Rhinoviruses 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 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. 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
co-translational myristoylation of a specific virus-encoded protein (VP0) by
IMP-1088 potently blocks a key step in viral capsid assembly, delivering low
nanomolar antiviral activity against multiple rhinovirus 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.
The easy functionalization of tags and solid supports with the vinyl sulfone function is a valuable tool in omic sciences that allows their coupling with the amine and thiol groups present in the proteogenic residues of proteins, in mild and green conditions compatible with their biological function.
Post-translational farnesylation or geranylgeranylation at a C-terminal cysteine residue regulates localization and function of over 100 proteins, including the Ras isoforms, and is a therapeutic target in diseases including cancer and infection. Here we report global and selective profiling of prenylated proteins in living cells enabled by development of isoprenoid analogues YnF and YnGG in combination with quantitative chemical proteomics. Eighty prenylated proteins were identified in a single human cell line, 64 for the first time at endogenous abundance without metabolic perturbation. We further demonstrate that YnF and YnGG enable direct identification of post-translationally processed prenylated peptides, proteome-wide quantitative analysis of prenylation dynamics and alternative prenylation in response to four different prenyltransferase inhibitors, and quantification of defective Rab prenylation in a model of the retinal degenerative disease Choroideremia.
N-Myristoyltransferase (NMT) covalently attaches
a C14 fatty acid to the N-terminal glycine of proteins and has been
proposed as a therapeutic target in cancer. We have recently shown
that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells,
and cytotoxicity in cancer cells. N-myristoylation
lies upstream of multiple pro-proliferative and oncogenic pathways,
but to date the complex substrate specificity of NMT has limited determination
of which diseases are most likely to respond to a selective NMT inhibitor.
We describe here the phenotype of NMT inhibition in HeLa cells and
show that cells die through apoptosis following or concurrent with
accumulation in the G1 phase. We used quantitative proteomics to map
protein expression changes for more than 2700 proteins in response
to treatment with an NMT inhibitor in HeLa cells and observed down-regulation
of proteins involved in cell cycle regulation and up-regulation of
proteins involved in the endoplasmic reticulum stress and unfolded
protein response, with similar results in breast (MCF-7, MDA-MB-231)
and colon (HCT116) cancer cell lines. This study describes the cellular
response to NMT inhibition at the proteome level and provides a starting
point for selective targeting of specific diseases with NMT inhibitors,
potentially in combination with other targeted agents.
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