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@ARTICLE{Eberle:909095,
author = {Eberle, Raphael and Sevenich, Marc and Gering, Ian and
Scharbert, Lara and Strodel, Birgit and Santur, Karoline and
Mohrlüder, Jeannine and Coronado, Mônika and Willbold,
Dieter},
title = {{D}iscovery of all-{D}-peptide inhibitors of {SARS} {C}o{V}
2 3{C}-like protease},
reportid = {FZJ-2022-03008},
year = {2022},
abstract = {During the replication process of SARS-CoV-2 the main
protease of the virus (3-chymotrypsin-like protease
(3CLpro)) plays a pivotal role and is essential for the life
cycle of the pathogen. Numerous studies have been conducted
so far, which have confirmed 3CLpro as an attractive drug
target to combat COVID-19. We describe a novel and efficient
next generation sequencing (NGS) supported phage display
selection strategy for the identification of a set of
SARS-CoV-2 3CLpro targeting peptide ligands that inhibit the
3CL protease, in a competitive or non-competetive mode, in
the low µM range. From the most efficient L-peptides
obtained from the phage display, we designed all-D-peptides
based on the retro-inverso (ri) principle. They had IC50
values also in the low µM range, and in combination even in
the sub-micromolar range. The inhibition modes of these D-ri
peptides were the same as their respective L-peptide
versions. Our results demonstrate that retro-inverso
obtained all-D-peptides interact with high-affinity and
inhibit the SARS-CoV-2 3CL protease, thus reinforcing their
potential as therapeutic agents. The here described D-ri
peptides address limitations associated with current
L-peptide inhibitors and are promising lead compounds.
Further optimization regarding pharmacokinetic properties
will allow the development of even more potent D-peptides to
be used for the prevention and treatment of COVID-19.},
cin = {IBI-7},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)25},
doi = {10.26434/chemrxiv-2022-rjdzz},
url = {https://juser.fz-juelich.de/record/909095},
}