posted on 2022-01-04, 15:03authored byNa Liu, Yichi Zhang, Yingshou Lei, Rui Wang, Meimiao Zhan, Jianbo Liu, Yuhao An, Yaoqi Zhou, Jian Zhan, Feng Yin, Zigang Li
Coronavirus
disease 2019 (COVID-19) pandemic, a global health threat,
was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized
as a promising drug target because of multiple functions in virus
maturation and antiviral immune responses. Inhibitor GRL0617 occupied
the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket
and showed an effective antiviral inhibition. Here, we described a
novel peptide–drug conjugate (PDC), in which GRL0617 was linked
to a sulfonium-tethered peptide derived from PLpro-specific substrate
LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively.
EC-M could covalently label PLpro active site C111 and display anti-ISGylation
activities in cellular assays. The results represent the first attempt
to design PDCs composed of stabilized peptide inhibitors and GRL0617
to inhibit PLpro. These novel PDCs provide promising opportunities
for antiviral drug design.