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000909095 1001_ $$0P:(DE-Juel1)179561$$aEberle, Raphael$$b0$$eFirst author
000909095 245__ $$aDiscovery of all-D-peptide inhibitors of SARS CoV 2 3C-like protease
000909095 260__ $$c2022
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000909095 520__ $$aDuring the replication process of SARS-CoV-2 the main protease of the virus (3-chymotrypsin-like protease (3CLpro)) plays a pivotal role and is essential for the life cycle of the pathogen. Numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat COVID-19. We describe a novel and efficient next generation sequencing (NGS) supported phage display selection strategy for the identification of a set of SARS-CoV-2 3CLpro targeting peptide ligands that inhibit the 3CL protease, in a competitive or non-competetive mode, in the low µM range. From the most efficient L-peptides obtained from the phage display, we designed all-D-peptides based on the retro-inverso (ri) principle. They had IC50 values also in the low µM range, and in combination even in the sub-micromolar range. The inhibition modes of these D-ri peptides were the same as their respective L-peptide versions. Our results demonstrate that retro-inverso obtained all-D-peptides interact with high-affinity and inhibit the SARS-CoV-2 3CL protease, thus reinforcing their potential as therapeutic agents. The here described D-ri peptides address limitations associated with current L-peptide inhibitors and are promising lead compounds. Further optimization regarding pharmacokinetic properties will allow the development of even more potent D-peptides to be used for the prevention and treatment of COVID-19.
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000909095 7001_ $$0P:(DE-Juel1)165152$$aSevenich, Marc$$b1$$ufzj
000909095 7001_ $$0P:(DE-Juel1)171922$$aGering, Ian$$b2$$ufzj
000909095 7001_ $$0P:(DE-Juel1)185030$$aScharbert, Lara$$b3$$ufzj
000909095 7001_ $$0P:(DE-Juel1)132024$$aStrodel, Birgit$$b4$$ufzj
000909095 7001_ $$0P:(DE-Juel1)169248$$aSantur, Karoline$$b5
000909095 7001_ $$0P:(DE-Juel1)132012$$aMohrlüder, Jeannine$$b6$$ufzj
000909095 7001_ $$0P:(DE-Juel1)180738$$aCoronado, Mônika$$b7$$eCorresponding author$$ufzj
000909095 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b8$$eCorresponding author$$ufzj
000909095 773__ $$a10.26434/chemrxiv-2022-rjdzz
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