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Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor
J. Schimer, M. Pávová, M. Anders, P. Pachl, P. Šácha, P. Cígler, J. Weber, P. Majer, P. Řezáčová, HG. Kräusslich, B. Müller, J. Konvalinka,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Free Medical Journals od 2010
Nature Open Access od 2010-12-01
PubMed Central od 2012
Europe PubMed Central od 2012
ProQuest Central od 2010-01-01
Open Access Digital Library od 2015-01-01
Open Access Digital Library od 2015-01-01
Medline Complete (EBSCOhost) od 2012-11-01
Health & Medicine (ProQuest) od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources od 2010
Odkazy
PubMed
25751579
DOI
10.1038/ncomms7461
Knihovny.cz E-zdroje
- MeSH
- aminokumariny chemická syntéza farmakologie MeSH
- časové faktory MeSH
- fotolýza MeSH
- HEK293 buňky MeSH
- HIV-1 účinky léků fyziologie účinky záření MeSH
- HIV-proteasa chemie metabolismus MeSH
- inhibitory HIV-proteasy chemická syntéza farmakologie MeSH
- karbamáty chemická syntéza farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- molekulární modely MeSH
- proteinové prekurzory antagonisté a inhibitory chemie metabolismus MeSH
- proteolýza účinky léků MeSH
- replikace viru MeSH
- světlo MeSH
- valin analogy a deriváty chemická syntéza farmakologie MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
HIV protease (PR) is required for proteolytic maturation in the late phase of HIV replication and represents a prime therapeutic target. The regulation and kinetics of viral polyprotein processing and maturation are currently not understood in detail. Here we design, synthesize, validate and apply a potent, photodegradable HIV PR inhibitor to achieve synchronized induction of proteolysis. The compound exhibits subnanomolar inhibition in vitro. Its photolabile moiety is released on light irradiation, reducing the inhibitory potential by 4 orders of magnitude. We determine the structure of the PR-inhibitor complex, analyze its photolytic products, and show that the enzymatic activity of inhibited PR can be fully restored on inhibitor photolysis. We also demonstrate that proteolysis of immature HIV particles produced in the presence of the inhibitor can be rapidly triggered by light enabling thus to analyze the timing, regulation and spatial requirements of viral processing in real time.
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- $a Schimer, Jiří $u 1] Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n.2, 166 10, Prague 6, Czech Republic [2] Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43, Prague 2, Czech Republic.
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- $a HIV protease (PR) is required for proteolytic maturation in the late phase of HIV replication and represents a prime therapeutic target. The regulation and kinetics of viral polyprotein processing and maturation are currently not understood in detail. Here we design, synthesize, validate and apply a potent, photodegradable HIV PR inhibitor to achieve synchronized induction of proteolysis. The compound exhibits subnanomolar inhibition in vitro. Its photolabile moiety is released on light irradiation, reducing the inhibitory potential by 4 orders of magnitude. We determine the structure of the PR-inhibitor complex, analyze its photolytic products, and show that the enzymatic activity of inhibited PR can be fully restored on inhibitor photolysis. We also demonstrate that proteolysis of immature HIV particles produced in the presence of the inhibitor can be rapidly triggered by light enabling thus to analyze the timing, regulation and spatial requirements of viral processing in real time.
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