Nature communications, 2015-03, Vol.6 (1), p.6461-6461, Article 6461
2015
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Details
- Autor(en) / Beteiligte
- Titel
- Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor
- Ist Teil von
- Nature communications, 2015-03, Vol.6 (1), p.6461-6461, Article 6461
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/ncomms7461Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4366505
- Format
- –
- Schlagworte
- Aminocoumarins - chemical synthesis, Aminocoumarins - pharmacology, Binding Sites, Carbamates - chemical synthesis, Carbamates - pharmacology, HEK293 Cells, HIV Protease - chemistry, HIV Protease - metabolism, HIV Protease Inhibitors - chemical synthesis, HIV Protease Inhibitors - pharmacology, HIV-1 - drug effects, HIV-1 - physiology, HIV-1 - radiation effects, Humans, Kinetics, Light, Models, Molecular, Photolysis, Protein Binding, Protein Precursors - antagonists & inhibitors, Protein Precursors - chemistry, Protein Precursors - metabolism, Proteolysis - drug effects, Time Factors, Valine - analogs & derivatives, Valine - chemical synthesis, Valine - pharmacology, Virus Replication