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

Nature Communications
Jiří SchimerJan Konvalinka

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.

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Citations

Mar 31, 2015·Virology·Jan KonvalinkaBarbara Müller
Apr 28, 2016·FEBS Letters·Janina HanneHans-Georg Kräusslich
May 4, 2017·The Journal of Organic Chemistry·Albert GandiosoVicente Marchán
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May 28, 2021·RSC Chemical Biology·Amirrasoul TavakoliJung-Hyun Min
Dec 10, 2016·The Journal of Organic Chemistry·Albert GandiosoVicente Marchán
Nov 5, 2020·ACS Central Science·Takuma ImotoKazuya Kikuchi

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acetylation
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transfection

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