Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations

Abstract

Papain-like proteases (PLpro) of coronaviruses (CoVs) support viral reproduction and suppress the immune response of the host, which makes CoV PLpro perspective pharmaceutical targets. Their inhibition could both prevent viral replication and boost the immune system of the host, leading to the speedy recovery of the patient. Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third CoV outbreak in the last 20 years. Frequent mutations of the viral genome likely lead to the emergence of more CoVs. Inhibitors for CoV PLpro can be broad-spectrum and can diminish present and prevent future CoV outbreaks as PLpro from different CoVs have conservative structures. Several inhibitors have been developed to withstand SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). This review summarizes the structural features of CoV PLpro, the inhibitors that have been identified over the last 20 years, and the compounds that have the potential to become novel effective therapeutics against CoVs in the near future.

Keywords: coronavirus; inhibitor; outbreak; papain-like proteases.

Figure 1

(A) Coronaviruses (CoV) papain-like proteases (PLpro) processes viral polyproteins, and thus promotes viral replication. Simultaneously, PLpro removes ubiquitin (Ub) chains and interferon-stimulated gene 15 product (ISG15) from the proteins involved in the antiviral immune response. Together, these factors produce viral spreading. (B) The inhibitor for CoV PLpro reduces the processing of the polyproteins, which prevent viral replication. Moreover, unimpaired immune response induces interferon (IFN) expression. All this results in suppression of viral spreading.

Figure 2

The figure shows the structures aligned in PyMOL of transmissible gastroenteritis virus (TGEV) PLpro (Protein Data Bank Identifier (PDB ID): 3MP2; green), Middle East respiratory syndrome CoV (MERS-CoV) PLpro (PDB: 4P16; yellow), severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro (PDB: 2FE8; blue), and SARS-CoV-2 PLpro (PDB: 6W9C; pink); UBL—ubiquitin-like domain.