Papain-like Proteases

Papain-like protease (PLpro) is a viral cysteine protease that plays a key role in the viral life cycle, by cleaving non-structural proteins from polyproteins encoded by RNA. PLpro also has deubiquitinating activity and may act on host proteins to interfere with the host immune response.

Literature (1)


Cat. No. Product Name / Activity
7280 GRL 0617
Coronavirus PLpro inhibitor
4103 6-Mercaptopurine
SARS-CoV PLpro inhibitor; purine analog
7357 PLpro inhibitor 6
SARS-CoV and SARS-CoV-2 PLpro inhibitor
4061 6-Thioguanine
SARS-CoV PLpro inhibitor; purine analog

Papain-like protease (PLpro) is a 35kDa cysteine protease found in coronaviruses. This enzyme is a functional monomer with four structural domains named finger, palm, thumb and ubiquitin-like. The active site is located at the interface of the palm and thumb domains. Sequence modelling suggests the PLpro has 6 transmembrane domains towards the c-terminal, and a long tail that extends into the cytoplasm. Although the structure of the active site is highly conserved between PLpro from SARS-COV and SARS-CoV-2, the full-length enzymes share only 85% sequence identity. In comparison, both SARS-COV and SARS-CoV-2 PLpro share poor sequence identity with MERS-CoV PLpro, with only 34% and 33% similarity, respectively.

An essential function of PLpro is to release non-structural proteins from the polyproteins that are encoded by coronavirus mRNA, together with 3C-like protease (3CLpro, also known as Mpro). PLpro cleaves polyprotein 1a at three sites, while Mpro cleaves both polyproteins 1a and 1b at a total of 11 sites. Although most coronaviruses express a single PLpro, some viruses including mouse hepatitis virus and human CoV-229E are thought to have two forms.

Deubiquitinating activity of PLpro

In addition to its action on viral polyproteins, PLpro can also reverse the post-translational ubiquitination and ISGylation of host proteins. Both modifications are important in host immune responses, where they are associated with stimulation of NF-κB-mediated inflammation, interferon responses, as well as the production of cytokines and chemokines. PLpro from different coronaviruses may have differing preferences for modified proteins; SARS-CoV PLpro displays greater action against ubiquitinated proteins, while SARS-CoV-2 PLpro preferentially acts on ISGylated substrates.

SARS-CoV-2 Mpro protein structure

Figure 1: Structure of PLpro from MERS. Structure taken from Protein Data Bank, PDBID: 4REZ. Bailey-Elkin et al (2014) Crystal Structure of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Papain-like Protease Bound to Ubiquitin Facilitates Targeted Disruption of Deubiquitinating Activity to Demonstrate Its Role in Innate Immune Suppression. J Biol Chem 289: 34667-34682

Literature for Papain-like Proteases

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Immunology Product Listing

A collection of over 190 products for immunology research, the guide includes research tools for the study of:

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  • Chemotaxis
  • Complement System
  • Immune Cell Signaling
  • Inflammation