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

Schimer J, Pávová M, Anders M, Pachl P, Šácha P, Cígler P, Weber J, Majer P, Řezáčová P, Kräusslich HG, Müller B, Konvalinka J
Nat Commun 6 6461 (2015)
Cited: 17 times
EuropePMC logo PMID: 25751579

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.

Articles - 4u7q mentioned but not cited (3)

  1. Triggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor. Schimer J, Pávová M, Anders M, Pachl P, Šácha P, Cígler P, Weber J, Majer P, Řezáčová P, Kräusslich HG, Müller B, Konvalinka J. Nat Commun 6 6461 (2015)
  2. Effective estimation of the inhibitor affinity of HIV-1 protease via a modified LIE approach. Ngo ST, Hong ND, Quynh Anh LH, Hiep DM, Tung NT. RSC Adv 10 7732-7739 (2020)
  3. Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures. Lockbaum GJ, Leidner F, Royer WE, Kurt Yilmaz N, Schiffer CA. Acta Crystallogr D Struct Biol 76 302-310 (2020)


Reviews citing this publication (3)

  1. Maturation of retroviruses. Pornillos O, Ganser-Pornillos BK. Curr Opin Virol 36 47-55 (2019)
  2. Super-resolved insights into human immunodeficiency virus biology. Hanne J, Zila V, Heilemann M, Müller B, Kräusslich HG. FEBS Lett 590 1858-1876 (2016)
  3. Application of Advanced Light Microscopy to the Study of HIV and Its Interactions with the Host. Saffarian S. Viruses 13 223 (2021)

Articles citing this publication (11)

  1. Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state. Chojnacki J, Waithe D, Carravilla P, Huarte N, Galiani S, Enderlein J, Eggeling C. Nat Commun 8 545 (2017)
  2. Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work. Ngo ST, Hung HM, Nguyen MT. J Comput Chem 37 2734-2742 (2016)
  3. Biochemical Reconstitution of HIV-1 Assembly and Maturation. Kucharska I, Ding P, Zadrozny KK, Dick RA, Summers MF, Ganser-Pornillos BK, Pornillos O. J Virol 94 e01844-19 (2020)
  4. Sequential Uncaging with Green Light can be Achieved by Fine-Tuning the Structure of a Dicyanocoumarin Chromophore. Gandioso A, Palau M, Nin-Hill A, Melnyk I, Rovira C, Nonell S, Velasco D, García-Amorós J, Marchán V. ChemistryOpen 6 375-384 (2017)
  5. The HIV-1 Viral Protease Is Activated during Assembly and Budding Prior to Particle Release. Tabler CO, Wegman SJ, Chen J, Shroff H, Alhusaini N, Tilton JC. J Virol 96 e0219821 (2022)
  6. Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets. Mitchell MO. J Mol Model 23 287 (2017)
  7. Dynamics of HIV-1 Gag Processing as Revealed by Fluorescence Lifetime Imaging Microscopy and Single Virus Tracking. Qian C, Flemming A, Müller B, Lamb DC. Viruses 14 340 (2022)
  8. Light-induced modulation of DNA recognition by the Rad4/XPC damage sensor protein. Tavakoli A, Paul D, Mu H, Kuchlyan J, Baral S, Ansari A, Broyde S, Min JH. RSC Chem Biol 2 523-536 (2021)
  9. A Photodeactivatable Antagonist for Controlling CREB-Dependent Gene Expression. Imoto T, Minoshima M, Yokoyama T, Emery BP, Bull SD, Bito H, Kikuchi K. ACS Cent Sci 6 1813-1818 (2020)
  10. Neutral sphingomyelinase 2 is required for HIV-1 maturation. Waheed AA, Zhu Y, Agostino E, Naing L, Hikichi Y, Soheilian F, Yoo SW, Song Y, Zhang P, Slusher BS, Haughey NJ, Freed EO. Proc Natl Acad Sci U S A 120 e2219475120 (2023)
  11. Deactivatable Bisubstrate Inhibitors of Protein Kinases. Sõrmus T, Lavogina D, Enkvist E, Uri A, Viht K. Molecules 27 6689 (2022)


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