Antiviral compounds modulate elasticity, strength and material fatigue of a virus capsid framework

Domínguez‐Zotes, Santos; Valbuena, Alejandro; Mateu, Mauricio G.

doi:10.1016/j.bpj.2022.02.014

Cited by 10 publications

(8 citation statements)

References 76 publications

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“…Using three different viruses (MVM, human rhinovirus and the human immunodeficiency virus), we had previously found evidence for an intimate relationship between mechanical stiffening and impaired conformational dynamics (transitions between equilibrium states and/or conformational fluctuations at equilibrium) (Carrillo et al, 2017; Castellanos, Carrillo, & Mateu, 2015; Castellanos et al, 2012; Dominguez-Zotes, Valbuena, & Mateu, 2022; Guerra et al, 2017; Valbuena & Mateu, 2015; Valbuena, Rodriguez-Huete, & Mateu, 2018). For MVM, different capsid-stiffening mutations impaired different biologically relevant transitions between conformational states (Castellanos et al, 2015; Castellanos et al, 2012), but it was unclear whether the equilibrium dynamics was also impaired.…”

Section: Resultsmentioning

confidence: 99%

“…We had previously found evidence for a relationship between global or local stiffening (determined by AFM) of virus particles and impaired conformational transitions and/or quenched equilibrium dynamics, and this linkage was rationalized in simple physical terms (Carrillo et al, 2017; Castellanos et al, 2015; Castellanos et al, 2012; Dominguez-Zotes et al, 2022; Guerra et al, 2017; Mateu, 2012; Valbuena & Mateu, 2015; Valbuena et al, 2018). A discriminating experiment using MVM capsid mutants was devised here to challenge the hypothesis of a linkage between mechanical stiffening and impaired equilibrium dynamics.…”

Section: Discussionmentioning

confidence: 97%

Section: A Linkage Between Mutation-induced Changes In Mechanical Ela...mentioning

confidence: 99%

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Equilibrium dynamics of a biomolecular complex analyzed at single-amino acid resolution by cryo-electron microscopy

Luque

Ortega-Esteban

Valbuena

et al. 2022

Preprint

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The biological function of macromolecular complexes depends not only on large-scale transitions between conformations, but also on small-scale conformational fluctuations at equilibrium. This study shows that detailed information on the equilibrium dynamics of a biocomplex obtained from local resolution (LR) data in cryo-electron microscopy (cryo-EM) density maps matches the information obtained in solution by hydrogen-deuterium exchange mass-spectrometry. The structure of the minute virus of mice (MVM) capsid as a model system was determined by cryo-EM, and LR values were found to correlate with both crystallographic B-factors and hydrogen-deuterium exchange values. Once validated, the cryo-EM LR-based approach was used to compare the equilibrium dynamics of wild-type and two mutant MVM capsids. The results revealed a linkage between mechanical stiffening and impaired equilibrium dynamics in a biocomplex. Cryo-EM is emerging as a powerful approach for simultaneously acquiring information on the atomic structure and local equilibrium dynamics of biomolecular complexes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: A Linkage Between Mutation-induced Changes In Mechanical Ela...mentioning

confidence: 99%

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Equilibrium dynamics of a biomolecular complex analyzed at single-amino acid resolution by cryo-electron microscopy

Luque

Ortega-Esteban

Valbuena

et al. 2022

Preprint

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“…Both compounds act as stabilizers to prevent the dissociation of CA subunits from hexamers adjacent to the defect, which is critical for capsid assembly ( Bester et al, 2020 ). Additionally, biophysical analysis suggests that PF74 significantly enhances the resistance of the capsid lattice to mechanical stress and reduces the likelihood of dislocation and material fatigue, thereby enthalpically strengthening the lattice against breakage and disintegration ( Domínguez-Zotes et al, 2022 ). In the case of CAI, its binding to CA results in a conformational change in the CA CTD to accommodate the peptide.…”

Section: Discussionmentioning

confidence: 99%

Modulation of HIV-1 capsid multimerization by sennoside A and sennoside B via interaction with the NTD/CTD interface in capsid hexamer

Zhang,

Xu,

Zhou

et al. 2023

Front. Microbiol.

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Small molecules that bind to the pocket targeted by a peptide, termed capsid assembly inhibitor (CAI), have shown antiviral effects with unique mechanisms of action. We report the discovery of two natural compounds, sennoside A (SA) and sennoside B (SB), derived from medicinal plants that bind to this pocket in the C-terminal domain of capsid (CA CTD). Both SA and SB were identified via a drug-screening campaign that utilized a time-resolved fluorescence resonance energy transfer assay. They inhibited the HIV-1 CA CTD/CAI interaction at sub-micromolar concentrations of 0.18 μM and 0.08 μM, respectively. Mutation of key residues (including Tyr 169, Leu 211, Asn 183, and Glu 187) in the CA CTD decreased their binding affinity to the CA monomer, from 1.35-fold to 4.17-fold. Furthermore, both compounds induced CA assembly in vitro and bound directly to the CA hexamer, suggesting that they interact with CA beyond the CA CTD. Molecular docking showed that both compounds were bound to the N-terminal domain (NTD)/CTD interface between adjacent protomers within the CA hexamer. SA established a hydrogen-bonding network with residues N57, V59, Q63, K70, and N74 of CA1-NTD and Q179 of CA2-CTD. SB formed hydrogen bonds with the N53, N70, and N74 residues of CA1-NTD, and the A177and Q179 residues of CA2-CTD. Both compounds, acting as glue, can bring αH4 in the NTD and αH9 in the CTD of the NTD/CTD interface close to each other. Collectively, our research indicates that SA and SB, which enhance CA assembly, could serve as novel chemical tools to identify agents that modulate HIV-1 CA assembly. These natural compounds may potentially lead to the development of new antiviral therapies with unique mechanisms of action.

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“…Studies of the HIV-1 capsid have demonstrated that the inter-subunit interfaces are structurally variable, indicating that the capsid is flexible 34,35 . We hypothesized that capsid elasticity is required for HIV-1 nuclear entry.…”

mentioning

confidence: 99%

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

Deshpande,

Bryer,

Andino

et al. 2023

Preprint

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HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid1,2. Recent studies have shown that HIV- 1 cores enter the nucleus prior to capsid disassembly3–5. Interactions with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Suppressors of the mutants restored elasticity and rescued infectivity and nuclear entry. Elasticity was also reduced by treatment of cores with the capsid-targeting compound PF74 and the antiviral drug lenacapavir. Our results indicate that capsid elasticity is a fundamental property of the HIV-1 core that enables its passage through the nuclear pore complex, thereby facilitating infection. These results provide new insights into the mechanisms of HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.

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Antiviral compounds modulate elasticity, strength and material fatigue of a virus capsid framework

Cited by 10 publications

References 76 publications

Equilibrium dynamics of a biomolecular complex analyzed at single-amino acid resolution by cryo-electron microscopy

Equilibrium dynamics of a biomolecular complex analyzed at single-amino acid resolution by cryo-electron microscopy

Modulation of HIV-1 capsid multimerization by sennoside A and sennoside B via interaction with the NTD/CTD interface in capsid hexamer

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

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