6-thioguanine for COVID-19

Papain-like protease (PLpro), a crucial functional domain of the SARS-CoV-2 non-structural protein 3 (nsp3), plays a dual role in both hydrolyzing viral polyprotein precursors and modulating host immune responses. These critical functions position PLpro as a key target in the ongoing development of antiviral therapies for SARS-CoV-2. This review analyzes more than 100 PLpro-ligand co-crystal structures and summarizes the major binding modes between these ligands and PLpro. Most of these ligands bind to sites analogous to those targeted by the classical non-covalent inhibitor GRL0617, primarily involving the P3 and P4 subsites and the BL2 loop. Based on these structural insights, optimized inhibitors have expanded targeting beyond the canonical binding site to auxiliary regions such as the BL2 groove and the Val70 site, and in some cases toward the catalytic Cys111 buried within a narrow pocket. Certain ligands identified through various screening approaches bind to non-canonical or allosteric regions, such as the S1 and S2 sites or the zinc-finger domain, engaging PLpro through distinct interaction modes and thereby offering additional opportunities for PLpro inhibitor design. The review also discusses potential strategies for future PLpro inhibitor development informed by recent structural advances. Taken together, these structural and functional insights support ongoing efforts in the structure-guided design and optimization of PLpro inhibitors.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the Coronaviridae family. The COVID-19 pandemic, caused by SARS-CoV-2, has undoubtedly been the largest crisis of the twenty-first century, resulting in over 6.8 million deaths and 686 million confirmed cases, creating a global public health issue. Hundreds of notable articles have been published since the onset of this pandemic to justify the cause of viral spread, viable preventive measures, and future therapeutic approaches. As a result, this review was developed to provide a summary of the current anti-COVID-19 drugs, as well as their timeline, molecular mode of action, and efficacy. It also sheds light on potential future treatment options. Several medications, notably hydroxychloroquine and lopinavir/ritonavir, were initially claimed to be effective in the treatment of SARS-CoV-2 but eventually demonstrated inadequate activity, and the Food and Drug Administration (FDA) withdrew hydroxychloroquine. Clinical trials and investigations, on the other hand, have demonstrated the efficacy of remdesivir, convalescent plasma, and monoclonal antibodies, 6-Thioguanine, hepatitis C protease inhibitors, and molnupiravir. Other therapeutics, including inhaled medicines, flavonoids, and aptamers, could pave the way for the creation of novel anti-COVID-19 therapies. As future pandemics are unavoidable, this article urges immediate action and extensive research efforts to develop potent specialized anti-COVID-19 medications.

The review outlines coronavirus SARS-CoV-2 morphology, life cycle, and essential proteins, focusing on a design strategy for dual-acting inhibitors for PLpro and Mpro proteases.