Triggering HIV Polyprotein Processing by Light Using Rapid Photodegradation of a Tight-binding Protease Inhibitor

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Mar 10

PMID 25751579

Citations 15

Authors

Jiri Schimer

Marcela Pavova

Maria Anders

Petr Pachl

Pavel Sacha

Petr Cigler

Jan Weber

Pavel Majer

Pavlina rezacova

Hans-Georg Krausslich

Barbara Muller

Jan Konvalinka

Affiliations

Soon will be listed here.

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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