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

<div class='caption-title'>Proposed pathway for generation of infectious rhinovirus particles in an infected host cell.</div>
<div class='caption-title'>Structure-guided discovery of potent human N-myristoyltransferase inhibitors.</div>
<div class='caption-title'>Potent inhibitors of human N-myristoyltransferases inhibit rhinovirus myristoylation in infected cells.</div>
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
OpenAccess logo Nat Chem 10 599-606 (2018)
Related entries: 5mu6, 5o48, 5o6h, 5o6j

Cited: 53 times
EuropePMC logo PMID: 29760414

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.

Articles - 5o4v mentioned but not cited (2)

  1. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. 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. Nat Chem 10 599-606 (2018)
  2. Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency. Spassov DS, Atanasova M, Doytchinova I. Int J Mol Sci 24 11610 (2023)


Reviews citing this publication (17)

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  5. Protein Lipidation by Palmitoylation and Myristoylation in Cancer. Fhu CW, Ali A. Front Cell Dev Biol 9 673647 (2021)
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  7. N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections. Kosciuk T, Lin H. ACS Chem Biol 15 1747-1758 (2020)
  8. Proteome-wide analysis of protein lipidation using chemical probes: in-gel fluorescence visualization, identification and quantification of N-myristoylation, N- and S-acylation, O-cholesterylation, S-farnesylation and S-geranylgeranylation. Kallemeijn WW, Lanyon-Hogg T, Panyain N, Goya Grocin A, Ciepla P, Morales-Sanfrutos J, Tate EW. Nat Protoc 16 5083-5122 (2021)
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  10. Incorporating Target-Specific Pharmacophoric Information into Deep Generative Models for Fragment Elaboration. Hadfield TE, Imrie F, Merritt A, Birchall K, Deane CM. J Chem Inf Model 62 2280-2292 (2022)
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  15. Elucidating the Interaction of CF Airway Epithelial Cells and Rhinovirus: Using the Host-Pathogen Relationship to Identify Future Therapeutic Strategies. Ling KM, Garratt LW, Lassmann T, Stick SM, Kicic A, WAERP, AusREC, Australian Respiratory Early Surveillance Team for Cystic Fibrosis. Front Pharmacol 9 1270 (2018)
  16. Insights into auto-S-fatty acylation: targets, druggability, and inhibitors. Hu L, Tao Z, Wu X. RSC Chem Biol 2 1567-1579 (2021)
  17. [Rhinoviruses]. Grünewaldt A, Hügel C, Rohde GGU. Internist (Berl) 60 1151-1154 (2019)

Articles citing this publication (34)

