Lenacapavir-induced Lattice Hyperstabilization is Central to HIV-1 Capsid Failure at the Nuclear Pore Complex and in the Cytoplasm DOI Creative Commons
Arpa Hudait, Ryan C. Burdick,

Ellie K. Bare

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Abstract Lenacapavir (LEN) is the first HIV-1 capsid inhibitor approved for clinical use. It inhibits multiple steps of viral life cycle; however, molecular details effect LEN on structure and mechanistic inhibition are not understood. Recent studies show that intact cone-shaped capsids with LEN-induced breaks can dock at nuclear pore complexes (NPC), but only enter nucleus. In this work, we combined large-scale coarse-grained dynamics simulations live-cell imaging to investigate stepwise mechanism docking LEN-treated into NPC. Capsids bound substoichiometric concentrations reach NPC central channel. As advances end, lattice defects formed pentamer-hexamer interface – primarily narrower end leading pentamer dissociation. Dissociation pentamers detrimental integrity, both rupture narrow destabilization hexamer-hexamer interface. Structural analysis LEN-capsid in our demonstrate heterogeneous hyperstabilization loss essential pliability protein lattice. Live-cell cores labeled two different fluorescent markers showed ruptured were docked imported We conclude contributes elasticity inhibiting entry replication. Significance For replicate, core must nucleus, undergo reverse transcription, uncoat near integration sites. Here, using a computational experimental approach, Lenacapavir-treated stably bind during docking; broken associated defective entry. modulates structures by generating hyperstabilized domains, elasticity, adaptation crowded environment channel import. Our findings altering material properties be an effective strategy designing antiviral drugs disrupt

Language: Английский

Lenacapavir-induced Lattice Hyperstabilization is Central to HIV-1 Capsid Failure at the Nuclear Pore Complex and in the Cytoplasm DOI Creative Commons
Arpa Hudait, Ryan C. Burdick,

Ellie K. Bare

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Abstract Lenacapavir (LEN) is the first HIV-1 capsid inhibitor approved for clinical use. It inhibits multiple steps of viral life cycle; however, molecular details effect LEN on structure and mechanistic inhibition are not understood. Recent studies show that intact cone-shaped capsids with LEN-induced breaks can dock at nuclear pore complexes (NPC), but only enter nucleus. In this work, we combined large-scale coarse-grained dynamics simulations live-cell imaging to investigate stepwise mechanism docking LEN-treated into NPC. Capsids bound substoichiometric concentrations reach NPC central channel. As advances end, lattice defects formed pentamer-hexamer interface – primarily narrower end leading pentamer dissociation. Dissociation pentamers detrimental integrity, both rupture narrow destabilization hexamer-hexamer interface. Structural analysis LEN-capsid in our demonstrate heterogeneous hyperstabilization loss essential pliability protein lattice. Live-cell cores labeled two different fluorescent markers showed ruptured were docked imported We conclude contributes elasticity inhibiting entry replication. Significance For replicate, core must nucleus, undergo reverse transcription, uncoat near integration sites. Here, using a computational experimental approach, Lenacapavir-treated stably bind during docking; broken associated defective entry. modulates structures by generating hyperstabilized domains, elasticity, adaptation crowded environment channel import. Our findings altering material properties be an effective strategy designing antiviral drugs disrupt

Language: Английский

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