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Exploiting the unique features of Zika and Dengue proteases for inhibitor design
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SYSNO ASEP 0517405 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Exploiting the unique features of Zika and Dengue proteases for inhibitor design Author(s) Majerová, Taťána (UOCHB-X) RID, ORCID
Novotný, Pavel (UOCHB-X)
Krýsová, Eliška (UOCHB-X)
Konvalinka, Jan (UOCHB-X) RID, ORCIDSource Title Biochimie. - : Elsevier - ISSN 0300-9084
Roč. 166, Nov (2019), s. 132-141Number of pages 10 s. Language eng - English Country FR - France Keywords active-site inhibitors ; allosteric inhibitors ; aptamers ; precursor ; Dengue protease ; Zika protease Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects LO1302 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000492314700012 EID SCOPUS 85065797472 DOI 10.1016/j.biochi.2019.05.004 Annotation Zika and Dengue viruses have attracted substantial attention from researchers in light of recent outbreaks of Dengue fever and increases in cases of congenital microcephaly in areas with Zika incidence. This review summarizes the current state of knowledge about Zika and Dengue proteases. These enzymes have several interesting features: 1) NS3 serine protease requires the activating co-factor NS2B, which is anchored in the membrane of the endoplasmic reticulum, 2) NS2B displays extensive conformational dynamics, 3) NS3 is a multidomain protein with proteolytic, NTPase, RNA 5' triphosphatase and helicase activity and has many protein-protein interaction partners, 4) NS3 is autoproteolytically released from its precursor. Attempts to design tight-binding and specific active-site inhibitors are complicated by the facts that the substrate pocket of the NS2B-NS3 protease is flat and the active-site ligands are charged. The ionic character of potential active-site inhibitors negatively influences their cell permeability. Possibilities to block cis-autoprocessing of the protease precursor have recently been considered. Additionally, potential allosteric sites on NS2B-NS3 proteases have been identified and allosteric compounds have been designed to impair substrate binding and/or block the NS2B-NS3 interaction. Such compounds could be specific to viral proteases, without off-target effects on host serine proteases, and could have favorable pharmacokinetic profiles. This review discusses various groups of inhibitors of these proteases according to their mechanisms of action and chemical structures. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2020 Electronic address https://www.sciencedirect.com/science/article/abs/pii/S0300908419301439?via%3Dihub
Number of the records: 1