  1. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. Science 365 eaaw4912 (2019)
  2. NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle. Kosciuk T, Price IR, Zhang X, Zhu C, Johnson KN, Zhang S, Halaby SL, Komaniecki GP, Yang M, DeHart CJ, Thomas PM, Kelleher NL, Fromme JC, Lin H. Nat Commun 11 1067 (2020)
  3. High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation. Dian C, Pérez-Dorado I, Rivière F, Asensio T, Legrand P, Ritzefeld M, Shen M, Cota E, Meinnel T, Tate EW, Giglione C. Nat Commun 11 1132 (2020)
  4. Cellular N-myristoyltransferases play a crucial picornavirus genus-specific role in viral assembly, virion maturation, and infectivity. Corbic Ramljak I, Stanger J, Real-Hohn A, Dreier D, Wimmer L, Redlberger-Fritz M, Fischl W, Klingel K, Mihovilovic MD, Blaas D, Kowalski H. PLoS Pathog 14 e1007203 (2018)
  5. Validation and Invalidation of Chemical Probes for the Human N-myristoyltransferases. Kallemeijn WW, Lueg GA, Faronato M, Hadavizadeh K, Goya Grocin A, Song OR, Howell M, Calado DP, Tate EW. Cell Chem Biol 26 892-900.e4 (2019)
  6. Acylation-coupled lipophilic induction of polarisation (Acyl-cLIP): a universal assay for lipid transferase and hydrolase enzymes. Lanyon-Hogg T, Ritzefeld M, Sefer L, Bickel JK, Rudolf AF, Panyain N, Bineva-Todd G, Ocasio CA, O'Reilly N, Siebold C, Magee AI, Tate EW. Chem Sci 10 8995-9000 (2019)
  7. Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins. Alzahofi N, Welz T, Robinson CL, Page EL, Briggs DA, Stainthorp AK, Reekes J, Elbe DA, Straub F, Kallemeijn WW, Tate EW, Goff PS, Sviderskaya EV, Cantero M, Montoliu L, Nedelec F, Miles AK, Bailly M, Kerkhoff E, Hume AN. Nat Commun 11 3495 (2020)
  8. Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration. Broncel M, Dominicus C, Vigetti L, Nofal SD, Bartlett EJ, Touquet B, Hunt A, Wallbank BA, Federico S, Matthews S, Young JC, Tate EW, Tardieux I, Treeck M. Elife 9 e57861 (2020)
  9. Whole Proteome Profiling of N-Myristoyltransferase Activity and Inhibition Using Sortase A. Goya Grocin A, Serwa RA, Morales Sanfrutos J, Ritzefeld M, Tate EW. Mol Cell Proteomics 18 115-126 (2019)
  10. Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes. Bell AS, Yu Z, Hutton JA, Wright MH, Brannigan JA, Paape D, Roberts SM, Sutherell CL, Ritzefeld M, Wilkinson AJ, Smith DF, Leatherbarrow RJ, Tate EW. J Med Chem 63 7740-7765 (2020)
  11. Nonlytic cellular release of hepatitis A virus requires dual capsid recruitment of the ESCRT-associated Bro1 domain proteins HD-PTP and ALIX. Shirasaki T, Feng H, Duyvesteyn HME, Fusco WG, McKnight KL, Xie L, Boyce M, Kumar S, Barouch-Bentov R, González-López O, McNamara R, Wang L, Hertel-Wulff A, Chen X, Einav S, Duncan JA, Kapustina M, Fry EE, Stuart DI, Lemon SM. PLoS Pathog 18 e1010543 (2022)
  12. A facile route to 1H- and 2H-indazoles from readily accessible acyl hydrazides by exploiting a novel aryne-based molecular rearrangement. Shamsabadi A, Chudasama V. Chem Commun (Camb) 54 11180-11183 (2018)
  13. Myristoylation of EV71 VP4 is Essential for Infectivity and Interaction with Membrane Structure. Cao J, Qu M, Liu H, Wan X, Li F, Hou A, Zhou Y, Sun B, Cai L, Su W, Jiang C. Virol Sin 35 599-613 (2020)
  14. Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion. Schlott AC, Knuepfer E, Green JL, Hobson P, Borg AJ, Morales-Sanfrutos J, Perrin AJ, Maclachlan C, Collinson LM, Snijders AP, Tate EW, Holder AA. PLoS Biol 19 e3001408 (2021)
  15. Photoactivatable Myristic Acid Probes for UNC119-Cargo Interactions. Kaiser N, Mejuch T, Fedoryshchak R, Janning P, Tate EW, Waldmann H. Chembiochem 20 134-139 (2019)
  16. Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. Priyamvada L, Kallemeijn WW, Faronato M, Wilkins K, Goldsmith CS, Cotter CA, Ojeda S, Solari R, Moss B, Tate EW, Satheshkumar PS. PLoS Pathog 18 e1010662 (2022)
