One Step Beyond: Design of substrates spanning primed positions of Zika virus NS2B-NS3 protease

Natalia Gruba , Jose Ignacio Rodriguez Martinez , Renata Grzywa , Magdalena Wysocka , Marcin Skoreński , Agnieszka Dabrowska , Maria Łęcka , Piotr Suder , Marcin Sieńczyk , Krzysztof Pyrc , Adam Lesner

Abstract

Although the mosquito-borne Zika virus was discovered in the late 1940s of the 20th century, for years it was neglected, as the disease in humans was rare and relatively mild. Viral NS2B-NS3 protease is essential for virus replication, and except for maturation of viral proteins, it also modulates the infection microenvironment to facilitate virus invasion. Here, we report the combinatorial chemistry approach for the synthesis of internally quenched substrates of the Zika virus NS2B-NS3 protease that were optimized in prime positions of the peptide chain. Final substrate ABZ-Val- Lys-Lys-Arg-Ala-Ala-Trp-Tyr(3-NO 2 )-NH 2 displays an excel- lent kinetic parameter ( k cat / K M reaching nearly 1.26 × 10(8) M−1 × s−1), which is over 10 times greater than previously reported (7.7 × 10(6) M−1 × s−1) substrate. Moreover, it was found to be selective over West Nile virus protease.
Publication typeIn press (online first, early view)
Author Natalia Gruba (FCh / DMB / LBA)
Natalia Gruba,,
- Laboratory of Biochemical Analytics
, Jose Ignacio Rodriguez Martinez
Jose Ignacio Rodriguez Martinez,,
-
, Renata Grzywa
Renata Grzywa,,
-
, Magdalena Wysocka (FCh / DBCh / LMCh)
Magdalena Wysocka,,
- Laboratory of Medical Chemistry
, Marcin Skoreński
Marcin Skoreński,,
-
, Agnieszka Dabrowska
Agnieszka Dabrowska,,
-
, Maria Łęcka
Maria Łęcka,,
-
, Piotr Suder
Piotr Suder,,
-
, Marcin Sieńczyk
Marcin Sieńczyk,,
-
, Krzysztof Pyrc
Krzysztof Pyrc,,
-
et al.`
Journal seriesACS Medicinal Chemistry Letters, ISSN 1948-5875, (A 35 pkt)
Issue year2018
Noonline first
Pages1-5
Publication size in sheets0.5
Keywords in EnglishZika virus, NS2B-NS3 protease, internally quenched peptides, peptide library, combinatorial chemistry
DOIDOI:10.1021/acsmedchemlett.8b00316
URL https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.8b00316
Languageen angielski
Score (nominal)35
ScoreMinisterial score = 35.0, 10-09-2018, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, 10-09-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 3.746 (2) - 2016=3.594 (5)
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