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 Cigler,Jan Weber,Pavel Majer,Pavlína Řezáčová,Hans-Georg Kräusslich,Barbara Müller,Jan Konvalinka +11 more
TL;DR: It is demonstrated 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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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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Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work.
TL;DR: The fast pulling ligand (FPL) out of binding cavity using non‐equilibrium molecular dynamics simulations was demonstrated to be a rapid, accurate and low CPU demand method for the determination of the relative binding affinities of a large number of HIV‐1 protease (PR) inhibitors.
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Development of Green/Red-Absorbing Chromophores Based on a Coumarin Scaffold That Are Useful as Caging Groups
Albert Gandioso,Sara Contreras,Ivanna Melnyk,Javier Oliva,Santi Nonell,Dolores Velasco,Jaume Garcia-Amorós,Vicente Marchán +7 more
TL;DR: Preliminary photolysis studies with green light have demonstrated that the structure of the coumarin chromophore influences the rate of the uncaging process, opening the way to exploiting these new cou marin scaffolds as caging groups that can be removed with visible light.
A Green Light-Triggerable RGD Peptide for Photocontrolled Targeted Drug Delivery: Synthesis and Photolysis Studies
TL;DR: The fact that green-light triggered photoactivation can be efficiently performed both with the caged peptide and with its ruthenocenoyl bioconjugate reveals great potential for DEAdcCE-caged peptides sequences as selective drug carriers in the context of photocontrolled targeted anticancer strategies.
Stimulated Emission Depletion Nanoscopy Reveals Time-Course of Human Immunodeficiency Virus Proteolytic Maturation.
Janina Hanne,Janina Hanne,Fabian Göttfert,Jiří Schimer,Jiří Schimer,Jiří Schimer,Maria Anders-Össwein,Jan Konvalinka,Jan Konvalinka,Johann Engelhardt,Barbara Müller,Barbara Müller,Stefan W. Hell,Hans-Georg Kräusslich,Hans-Georg Kräusslich +14 more
TL;DR: This study shows the rearrangement of subviral structures in a super-resolution light microscope over time, outwitting phototoxicity and fluorophore bleaching through synchronization of a biological process by an optical switch.
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