Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor

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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Jiří Schimer: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Marcela Pávová: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Maria Anders: Virology, University Hospital Heidelberg
Petr Pachl: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Pavel Šácha: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Petr Cígler: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Jan Weber: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Pavel Majer: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Pavlína Řezáčová: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center
Hans-Georg Kräusslich: Virology, University Hospital Heidelberg
Barbara Müller: Virology, University Hospital Heidelberg
Jan Konvalinka: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7461

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