Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

Aurelie Mousnier, Andrew S. Bell, Dawid P. Swieboda, Julia Morales-Sanfrutos, Inmaculada Pérez-Dorado, James A. Brannigan, Joseph Newman, Markus Ritzefeld, Jennie A. Hutton, Anabel Guedán, Amin S. Asfor, Sean W. Robinson, Iva Hopkins-Navratilova, Anthony J. Wilkinson, Sebastian L. Johnston, Robin J. Leatherbarrow, Tobias J. Tuthill, Roberto Solari, Edward W. Tate

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Abstract

Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.
Original languageEnglish
Pages (from-to)599-606
Number of pages8
JournalNature chemistry
Volume10
Issue number6
DOIs
Publication statusPublished - 14 May 2018

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Viruses
Pulmonary diseases
Pathogens
Cytotoxicity
Antiviral Agents
Proteins
Geometry
Pharmaceutical Preparations
glycylpeptide N-tetradecanoyltransferase

Cite this

Mousnier, A., Bell, A. S., Swieboda, D. P., Morales-Sanfrutos, J., Pérez-Dorado, I., Brannigan, J. A., ... Tate, E. W. (2018). Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. Nature chemistry, 10(6), 599-606. https://doi.org/10.1038/s41557-018-0039-2
Mousnier, Aurelie ; Bell, Andrew S. ; Swieboda, Dawid P. ; Morales-Sanfrutos, Julia ; Pérez-Dorado, Inmaculada ; Brannigan, James A. ; Newman, Joseph ; Ritzefeld, Markus ; Hutton, Jennie A. ; Guedán, Anabel ; Asfor, Amin S. ; Robinson, Sean W. ; Hopkins-Navratilova, Iva ; Wilkinson, Anthony J. ; Johnston, Sebastian L. ; Leatherbarrow, Robin J. ; Tuthill, Tobias J. ; Solari, Roberto ; Tate, Edward W. / Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. In: Nature chemistry. 2018 ; Vol. 10, No. 6. pp. 599-606.
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abstract = "Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.",
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Mousnier, A, Bell, AS, Swieboda, DP, Morales-Sanfrutos, J, Pérez-Dorado, I, Brannigan, JA, Newman, J, Ritzefeld, M, Hutton, JA, Guedán, A, Asfor, AS, Robinson, SW, Hopkins-Navratilova, I, Wilkinson, AJ, Johnston, SL, Leatherbarrow, RJ, Tuthill, TJ, Solari, R & Tate, EW 2018, 'Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus', Nature chemistry, vol. 10, no. 6, pp. 599-606. https://doi.org/10.1038/s41557-018-0039-2

Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. / Mousnier, Aurelie; Bell, Andrew S.; Swieboda, Dawid P.; Morales-Sanfrutos, Julia; Pérez-Dorado, Inmaculada; Brannigan, James A.; Newman, Joseph; Ritzefeld, Markus; Hutton, Jennie A.; Guedán, Anabel; Asfor, Amin S.; Robinson, Sean W.; Hopkins-Navratilova, Iva; Wilkinson, Anthony J.; Johnston, Sebastian L.; Leatherbarrow, Robin J.; Tuthill, Tobias J.; Solari, Roberto; Tate, Edward W.

In: Nature chemistry, Vol. 10, No. 6, 14.05.2018, p. 599-606.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

AU - Mousnier, Aurelie

AU - Bell, Andrew S.

AU - Swieboda, Dawid P.

AU - Morales-Sanfrutos, Julia

AU - Pérez-Dorado, Inmaculada

AU - Brannigan, James A.

AU - Newman, Joseph

AU - Ritzefeld, Markus

AU - Hutton, Jennie A.

AU - Guedán, Anabel

AU - Asfor, Amin S.

AU - Robinson, Sean W.

AU - Hopkins-Navratilova, Iva

AU - Wilkinson, Anthony J.

AU - Johnston, Sebastian L.

AU - Leatherbarrow, Robin J.

AU - Tuthill, Tobias J.

AU - Solari, Roberto

AU - Tate, Edward W.

PY - 2018/5/14

Y1 - 2018/5/14

N2 - Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

AB - Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

U2 - 10.1038/s41557-018-0039-2

DO - 10.1038/s41557-018-0039-2

M3 - Article

VL - 10

SP - 599

EP - 606

JO - Nature chemistry

JF - Nature chemistry

SN - 1755-4330

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