posted on 2021-10-19, 17:08authored byZhengnan Shen, Kiira Ratia, Laura Cooper, Deyu Kong, Hyun Lee, Youngjin Kwon, Yangfeng Li, Saad Alqarni, Fei Huang, Oleksii Dubrovskyi, Lijun Rong, Gregory R. J. Thatcher, Rui Xiong
Antiviral agents that complement
vaccination are urgently needed
to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease
(PLpro), one of only two essential cysteine proteases that regulate
viral replication, also dysregulates host immune sensing by binding
and deubiquitination of host protein substrates. PLpro is a promising
therapeutic target, albeit challenging owing to featureless P1 and
P2 sites recognizing glycine. To overcome this challenge, we leveraged
the cooperativity of multiple shallow binding sites on the PLpro surface,
yielding novel 2-phenylthiophenes with nanomolar inhibitory potency.
New cocrystal structures confirmed that ligand binding induces new
interactions with PLpro: by closing of the BL2 loop of PLpro forming
a novel “BL2 groove” and by mimicking the binding interaction
of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity
translates to the most potent PLpro inhibitors reported to date, with
slow off-rates, improved binding affinities, and low micromolar antiviral
potency in SARS-CoV-2-infected human cells.