Virus structure and structure-based antivirals

Plavec, Zlatka; Pöhner, Ina; Poso, Antti; Butcher, S.J.

doi:10.1016/j.coviro.2021.09.005

Cited by 11 publications

(4 citation statements)

References 90 publications

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“…Given the essential role N protein:RNA interaction has in coronavirus lifecycles, our work here hints at principles to enable the rational design of bivalent molecules that might enable specific NTD-RBD inhibition by outcompeting with RNA to bind in a conformationally-conserved manner. If conventional antiviral structure-guided drug design focusses on conserved structural features, targeting conserved conformational features offers an alternative but conceptually analogous route to pharmacological intervention against regions traditionally considered ‘undruggable’ 91 , 92 .…”

Section: Discussionmentioning

confidence: 99%

Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

Holehouse,

Alston,

Soranno

2024

Preprint

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Intrinsically disordered regions (IDRs) are critical for cellular function yet often appear to lack sequence conservation when assessed by multiple sequence alignments. This raises the question of if and how function can be encoded and preserved in these regions despite massive sequence variation. To address this question, we have applied coarse-grained molecular dynamics simulations to investigate non-specific RNA binding of coronavirus nucleocapsid proteins. Coronavirus nucleocapsid proteins consist of multiple interspersed disordered and folded domains that bind RNA. Here, we focus on the first two domains of coronavirus nucleocapsid proteins: the disordered N-terminal domain (NTD) and the folded RNA binding domain (RBD). While the NTD is highly variable across evolution, the RBD is structurally conserved. This combination makes the NTD-RBD a convenient model system for exploring the interplay between an IDR adjacent to a folded domain and how changes in IDR sequence can influence molecular recognition of a partner. Our results reveal a surprising degree of sequence-specificity encoded by both the composition and the precise order of the amino acids in the NTD. The presence of an NTD can – depending on the sequence – either suppress or enhance RNA binding. Despite this sensitivity, large-scale variation in NTD sequences is possible while certain sequence features are retained. Consequently, a conformationally-conserved dynamic and disordered RNA:protein complex is found across nucleocapsid protein orthologs despite large-scale changes in both NTD sequence and RBD surface chemistry. Taken together, these insights shed light on the ability of disordered regions to preserve functional characteristics despite their sequence variability.

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Section: Discussionmentioning

confidence: 99%

Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

Holehouse,

Alston,

Soranno

2024

Preprint

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“…Membrane fusion is an essential step for enveloped viruses and inhibitors that can impede the functionality of viral fusion protein have been extensively explored. 3 , 27 , 28 Peptides derived from the fusion protein HR2 domain have strong antiviral activity through blocking 6‐HB structure. 29 , 30 Comparing with unmodified template peptides, lipid‐modified lipopeptides possess greatly improved pharmaceutical properties, including binding affinity, inhibitory activity, and in vivo stability.…”

Section: Discusiionmentioning

confidence: 99%

Development of potent pan‐coronavirus fusion inhibitors with a new design strategy

Zhu,

Gao,

Feng

et al. 2024

MedComm

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Development of potent and broad‐spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion‐inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α‐helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS‐CoV‐2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross‐neutralize the bat‐ and pangolin‐isolated SARS‐CoV‐2‐related CoVs (RatG13, PCoV‐GD, and PCoV‐GX) and other human CoVs (SARS‐CoV, MERS‐CoV, HCoV‐NL63, and HCoV‐229E). Fourth, IPB29 administrated as an inhalation solution (IPB29‐IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS‐CoV‐2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29‐IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS‐CoV‐2 and other coronaviruses.

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“…These three-dimensional reconstructions combined with computational algorithms and complementary experimental techniques are leading to a mechanistic characterization of the assembly, dynamics, and stability of viral capsids, opening the doors to new antiviral strategies (Johnson et al 2021; Twarock and Stockley 2019; Organtini et al 2017; Kizziah, Rodenburg, and Dokland 2020; Yeager et al 1990; Qazi et al 2018; Li et al 2008; Mata et al 2020; de Pablo and San Martín 2022; X. Zhang et al 2013; Bayfield, Steven, and Antson 2020; Montiel-Garcia et al 2021; Podgorski et al 2020; Hua et al 2017; Mohajerani et al 2022; Wilson and Roof 2021; Bruinsma, Wuite, and Roos 2021; Luque and Reguera 2013; Lee et al 2022; Grime et al 2016; Plavec et al 2021). Among the computational methods, molecular dynamics algorithms have improved dramatically in the last decades and can infer the dynamics of large protein complexes.…”

Section: Introductionmentioning

confidence: 99%

pyCapsid: Identifying dominant dynamics and quasi-rigid mechanical units in protein shells

Brown,

Agarwal,

Luque

2023

Preprint

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Summary: pyCapsid is a Python package developed to facilitate the characterization of the dynamics and mechanical units of protein shells and other protein complexes. The package was developed in response to the rapid increase of high-resolution structures, particularly capsids of viruses, requiring multiscale biophysical analyses. Given a protein shell, pyCapsid generates the collective vibrations of its amino-acid residues, identifies quasi-rigid mechanical regions, and maps the results back to the input proteins for interpretation. pyCapsid summarizes the main results in a report that includes publication-quality figures. Availability and Implementation: pyCapsid's source code is available under MIT License on GitHub (https://github.com/luquelab/pycapsid). It is compatible with Python 3.8-3.10 and has been deployed in two leading Python package-management systems, PIP (https://pypi.org/project/pyCapsid/) and Conda (https://anaconda.org/luque_lab/pycapsid). Installation instructions and tutorials are available in the GitHub Page-style online documentation (https://luquelab.github.io/pyCapsid). Additionally, a cloud-based implementation of pyCapsid is available as a Google Colab notebook (https://colab.research.google.com/github/luquelab/pyCapsid/blob/main/notebooks/pyCapsid_colab_notebook.ipynb). pyCapsid Colab does not require installation and generates the same report and outputs as the installable version. Users can post issues regarding pyCapsid in the GitHub repository (https://github.com/luquelab/pyCapsid/issues).

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Virus structure and structure-based antivirals

Cited by 11 publications

References 90 publications

Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

Development of potent pan‐coronavirus fusion inhibitors with a new design strategy

pyCapsid: Identifying dominant dynamics and quasi-rigid mechanical units in protein shells

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