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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F15%3A10314968" target="_blank" >RIV/00216208:11310/15:10314968 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388963:_____/15:00443993

Výsledek na webu

<a href="http://dx.doi.org/10.1038/ncomms7461" target="_blank" >http://dx.doi.org/10.1038/ncomms7461</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/ncomms7461" target="_blank" >10.1038/ncomms7461</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 alsodemonstrate 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 alsodemonstrate 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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

CE - Biochemie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2015

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

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Svazek periodika

6

Číslo periodika v rámci svazku

09 March 2015

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

8

Strana od-do

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Kód UT WoS článku

000352697100002

EID výsledku v databázi Scopus

2-s2.0-84924390132