Exploiting the unique features of Zika and Dengue proteases for inhibitor design
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články, přehledy
PubMed
31077760
DOI
10.1016/j.biochi.2019.05.004
PII: S0300-9084(19)30143-9
Knihovny.cz E-zdroje
- Klíčová slova
- Active-site inhibitors, Allosteric inhibitors, Aptamers, Dengue protease, Precursor, Zika protease,
- MeSH
- alosterické místo MeSH
- antivirové látky chemie farmakologie MeSH
- dengue farmakoterapie virologie MeSH
- infekce virem zika farmakoterapie virologie MeSH
- inhibitory proteas chemie farmakologie MeSH
- katalytická doména MeSH
- kinetika MeSH
- konformace proteinů MeSH
- lidé MeSH
- proteasy chemie metabolismus MeSH
- racionální návrh léčiv * MeSH
- serinové endopeptidasy chemie metabolismus MeSH
- virové proteiny antagonisté a inhibitory chemie metabolismus MeSH
- virus dengue účinky léků enzymologie MeSH
- virus zika účinky léků enzymologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antivirové látky MeSH
- inhibitory proteas MeSH
- NS3 protease, dengue virus MeSH Prohlížeč
- NS3 protein, zika virus MeSH Prohlížeč
- proteasy MeSH
- serinové endopeptidasy MeSH
- virové proteiny MeSH
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.
Citace poskytuje Crossref.org
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