A Patent Review on SARS Coronavirus Papain‐Like Protease (PL^pro) Inhibitors

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic is an unprecedented global health emergency causing more than 6.6 million fatalities by 31 December 2022. So far, only three antiviral drugs have been granted emergency use authorisation or approved by the FDA. The SARS‐CoV‐2 papain‐like protease (PLpro) is deemed an attractive drug target as it plays an essential role in viral polyprotein processing and pathogenesis although no inhibitors have yet been approved. This patent review discusses coronavirus PLpro inhibitors reported in patents published between 1 January 2003 to 2 March 2023, giving an overview on the inhibitors that have generated commercial interest, especially amongst drug companies.

Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape

“…Indeed, the MERS PLpro blocking loop differs in sequence and length, indicating that residues at these positions are not highly conserved (Lee et al 2015). This property of PLpro may impact drug-discovery efforts as most reported inhibitors currently engage this flexible region (Brian Chia and Pheng Lim 2023;Zhao et al 2021). We therefore decided to employ our DMS screen to systematically investigate whether we could detect drug-escape variants to published PLpro inhibitors 3k, its analogue 5c (Báez-Santos, St John, and Mesecar 2015), GRL0617 (Ratia et al 2008a), Jun9-84-3 (Ma et al 2021) and XR8-89 (Shen et al 2022).…”

Therapeutic cysteine protease inhibitors: a patent review (2018–present)

“…In SARS-CoV-2 infec�on the inhibi�on of viral cysteine proteases (PL pro and M pro ) -playing a pivotal role at the first stages of viral infec�on and replica�on -has been explored for the treatment of the disease. [49][50][51] M pro (main protease) and PL pro (papain-like protease) are two highly conserved viral cysteine proteases of Coronavirus that are both crucial for viral replication and infection. In par�cular, M pro (also known as 3CL pro -3C like protease) is a homodimer with a cataly�c dyad at the ac�ve site in each monomer.…”

“…A broad variety of structurally diverse SARS-CoV-2 PL pro inhibitors have been reported over the very recent years. [50,51] In 2020, pirfenidone 1 (Figure 1) -an approved drug for the treatment of idiopathic pulmonary fibrosis -was described in a patent as SARS-CoV-2 PL pro inhibitor, with an IC 50 of 5.88 ± 0.59 µM. [58] In 2022, the use of pirfenidone for the treatment of coronavirus infection was also described in a patent.…”

Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking

“…As PLpro is a cysteine protease with essential roles in the attack of coronaviruses (CoVs) on humans, it has become an important biological target ( Brian Chia and Pheng Lim, 2023 ). Both covalent and non-covalent inhibitors have emerged for PLpro, many of which were reported between 2008 and 2014 ( Ratia et al, 2008 ; Ghosh et al, 2009 ; Ghosh et al, 2010 ; Báez-Santos et al, 2014a ), prior to the onset of the COVID-19 pandemic.…”