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000916401 1001_ $$0P:(DE-Juel1)179561$$aEberle, Raphael J.$$b0
000916401 245__ $$aDiscovery of All- d -Peptide Inhibitors of SARS-CoV-2 3C-like Protease
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000916401 520__ $$aDuring the replication process of SARS-CoV-2, the main protease of the virus [3-chymotrypsin-like protease (3CLpro)] plays a pivotal role and is essential for the life cycle of the pathogen. Numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat COVID-19. We describe a novel and efficient next-generation sequencing (NGS) supported phage display selection strategy for the identification of a set of SARS-CoV-2 3CLpro targeting peptide ligands that inhibit the 3CL protease, in a competitive or noncompetitive mode, in the low μM range. From the most efficient l-peptides obtained from the phage display, we designed all-d-peptides based on the retro-inverso (ri) principle. They had IC50 values also in the low μM range and in combination, even in the sub-micromolar range. Additionally, the combination with Rutinprivir decreases 10-fold the IC50 value of the competitive inhibitor. The inhibition modes of these d-ri peptides were the same as their respective l-peptide versions. Our results demonstrate that retro-inverso obtained all-d-peptides interact with high affinity and inhibit the SARS-CoV-2 3CL protease, thus reinforcing their potential for further development toward therapeutic agents. The here described d-ri peptides address limitations associated with current l-peptide inhibitors and are promising lead compounds. Further optimization regarding pharmacokinetic properties will allow the development of even more potent d-peptides to be used for the prevention and treatment of COVID-19.
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000916401 7001_ $$0P:(DE-Juel1)165152$$aSevenich, Marc$$b1$$ufzj
000916401 7001_ $$0P:(DE-Juel1)171922$$aGering, Ian$$b2$$ufzj
000916401 7001_ $$0P:(DE-Juel1)185030$$aScharbert, Lara$$b3$$ufzj
000916401 7001_ $$0P:(DE-Juel1)132024$$aStrodel, Birgit$$b4
000916401 7001_ $$0P:(DE-Juel1)180657$$aLakomek, Nils A.$$b5$$ufzj
000916401 7001_ $$0P:(DE-Juel1)169248$$aSantur, Karoline$$b6
000916401 7001_ $$0P:(DE-Juel1)132012$$aMohrlüder, Jeannine$$b7
000916401 7001_ $$0P:(DE-Juel1)180738$$aCoronado, Mônika A.$$b8$$eCorresponding author$$ufzj
000916401 7001_ $$0P:(DE-Juel1)132029$$aWillbold, Dieter$$b9$$eCorresponding author
000916401 773__ $$0PERI:(DE-600)2221735-6$$a10.1021/acschembio.2c00735$$gVol. 18, no. 2, p. 315 - 330$$n2$$p315 - 330$$tACS chemical biology$$v18$$x1554-8929$$y2023
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