Interactions between SARS coronavirus 2 papain-like protease and immune system: A potential drug target for the treatment of COVID-19

Abstract

Coronaviruses (CoVs) are a large family of respiratory viruses which can cause mild to moderate upper respiratory tract infections. Recently, new coronavirus named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified which is a major threat to public health. Innate immune responses play a vital role in a host's defence against viruses. Interestingly, CoVs have evolved elaborate strategies to evade the complex system of sensors and signalling molecules to suppress host immunity. SARS-CoV-2 papain-like protease (PLpro), as an important coronavirus enzyme, regulates viral spread and innate immune responses. SCoV-2 PLpro is multifunctional enzyme with deubiquitinating (DUB) and deISGylating activity. The PLpro can interact with key regulators in signalling pathways such as STING, NF-κB, cytokine production, MAPK and TGF-β and hijack those to block the immune responses. Therefore, the PLpro can be as an important target for the treatment of COVID-19. Until now, several drugs or compounds have been identified that can inhibit PLpro activity. Here we discuss about the dysregulation effects of PLpro on immune system and drugs that have potential inhibitors for SCoV-2 PLpro.

Keywords: COVID-19; DeISGylating; deubiquitinating; papain-like protease; severe acute respiratory syndrome coronavirus 2.

FIGURE 1

Schematic diagram of SARS‐CoV‐2 genome organization. The single‐stranded RNA genome is 29903 nucleotides in size (NC‐045512), encoding 9967 amino acids. The G + C content is 37.97%. There are 12 putative, functional ORFs. The large replicase polyproteins 1a (490 kDa) and 1ab (794 kDa) cleaved into 16 putative NSPs. The 5′ and 3′ UTRs are 265 and 358 nucleotides long, respectively

FIGURE 2

Interaction between signalling pathways and PLpro. See text for more details

FIGURE 3

ISG15 is conjugated to a wide range of viral and cellular proteins, influencing immune responses. The PLpro can counter ISGylation by deconjugating ISG15. The ISG15 can be secreted from cells and can induce the secretion of inflammatory cytokines