Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor
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...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
9 Mar 2015
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| In: |
Nature Communications
Year: 2015, Volume: 6 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms7461 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/ncomms7461 Verlag, kostenfrei, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366505/ 
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| Author Notes: | Jiří Schimer, Marcela Pávová, Maria Anders, Petr Pachl, Pavel Šácha, Petr Cígler, Jan Weber, Pavel Majer, Pavlína Řezáčová, Hans-Georg Kräusslich, Barbara Müller and Jan Konvalinka |
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| 520 | |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. The study of HIV proteolysis during maturation and replication can be difficult since different steps in these processes occur simultaneously. Here, the authors present a photolabile HIV protease inhibitor which can be deactivated by light irradiation, allowing synchronized induction of viral maturation. | ||
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