Dr Theresa Klemm - Ubiquitin Signalling division

Dr Theresa Klemm - Ubiquitin Signalling division

Location: 
Online
Start Time: 
Wed, 01/07/2020 - 1:00pm
End Time: 
Wed, 01/07/2020 - 2:00pm

Mechanism and inhibition of SARS-CoV-2 PLpro

Online seminar: access Slido and enter code #WEHIWEDNESDAY
Including Q&A session

​Wednesday seminar hosted by Professor David Komander

Coronaviruses, including SARS-CoV-2, encode multifunctional proteases that are essential for viral replication and evasion of host innate immune mechanisms. The papain-like protease PLpro cleaves the viral polyprotein and reverses inflammatory ubiquitin and anti-viral ubiquitin-like ISG15 protein modifications. Drugs that target SARS-CoV-2 PLpro (SARS2 PLpro) may hence be effective as treatments or prophylaxis for COVID-19 reducing viral load and reinstating innate immune responses.

In our study we characterise SARS2 PLpro in molecular and biochemical detail. SARS2 PLpro cleaves Lys48-linked polyubiquitin and ISG15 modifications with high activity. Substrate-bound structures of SARS2 PLpro provide insight in substrate specificity and enable mutational analysis that explain substrate selectivity. We exploit two strategies to target PLpro. A high throughput screen against SARS2 PLpro using a library of approved drugs and clinical compounds identified no compounds that inhibited PLpro consistently or that could be validated in counter screens. More promisingly, we found that small molecules designed for SARS PLpro inhibition were able to inhibit SARS2 PLpro with high potency and excellent antiviral activity in SARS-CoV-2 infection models.