Inhibitors of the HIV-1 capsid, a target of opportunity

Current Opinion in HIV and AIDS, Journal Year: 2018, Volume and Issue: 13(4), P. 359 - 365

Published: May 19, 2018

To summarize recent advances in the discovery of chemical inhibitors targeting HIV capsid and research on their mechanisms action.HIV infection is critically dependent functions viral capsid. Numerous studies have reported identification a variety compounds that bind to protein; some these inhibit reverse transcription nuclear entry, steps required for infection. Other capsid-targeting appear act by perturbing assembly, resulting noninfectious progeny virions. Inhibitors may several different positions protein, including sites both protein domains. However, antiviral activity many has not been definitively linked binding. Until recently, low-to-moderate potency precluded further clinical development. In 2017, GS-CA1, highly potent inhibitor, was described holds promise development.Small molecules can be Capsid-targeting drugs are predicted exhibit high barriers resistance, ongoing work this area contributing an understanding molecular biology uncoating maturation.

Language: Английский

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Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: Sept. 11, 2017

Human immunodeficiency virus type 1 (HIV-1) assembles as immature particles, which require the proteolytic cleavage of structural polyprotein Gag and clustering envelope glycoprotein Env for infectivity. The details mechanisms underlying remain unknown. Here, we determine molecular dynamics on surface individual HIV-1 particles using scanning fluorescence correlation spectroscopy a super-resolution STED microscope. We find that undergoes maturation-induced increase in mobility, highlighting diffusion one cause clustering. This mobility is dependent Gag-interacting tail but not changes viral lipid order. Diffusion other incorporated proteins mature two orders magnitude slower than plasma membrane, indicating intrinsically low environment, mainly due to its general high Our results provide insights into dynamic properties particles.To become infectious, undergo maturation process involving Env. Chojnacki et al. employ STED-FCS microscopy study molecules show mobility.

Language: Английский

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Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(47)

Published: Nov. 7, 2017

The packaging and budding of Gag polyprotein viral RNA is a critical step in the HIV-1 life cycle. High-resolution structures have revealed that capsid (CA) spacer peptide 1 (SP1) domains contain important interfaces for self-assembly. However, molecular details multimerization process, especially presence cell membrane, remained unclear. In this work, we investigate mechanisms work concert between polyproteins, RNA, membrane to promote immature lattice growth. We develop coarse-grained (CG) computational model derived from subnanometer resolution structural data. Our simulations recapitulate contiguous hexameric assembly driven only by weak anisotropic attractions at helical CA-SP1 junction. Importantly, analysis CG single-particle tracking photoactivated localization (spt-PALM) trajectories indicates are constituents actively through scaffolding, while overexpression short competitor can suppress assembly. also find CA amino-terminal domain imparts intrinsic curvature lattice. As consequence, growth appears be coupled dynamics spontaneous deformation. findings elucidate simple network interactions regulate early stages budding.

Language: Английский

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Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein

Journal of Molecular Biology, Journal Year: 2016, Volume and Issue: 428(8), P. 1637 - 1655

Published: March 16, 2016

Language: Английский

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The Life-Cycle of the HIV-1 Gag–RNA Complex

Viruses, Journal Year: 2016, Volume and Issue: 8(9), P. 248 - 248

Published: Sept. 10, 2016

Human immunodeficiency virus type 1 (HIV-1) replication is a highly regulated process requiring the recruitment of viral and cellular components to plasma membrane for assembly into infectious particles. This review highlights recent understanding selection genomic RNA (gRNA) by Pr55(Gag) precursor polyprotein, processes leading its incorporation

Language: Английский

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