AbstractThe pharmacological inhibition of human N‐myristoyltransferase (HsNMT) has emerged as an efficient strategy to completely prevent the replication process of rhinoviruses, a potential treatment for the common cold. This was corroborated by the recent discovery of compound IMP‐1088, a novel inhibitor that demonstrated a dual‐inhibitory activity against the two HsNMT subtypes 1 and 2 without inducing cytotoxicity. However, the molecular and structural basis for the dual‐inhibitory potential of IMP‐1088 has not been investigated. As such, we employ molecular modelling techniques to resolve the structural mechanisms that account for the dual‐inhibitory prowess of IMP‐1088. Sequence and nanosecond‐based analyses identified Tyr296, Phe190, Tyr420, Leu453, Gln496, Val181, Leu474, Glu182, and Asn246 as residues common within the binding pockets of both HsNMT1 and HsNMT2 subtypes whose consistent interactions with IMP‐1088 underpin the basis for its dual inhibitory potency. Nano‐second‐based assessment of interaction dynamics revealed that Tyr296 consistently elicited high‐affinity π‐π stacked interaction with IMP‐1088, thus further highlighting its cruciality corroborating previous report. An exploration of resulting structural changes upon IMP‐1088 binding further revealed a characteristic impeding of residue fluctuations, structural compactness, and a consequential burial of crucial hydrophobic residues, features required for HsNMT1/2 functionality. Findings present essential structural perspectives that augment previous experimental efforts and could also advance drug development for treating respiratory tract infections, especially those mediated by rhinoviruses.

2018-06-01·Nature Chemistry1区 · 化学

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

1区 · 化学

Article

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

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.

PLOS Pathogens

Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry

Article

作者: Moss, Bernard ; Satheshkumar, Panayampalli Subbian ; Kallemeijn, Wouter W ; Ojeda, Suany ; Tate, Edward W ; Solari, Roberto ; Wilkins, Kimberly ; Priyamvada, Lalita ; Goldsmith, Cynthia S ; Faronato, Monica ; Cotter, Catherine A

We have recently shown that the replication of rhinovirus, poliovirus and foot-and-mouth disease virus requires the co-translational N-myristoylation of viral proteins by human host cell N-myristoyltransferases (NMTs), and is inhibited by treatment with IMP-1088, an ultrapotent small molecule NMT inhibitor. Here, we examine the importance of N-myristoylation during vaccinia virus (VACV) infection in primate cells and demonstrate the anti-poxviral effects of IMP-1088. N-myristoylated proteins from VACV and the host were metabolically labelled with myristic acid alkyne during infection using quantitative chemical proteomics. We identified VACV proteins A16, G9 and L1 to be N-myristoylated. Treatment with NMT inhibitor IMP-1088 potently abrogated VACV infection, while VACV gene expression, DNA replication, morphogenesis and EV formation remained unaffected. Importantly, we observed that loss of N-myristoylation resulted in greatly reduced infectivity of assembled mature virus particles, characterized by significantly reduced host cell entry and a decline in membrane fusion activity of progeny virus. While the N-myristoylation of VACV entry proteins L1, A16 and G9 was inhibited by IMP-1088, mutational and genetic studies demonstrated that the N-myristoylation of L1 was the most critical for VACV entry. Given the significant genetic identity between VACV, monkeypox virus and variola virus L1 homologs, our data provides a basis for further investigating the role of N-myristoylation in poxviral infections as well as the potential of selective NMT inhibitors like IMP-1088 as broad-spectrum poxvirus inhibitors.

100 项与 IMP-1088 相关的药物交易

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