More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules

Colibus, Luigi De; Wang, Xiangxi; Spyrou, John A. B.; Kelly, James; Ren, Jingshan; Grimes, Jonathan M.; Puerstinger, Gerhard; Stonehouse, Nicola J.; Walter, Thomas S.; Hu, Zhongliang; Wang, Junzhi; Li, Xuemei; Peng, Wei; Rowlands, David J.; Fry, Elizabeth E.; Rao, Zihe; Stuart, David I.

doi:10.1038/nsmb.2769

Cited by 90 publications

(105 citation statements)

References 48 publications

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“…Knowledge of the precise interactions between the viral capsid and capsid binding compounds may help to develop novel and yet more potent antivirals. A novel class of EV71 capsid binders was recently reported which were designed based on the crystal structure of the EV71 capsid (27). In that particular study, cocrystals of the EV71 capsid with the compounds revealed an interaction with Asp112 and/or Ile113, underlining the importance of these interactions and corroborating the findings of our modeling study.…”

supporting

confidence: 74%

The Capsid Binder Vapendavir and the Novel Protease Inhibitor SG85 Inhibit Enterovirus 71 Replication

Tijsma

Franco

Tucker³

et al. 2014

Antimicrob Agents Chemother

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c Antivirals against enterovirus 71 (EV71) are urgently needed. We demonstrate that the novel enteroviral protease inhibitor (PI) SG85 and capsid binder (CB) vapendavir efficiently inhibit the in vitro replication of 21 EV71 strains/isolates that are representative of the different genogroups A, B, and C. The PI rupintrivir, the CB pirodavir, and the host-targeting compound enviroxime, which were included as reference compounds, also inhibited the replication of all isolates. Remarkably, the CB compound pleconaril was devoid of any anti-EV71 activity. An in silico docking study revealed that pleconaril-unlike vapendavir and pirodavir-lacks essential binding interactions with the viral capsid. Vapendavir and SG85 (or analogues) should be further explored for the treatment of EV71 infections. The data presented here may serve as a reference when developing yet-novel inhibitors.

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supporting

confidence: 74%

The Capsid Binder Vapendavir and the Novel Protease Inhibitor SG85 Inhibit Enterovirus 71 Replication

Tijsma

Franco

Tucker³

et al. 2014

Antimicrob Agents Chemother

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“…The range of HBV capsid protein structures, liganded and apo, icosahedral and nonicosahedral, led us to suggest that in solution Cp can be found in a diverse ensemble of quaternary structures that can be biased by CpAM binding, mutations, and crystal contacts. An analogous observation was made with experimental antiviral ligands that bind to picornavirus capsids, which make small tertiary structure changes to the capsid and stabilize capsids to inhibit nucleic acid release; these ligands appear to act by modifying picornavirus capsid dynamics, entropically stabilizing them (45)(46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket

Venkatakrishnan

Katen

Francis

et al. 2016

J Virol

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Though the hepatitis B virus (HBV) core protein is an important participant in many aspects of the viral life cycle, its best-characterized activity is self-assembly into 240-monomer capsids. Small molecules that target core protein (core protein allosteric modulators [CpAMs]) represent a promising antiviral strategy. To better understand the structural basis of the CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association more than 100-fold, and induces assembly of nonicosahedral macrostructures. In a preformed capsid, HAP18 is found at quasiequivalent subunit-subunit interfaces. In a detailed comparison to the two other extant CpAM structures, we find that the HAP18-capsid structure presents a paradox. Whereas the two other structures expanded the capsid diameter by up to 10 Å, HAP18 caused only minor changes in quaternary structure and actually decreased the capsid diameter by ϳ3 Å. These results indicate that CpAMs do not have a single allosteric effect on capsid structure. We suggest that HBV capsids present an ensemble of states that can be trapped by CpAMs, indicating a more complex basis for antiviral drug design. IMPORTANCEHepatitis B virus core protein has multiple roles in the viral life cycle-assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions-making it an attractive antiviral target. Core protein allosteric modulators (CpAMs) are an experimental class of antivirals that bind core protein. The most recognized CpAM activity is that they accelerate core protein assembly and strengthen interactions between subunits. In this study, we observe that the CpAM-binding pocket has multiple conformations. We compare structures of capsids cocrystallized with different CpAMs and find that they also affect quaternary structure in different ways. These results suggest that the capsid "breathes" and is trapped in different states by the drug and crystallization. Understanding that the capsid is a moving target will aid drug design and improve our understanding of HBV interaction with its environment. Hepatitis B virus (HBV) causes degenerative liver disease and is the leading cause of liver cancer, with 240 million chronically infected individuals (1, 2). Current antiviral therapies control the progression of the disease but fail to eliminate the virus (3, 4). There is a need for improved therapies to combat chronic infections. One approach is to target virus assembly (5-7).HBV is an enveloped, double-stranded DNA virus with an icosahedral nucleoprotein core. The HBV capsid is the protein shell of the core. Beyond genome protection, the capsid is involved in intracellular trafficking, interaction with nuclear import machinery, regulation of reverse transcription, signaling, completion of reverse transcription, RNA chaperoning, and envelope acquisition (8). Capsid assembly is central to HBV replication. In vivo HBV capsids assemble around an RNA copy of the viral g...

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“…pro (6,20,21), and pleconaril, GPP3, and cyclosporine block the entry of enteroviruses and coxsackieviruses (22)(23)(24). However, none of these reported inhibitors have been able to be advanced to clinical therapeutics.…”

mentioning

confidence: 99%

Peptidyl Aldehyde NK-1.8k Suppresses Enterovirus 71 and Enterovirus 68 Infection by Targeting Protease 3C

Wang

Yang

Zhai

et al. 2015

Antimicrob Agents Chemother

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e Enterovirus (EV) is one of the major causative agents of hand, foot, and mouth disease in the Pacific-Asia region. In particular, EV71 causes severe central nervous system infections, and the fatality rates from EV71 infection are high. Moreover, an outbreak of respiratory illnesses caused by an emerging EV, EV68, recently occurred among over 1,000 young children in the United States and was also associated with neurological infections. Although enterovirus has emerged as a considerable global public health threat, no antiviral drug for clinical use is available. In the present work, we screened our compound library for agents targeting viral protease and identified a peptidyl aldehyde, NK-1.8k, that inhibits the proliferation of different EV71 strains and one EV68 strain and that had a 50% effective concentration of 90 nM. Low cytotoxicity (50% cytotoxic concentration, >200 M) indicated a high selective index of over 2,000. We further characterized a single amino acid substitution inside protease 3C (3C pro ), N69S, which conferred EV71 resistance to NK-1.8k, possibly by increasing the flexibility of the substrate binding pocket of 3Cpro . The combination of NK-1.8k and an EV71 RNA-dependent RNA polymerase inhibitor or entry inhibitor exhibited a strong synergistic anti-EV71 effect. Our findings suggest that NK-1.8k could potentially be developed for anti-EV therapy.

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More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules

Cited by 90 publications

References 48 publications

The Capsid Binder Vapendavir and the Novel Protease Inhibitor SG85 Inhibit Enterovirus 71 Replication

The Capsid Binder Vapendavir and the Novel Protease Inhibitor SG85 Inhibit Enterovirus 71 Replication

Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket

Peptidyl Aldehyde NK-1.8k Suppresses Enterovirus 71 and Enterovirus 68 Infection by Targeting Protease 3C

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