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@ARTICLE{Eberle:916401,
author = {Eberle, Raphael J. and Sevenich, Marc and Gering, Ian and
Scharbert, Lara and Strodel, Birgit and Lakomek, Nils A. and
Santur, Karoline and Mohrlüder, Jeannine and Coronado,
Mônika A. and Willbold, Dieter},
title = {{D}iscovery of {A}ll- d -{P}eptide {I}nhibitors of
{SARS}-{C}o{V}-2 3{C}-like {P}rotease},
journal = {ACS chemical biology},
volume = {18},
number = {2},
issn = {1554-8929},
address = {Washington, DC},
publisher = {Soc.},
reportid = {FZJ-2022-06201},
pages = {315 - 330},
year = {2023},
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 noncompetitive 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. Additionally, the combination with
Rutinprivir decreases 10-fold the IC50 value of the
competitive inhibitor. 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 for further development toward 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},
ddc = {540},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524) / DFG project 267205415 - SFB 1208: Identität
und Dynamik von Membransystemen - von Molekülen bis zu
zellulären Funktionen (267205415)},
pid = {G:(DE-HGF)POF4-5241 / G:(GEPRIS)267205415},
typ = {PUB:(DE-HGF)16},
pubmed = {36647580},
UT = {WOS:000921927600001},
doi = {10.1021/acschembio.2c00735},
url = {https://juser.fz-juelich.de/record/916401},
}