  17. A role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors. Spassov DS, Atanasova M, Doytchinova I. Front Mol Biosci 9 1066029 (2022)
  18. Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts. Rodríguez-Hernández D, Vijayan K, Zigweid R, Fenwick MK, Sankaran B, Roobsoong W, Sattabongkot J, Glennon EKK, Myler PJ, Sunnerhagen P, Staker BL, Kaushansky A, Grøtli M. Nat Commun 14 5408 (2023)
  19. Novel Hits for N-Myristoyltransferase Inhibition Discovered by Docking-Based Screening. Spassov DS, Atanasova M, Doytchinova I. Molecules 27 5478 (2022)
  20. Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2. Byrne DP, Shrestha S, Daly LA, Marensi V, Ramakrishnan K, Eyers CE, Kannan N, Eyers PA. Biochem J 480 141-160 (2023)
  21. Membrane Interactions and Uncoating of Aichi Virus, a Picornavirus That Lacks a VP4. Kelly JT, Swanson J, Newman J, Groppelli E, Stonehouse NJ, Tuthill TJ. J Virol 96 e0008222 (2022)
  22. Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation. Jia M, Wang Y, Wang J, Qin D, Wang M, Chai L, Fu Y, Zhao C, Gao C, Jia J, Zhao W. Nat Commun 14 660 (2023)
  23. Translational Biophysics - 20th IUPAB Congress Session Commentary. Perez-Gil J, Watts A. Biophys Rev 13 875-877 (2021)
  24. Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism. Fedoryshchak RO, Ocasio CA, Strutton B, Mattocks J, Corran AJ, Tate EW. RSC Chem Biol 1 68-78 (2020)
  25. 2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology. Lucchino M, Billet A, Versini A, Bavireddi H, Dasari BD, Debieu S, Colombeau L, Cañeque T, Wagner A, Masson G, Taran F, Karoyan P, Delepierre M, Gaillet C, Houdusse A, Britton S, Schmidt F, Florent JC, Belmont P, Monchaud D, Cossy J, Thomas C, Gautier A, Johannes L, Rodriguez R. Chembiochem 20 968-973 (2019)
  26. Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets. Davison D, Howell S, Snijders AP, Deu E. iScience 25 104996 (2022)
  27. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells. McHugh D, Sun B, Gutierrez-Muñoz C, Hernández-González F, Mellone M, Guiho R, Duran I, Pombo J, Pietrocola F, Birch J, Kallemeijn WW, Khadayate S, Dharmalingam G, Vernia S, Tate EW, Martínez-Barbera JP, Withers DJ, Thomas GJ, Serrano M, Gil J. Nat Cell Biol 25 1804-1820 (2023)
  28. Construction of a Vero Cell Line Expressing Human ICAM1 for the Development of Rhinovirus Vaccines. van den Braak WJP, Monica B, Limpens D, Rockx-Brouwer D, de Boer M, Oosterhoff D. Viruses 14 2235 (2022)
  29. Development of Monoclonal Antibody to Specifically Recognize VP0 but Not VP4 and VP2 of Foot-and-Mouth Disease Virus. Park SY, Jin JS, Kim D, Kim JY, Park SH, Park JH, Park CK, Ko YJ. Pathogens 11 1493 (2022)
  30. Discovery of lipid-mediated protein-protein interactions in living cells using metabolic labeling with photoactivatable clickable probes. Fedoryshchak RO, Gorelik A, Shen M, Shchepinova MM, Pérez-Dorado I, Tate EW. Chem Sci 14 2419-2430 (2023)
  31. Dual Role of ACBD6 in the Acylation Remodeling of Lipids and Proteins. Soupene E, Kuypers FA. Biomolecules 12 1726 (2022)
  32. Enterovirus D68 capsid formation and stability requires acidic compartments. Galitska G, Jassey A, Wagner MA, Pollack N, Miller K, Jackson WT. mBio 14 e0214123 (2023)
  33. Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development. Fenwick MK, Reers AR, Liu Y, Zigweid R, Sankaran B, Shin J, Hulverson MA, Hammerson B, Fernández Álvaro E, Myler PJ, Kaushansky A, Van Voorhis WC, Fan E, Staker BL. ACS Infect Dis 9 1821-1833 (2023)
  34. Pseudotyped Viruses for Enterovirus. Wu X, Cui L, Bai Y, Bian L, Liang Z. Adv Exp Med Biol 1407 209-228 (2023)


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