies. Moreover, it has been proven to be resistant to monoclonal antibodies and several different vaccines. This ability is associated with a huge number of mutations associated with its spike (S) glycoprotein, which presents at least 15 mutations. These mutations are able to modify the way how this virus interacts with the host angiotensin-converting enzyme 2 (ACE2), increasing its infectivity and making the therapeutic alternatives more ineffective. Concerning its chymotrypsin-like picornavirus 3C-like protease (3CL(pro)) and RNA-dependent RNA polymerase (RdRp), it has been seen that some compounds can be active against different SARS-CoV-2 variants, in a similar mode than its wild-type precursor. This broad spectrum of action for some drugs could be attributed to the fact that the currently identified mutations found in 3CL(pro) and RNA proteins being localized near the catalytic binding site, conserving their activities. Herein this review, we provide a great and unprecedented compilation of all identified and/or repurposed compounds/drugs against this threatening variant, Omicron. The main targets for those compounds are the protein-protein interface (PPI) of S protein with ACE2, 3CL(pro), RdRp, and Nucleocapsid (N) protein. Some of these studies have presented only in silico data, having a lack of experimental results to prove their findings. However, these should be considered here since other research teams can use their observations to design and investigate new potential agents. Finally, we believe that our review will contribute to several studies that are in progress worldwide, compiling several interesting aspects about VOCs associated with SARS-CoV-2, as well as describing the results for different chemical classes of compounds that could be promising as prototypes for designing new and more effective antiviral agents.