Title |
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
|
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Published in |
Nature Chemistry, May 2018
|
DOI | 10.1038/s41557-018-0039-2 |
Pubmed ID | |
Authors |
Aurélie 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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 34 | 22% |
United States | 16 | 11% |
Spain | 8 | 5% |
Japan | 6 | 4% |
Germany | 5 | 3% |
Netherlands | 4 | 3% |
Australia | 3 | 2% |
France | 3 | 2% |
Sweden | 2 | 1% |
Other | 16 | 11% |
Unknown | 55 | 36% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 92 | 61% |
Scientists | 51 | 34% |
Practitioners (doctors, other healthcare professionals) | 7 | 5% |
Science communicators (journalists, bloggers, editors) | 2 | 1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 195 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 45 | 23% |
Student > Ph. D. Student | 34 | 17% |
Student > Master | 24 | 12% |
Student > Bachelor | 22 | 11% |
Student > Doctoral Student | 10 | 5% |
Other | 21 | 11% |
Unknown | 39 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 60 | 31% |
Biochemistry, Genetics and Molecular Biology | 27 | 14% |
Medicine and Dentistry | 12 | 6% |
Agricultural and Biological Sciences | 12 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 5% |
Other | 28 | 14% |
Unknown | 46 | 24% |