Defining the HIV Capsid Binding Site of Nucleoporin 153

Li, Shunji; Patel, Jagdish Suresh; Yang, Jordan; Crabtree, Angela M.; Rubenstein, Brenda M.; Lund-Andersen, Peik K.; Ytreberg, F. Marty; Rowley, Paul A.

doi:10.1128/msphere.00310-22

Cited by 4 publications

(2 citation statements)

References 47 publications

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“…CA cone stability highly depends on intermolecular contacts such as NTD-NTD, NTD-CTD, and CTD-CTD between monomers of the hexamer or pentamer [ 16 ]. Notably, the NTD-CTD interprotomer pocket is the binding site of host factor cleavage and polyadenylation specificity factor 6 (CPSF6), nucleoporin 153 (NUP153), and Sec24C [ 17 , 18 , 19 ]. Interference with interactions between CA and host factors can affect HIV-1 replication.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators

Sun

Zalloum

et al. 2022

Molecules

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HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, F2-7f exhibited moderate anti-HIV-1 activity with an EC50 value of 5.89 μM, which was slightly weaker than the lead compound PF74 (EC50 = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by 7f with an HIV-2 EC50 value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC50 = 21.81 μM), equivalent to PF74 (EC50 = 4.16 μM). Furthermore, F2-7f preferred to bind to the CA hexamer rather than to the monomer, similar to PF74, according to surface plasmon resonance results. Molecular dynamics simulation indicated that F2-7f and PF74 bound at the same site. Additionally, we computationally analyzed the ADMET properties for 7f and F2-7f. Based on this analysis, 7f and F2-7f were predicted to have improved drug-like properties and metabolic stability over PF74, and no toxicities were predicted based on the chemotype of 7f and F2-7f. Finally, the experimental metabolic stability results of F2-7f in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that F2-7f is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.

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Section: Introductionmentioning

confidence: 99%

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators

Sun

Zalloum

et al. 2022

Molecules

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“…FoldX has been an integral tool in our group’s body of work that combines molecular modeling and mutagenesis experiments [ 12 – 14 ]. However, a measure of uncertainty significantly improves the usefulness of the computational prediction.…”

Section: Introductionmentioning

confidence: 99%

Statistical modeling to quantify the uncertainty of FoldX-predicted protein folding and binding stability

Sapozhnikov,

Patel,

Ytreberg

et al. 2023

BMC Bioinformatics

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Background Computational methods of predicting protein stability changes upon missense mutations are invaluable tools in high-throughput studies involving a large number of protein variants. However, they are limited by a wide variation in accuracy and difficulty of assessing prediction uncertainty. Using a popular computational tool, FoldX, we develop a statistical framework that quantifies the uncertainty of predicted changes in protein stability. Results We show that multiple linear regression models can be used to quantify the uncertainty associated with FoldX prediction for individual mutations. Comparing the performance among models with varying degrees of complexity, we find that the model precision improves significantly when we utilize molecular dynamics simulation as part of the FoldX workflow. Based on the model that incorporates information from molecular dynamics, biochemical properties, as well as FoldX energy terms, we can generally expect upper bounds on the uncertainty of folding stability predictions of ± 2.9 kcal/mol and ± 3.5 kcal/mol for binding stability predictions. The uncertainty for individual mutations varies; our model estimates it using FoldX energy terms, biochemical properties of the mutated residue, as well as the variability among snapshots from molecular dynamics simulation. Conclusions Using a linear regression framework, we construct models to predict the uncertainty associated with FoldX prediction of stability changes upon mutation. This technique is straightforward and can be extended to other computational methods as well.

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Structural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single particle cryo-EM

Cook,

Freniere,

et al. 2024

Preprint

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One of the most striking features of HIV is the capsid; a fullerene cone comprised of the pleomorphic capsid protein (CA) which shields the viral genome from cellular defense mechanisms and recruits cellular cofactors to the virus. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interaction, HIV-2 CA remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we were able to determine high resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and in complexes with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6. While the overall fold and mode of binding the FG-peptides are conserved with HIV-1, this study reveals distinctive structural features that define the HIV-2 CA lattice, potential differences in interactions with other host factors such as CypA, and divergence in the mechanism of formation of hexameric and pentameric CA assemblies. This study extends our understanding of HIV capsids and highlights an approach with significant potential to facilitate the study of lentiviral capsid biology.

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Defining the HIV Capsid Binding Site of Nucleoporin 153

Abstract: The human immunodeficiency virus (HIV) can infect nondividing cells by interacting with the host nuclear pore complex. The host nuclear pore protein NUP153 directly interacts with the HIV capsid to promote viral nuclear entry.

Cited by 4 publications

References 47 publications

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators

Statistical modeling to quantify the uncertainty of FoldX-predicted protein folding and binding stability

Structural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single particle cryo-EM

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