Inhibition of N‐myristoyltransferase1 affects dengue virus replication

Abstract

Dengue virus (DENV) causes dengue fever, a self‐limiting disease that could be fatal due to serious complications. No specific treatment is currently available and the preventative vaccine is only partially protective. To develop a potential drug target for dengue fever, we need to understand its biology and pathogenesis thoroughly. N‐myristoyltransferase (NMT) is an N‐terminal protein lipidation enzyme that catalyzes the covalent cotranslational attachment of fatty acids to the amino‐terminal glycine residue of a number of proteins, leading to the modulation of various signaling molecules. In this study, we investigated the interaction of dengue viral proteins with host NMT and its subsequent effect on DENV. Our bioinformatics, molecular docking, and far‐western blotting analyses demonstrated the interaction of viral envelope protein (E) with NMT. The gene expression of NMT was strongly elevated in a dependent manner during the viral replication phase in dendritic cells. Moreover, NMT gene silencing significantly inhibited DENV replication in dendritic cells. Further studies investigating the target cell types of other host factors are suggested.

Towards a broad-spectrum antiviral, the myristoyltransferase inhibitor IMP-1088 suppresses viral replication – the Yellow fever NS5 is myristoylated

“…This result indicates that the inhibition of myristoylation of viral DENV and YF NS5 proteins is responsible for the antiviral effect of IMP-1088. Similar results were obtained in previous experiments with myristoyl transferase 1-knockdown cells showing that NMT activity is required for DENV replication (16). The negative impact on other RNA viruses provides evidence that the observed effect is virus-specific, not related to the inhibition of general cellular factors.…”

Use of a Self-Delivering Anti-CCL3 FANA Oligonucleotide as an Innovative Approach to Target Inflammation after Spinal Cord Injury

“…One of the most important modification to the biological function of FANA ASO molecules is their ability to penetrate cells without the necessity of delivery vehicles required in transfection approaches. Our results revealed that FANA ASO molecules targeting CCL3 can indeed penetrate BMDMs in gymnotic fashion, as previously described for other cell types in vitro (Baby et al, 2020;Margiotta and Howard, 2020;Schmidt et al, 2019;Smaldone et al, 2019;Suwanmanee et al, 2019;Takahashi et al, 2019). We also demonstrated the successful suppression of CCL3 expression in BMDMs by CCL3 specific FANA ASOs.…”

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections

“…Dengue virus, the cause of dangerous dengue fever, appears to rely on NMT as well. NMT is upregulated during the infection of dendritic cells, and it interacts with the viral envelope protein, while NMT gene silencing significantly suppresses dengue virus replication . Thus, far myristoylation of the Dengue viral proteins has only been predicted but lacks experimental proof, which is also true for many other viruses .…”

“…NMT is upregulated during the infection of dendritic cells, and it interacts with the viral envelope protein, while NMT gene silencing significantly suppresses dengue virus replication. 86 Thus, far myristoylation of the Dengue viral proteins has only been predicted but lacks experimental proof, which is also true for many other viruses. 6 Coronaviruses, such as those that caused SARS and COVID-19 pandemics, are thought to lack myristoylation because they do not contain the preferred NMT recognition sequence; however, this has no experimental evidence.…”